bims-nurfan Biomed News
on NRF2 and Neurological Diseases
Issue of 2023–12–24
fifty-five papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University
  1. Urolithin B attenuates cerebral ischemia-reperfusion injury by modulating Nrf2-regulated anti-oxidation in rats.
  2. Ginsenoside Rk1 prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease via activating silence information regulator 3-mediated Nrf2/HO-1 signaling pathway.
  3. Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats.
  4. Sevoflurane alleviates oxygen-glucose deprivation/reoxygenation-induced damage in HT22 cells by activating the Keap1/Nrf2/ARE pathway to inhibit oxidative stress.
  5. Neuroprotective effect of whey protein hydrolysate containing LDIQK on HT22 cells in hydrogen peroxide-induced oxidative stress.
  6. Neuroprotective effect of curcumin against experimental autoimmune encephalomyelitis-induced cognitive and physical impairments in mice: an insight into the role of the AMPK/SIRT1 pathway.
  7. Combined exposure to manganese and iron decreases oxidative stress-induced nerve damage by increasing Nrf2/HO-1/NQO1 expression.
  8. Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation.
  9. Crosstalk between Nrf2 signaling pathway and inflammation in ischemic stroke: Mechanisms of action and therapeutic implications.
  10. Differential Effects of Paraquat, Rotenone, and MPTP on Cellular Bioenergetics of Undifferentiated and Differentiated Human Neuroblastoma Cells.
  11. Breviscapine attenuates lead‑induced myocardial injury by activating the Nrf2 signaling pathway.
  12. A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.
  13. Cath-KP, a novel peptide derived from frog skin, prevents oxidative stress damage in a Parkinson's disease model.
  14. Palmatine Protects PC12 Cells and Mice from Aβ25-35-Induced Oxidative Stress and Neuroinflammation via the Nrf2/HO-1 Pathway.
  15. Amlodipine alleviates renal ischemia/reperfusion injury in rats through Nrf2/Sestrin2/PGC-1α/TFAM Pathway.
  16. Puerarin reduces cell damage from cerebral ischemia-reperfusion by inhibiting ferroptosis.
  17. Elamipretide(SS-31) Attenuates Idiopathic Pulmonary Fibrosis by Inhibiting the Nrf2-Dependent NLRP3 Inflammasome in Macrophages.
  18. Melatonin exerts neuroprotective effects in mice with spinal cord injury by activating the Nrf2/Keap1 signaling pathway via the MT2 receptor.
  19. Upregulation of mitochondrial PGK1 by ROS-TBC1D15 pathway promotes neuronal death after oxygen-glucose deprivation/reoxygenation injury.
  20. Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia.
  21. Exosomal OIP5-AS1 attenuates cerebral ischemia-reperfusion injury by negatively regulating TXNIP protein stability and inhibiting neuronal pyroptosis.
  22. Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system injuries.
  23. Notoginsenoside R1 attenuates brain injury in rats with traumatic brain injury: Possible mediation of apoptosis via ERK1/2 signaling pathway.
  24. Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders.
  25. The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells.
  26. Quercetin attenuates cerebral ischemic injury by inhibiting ferroptosis via Nrf2/HO-1 signaling pathway.
  27. Polystyrene micro- and nanoplastics induce gastric toxicity through ROS mediated oxidative stress and P62/Keap1/Nrf2 pathway.
  28. Overexpression of SESN1 improves mitochondrial damage and mitophagy, a potential therapeutic strategy for cognitive dysfunction after anaesthesia.
  29. The SH-SY5Y cell line: a valuable tool for Parkinson's disease drug discovery.
  30. Antioxidant Capacity of Free and Bound Phenolics from Olive Leaves: In Vitro and In Vivo Responses.
  31. Hydrogen: A Rising Star in Gas Medicine as a Mitochondria-Targeting Nutrient via Activating Keap1-Nrf2 Antioxidant System.
  32. Multifunctional effect of flavonoids from Millettia brandisiana against Alzheimer's disease pathogenesis.
  33. Carvacrol Reduces Mercuric Chloride-Induced Testicular Toxicity by Regulating Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Histopathological Changes.
  34. Hyperbaric Oxygen Therapy Alleviates Memory and Motor Impairments Following Traumatic Brain Injury via the Modulation of Mitochondrial-Dysfunction-Induced Neuronal Apoptosis in Rats.
  35. Neuroprotective Effects of Aldehyde-Reducing Composition in an LPS-Induced Neuroinflammation Model of Parkinson's Disease.
  36. Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis.
  37. Defective autophagy contributes to bupivacaine-induced aggravation of painful diabetic neuropathy in db/db mice.
  38. Arctigenin attenuated spatial memory impairment in pR5 mice by regulating mitochondrial energy metabolism.
  39. Naringenin alleviates cognitive dysfunction in rats with cerebral ischemia/reperfusion injury through up-regulating hippocampal BDNF-TrkB signaling: involving suppression in neuroinflammation and oxidative stress.
  40. Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia.
  41. Human-specific translational control of neuronal mitochondria and excitability.
  42. Electroacupuncture ameliorates chronic unpredictable mild stress-induced depression-like behavior and cognitive impairment through suppressing oxidative stress and neuroinflammation in rats.
  43. Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.
  44. A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease.
  45. Renoprotective effects of extracellular fibroblast specific protein 1 via nuclear factor erythroid 2-related factor-mediated antioxidant activity.
  46. Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration.
  47. Eucalyptol regulates Nrf2 and NF-kB signaling and alleviates gentamicin-induced kidney injury in rats by downregulating oxidative stress, oxidative DNA damage, inflammation, and apoptosis.
  48. Minocycline mitigates tau pathology via modulating the TLR-4/NF-кβ signalling pathway in the hippocampus of neuroinflammation rat model.
  49. Improved Glycaemic Control and Nephroprotective Effects of Empagliflozin and Paricalcitol Co-Therapy in Mice with Type 2 Diabetes Mellitus.
  50. Berberine exerts antidepressant effects in vivo and in vitro through the PI3K/AKT/CREB/BDNF signaling pathway.
  51. Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling.
  52. Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson's Disease.
  53. Gynura divaricata (L.) DC. promotes diabetic wound healing by activating Nrf2 signaling in diabetic rats.
  54. Modulatory mechanisms of copperII-albumin complex toward N-nitrosodiethylamine-induced neurotoxicity in mice via regulating oxidative damage, inflammatory, and apoptotic signaling pathways.
  55. Tuning the Reactivity of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Optimal in Vivo Efficacy.
  1. Neuroscience. 2023 Dec 16. pii: S0306-4522(23)00489-X. [Epub ahead of print]
    Urolithin B attenuates cerebral ischemia-reperfusion injury by modulating Nrf2-regulated anti-oxidation in rats.
    Zhi-Wei Li, Hua Tang, Xin-Xin Chen, Xuan-Xuan Li, Huan-Huan Xu, Mao-Hua Chen, Hua-Jun Ba, Qun Lin, Jun-Xia Dai, Jian-Yong Cai, Chuan Lu, Xian-Dong Chen, Guo-Sheng Han, Jun Sun.
      Ischemia-reperfusion (IR) induces a wide range of irreversible injuries. Cerebral IR injury (IRI) refers to additional brain tissue damage that occurs after blood flow is restored following cerebral ischemia. Currently, no established methods exist for treating IRI. Oxidative stress is recognized as a primary mechanism initiating IRI and a crucial focal target for its treatment. Urolithin B, a metabolite derived from ellagitannins, antioxidant polyphenols, has demonstrated protective effects against oxidative stress in various disease conditions. However, the precise mechanism underlying UB's effect on IRI remains unclear. In our current investigation, we assessed UB's ability to mitigate neurological functional impairment induced by IR using a neurological deficit score. Additionally, we examined cerebral infarction following UB administration through TTC staining and neuron Nissl staining. UB's inhibition of neuronal apoptosis was demonstrated through the TUNEL assay and Caspase-3 measurement. Additionally, we examined UB's effect on oxidative stress levels by analyzing malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, and immunohistochemistry analysis of inducible nitric oxide synthase (iNOS) and 8-hydroxyl-2'-deoxyguanosine (8-OHdG). Notably, UB demonstrated a reduction in oxidative stress levels. Mechanistically, UB was found to stimulate the Nrf2/HO-1 signaling pathway, as evidenced by the significant reduction in UB's neuroprotective effects upon administration of ATRA, an Nrf2 inhibitor. In summary, UB effectively inhibits oxidative stress induced by IR through the activation of the Nrf2/HO-1 signaling pathway. These findings suggest that UB holds promise as a therapeutic agent for the treatment of IRI.
    Keywords:  Cerebral ischemia; Ischemia-reperfusion; Ischemic stroke; MCAO; Medicine treatment; Oxidative stress; Urolithin B
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.11.002
  2. Hum Exp Toxicol. 2023 Jan-Dec;42:42 9603271231220610
    Ginsenoside Rk1 prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease via activating silence information regulator 3-mediated Nrf2/HO-1 signaling pathway.
    Yi Ren, Dan Ye, Yiping Ding, Ning Wei.
      Objectives: Ginsenoside Rk1, a novel ginsenoside isolated from red ginseng, has anti-inflammatory and anti-tumor activities. This study was designed to elucidate the role of RK1 in an in vitro 1-methyl-4-phenylpyridinium (MPP+) cell model and an in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of Parkinson's disease (PD).Methods: The grasping test, pole-climbing test, and rotarod test were performed to measure the effects of RK1 on MPTP-induced motor disorders. The expression of tyrosine hydroxylase (TH) and IBA-1 were evaluated by western blotting. CCK-8 and flow cytometry  assays were utilized to assess cell viability and apoptosis. Reactive oxygen species (ROS), Lactate dehydrogenase (LDH), and superoxide dismutase (SOD) were detected to analyze the effects of RK1 on oxidative stress. The levels of inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA).Results: The results showed that RK1 allayed motor deficit elicited by MPTP in a mouse model. RK1 administration augmented tyrosine hydroxylase (TH) expression in the brain striatum and substantia nigra (SN) of MPTP-treated mice. Moreover, RK1 pretreatment promoted viability and suppressed apoptosis in MPP+-induced PC-12 cells. Further, RK1 also attenuated MPP+-stimulated oxidative stress and inflammatory response in PC-12 cells. Besides, RK1 augmented the level of SIRT3, and SIRT3 deletion counteracted RK1-induced repression on MPP+-elicited apoptosis, oxidative stress, and inflammatory response in PC-12 cells via modulating the Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)  pathway.Conclusions: RK1 might exert neuroprotective effects against MPP+/MPTP-induced neurotoxicity via activating SIRT3-mediated Nrf2/HO-1 signaling. RK1 might be a promising candidate against PD.
    Keywords:  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Ginsenoside Rk1; Nrf2/HO-1 pathway; Parkinson’s disease; inflammation
    DOI:  https://doi.org/10.1177/09603271231220610
  3. Metab Brain Dis. 2023 Dec 18.
    Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats.
    Sefa Küçükler, Cuneyt Caglayan, Selçuk Özdemir, Selim Çomaklı, Fatih Mehmet Kandemir.
      Chlorpyrifos (CPF), considered one of the most potent organophosphates, causes a variety of human disorders including neurotoxicity. The current study was designed to evaluate the efficacy of hesperidin (HSP) in ameliorating CPF-induced neurotoxicity in rats. In the study, rats were treated with HSP (orally, 50 and 100 mg/kg) 30 min after giving CPF (orally, 6.75 mg/kg) for 28 consecutive days. Molecular, biochemical, and histological methods were used to investigate cholinergic enzymes, oxidative stress, inflammation, and apoptosis in the brain tissue. CPF intoxication resulted in inhibition of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) enzymes, reduced antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH)], and elevation of malondialdehyde (MDA) levels and carbonic anhydrase (CA) activities. CPF increased histopathological changes and immunohistochemical expressions of 8-OHdG in brain tissue. CPF also increased levels of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NF-κB) while decreased levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Furthermore, CPF increased mRNA transcript levels of caspase-3, Bax, PARP-1, and VEGF, which are associated with apoptosis and endothelial damage in rat brain tissues. HSP treatment was found to protect brain tissue by reducing CPF-induced neurotoxicity. Overall, this study supports that HSP can be used to reduce CPF-induced neurotoxicity.
    Keywords:  Apoptosis; Chlorpyrifos; Hesperidin; Neurotoxicity, oxidative stress
    DOI:  https://doi.org/10.1007/s11011-023-01339-8
  4. Int J Neurosci. 2023 Dec 18. 1-8
    Sevoflurane alleviates oxygen-glucose deprivation/reoxygenation-induced damage in HT22 cells by activating the Keap1/Nrf2/ARE pathway to inhibit oxidative stress.
    Ke Yan, Lei Li, Siqi Ye, Qiao Xu, Li Ding.
      Objective: This study aimed to investigate the impact of sevoflurane on oxygen-glucose deprivation/reoxygenation-induced damage in HT22 cells and its associated mechanisms. Methods: HT22 cells were treated with sevoflurane, and an oxygen-glucose deprivation/reoxygenation injury model was established. The HT22 cells were randomly divided into the control group, oxygen-glucose deprivation/reoxygenation group, sevoflurane low-dose group, sevoflurane medium-dose group, and sevoflurane high-dose group. The proliferation of HT22 cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptosis rate and mitochondrial membrane potential of HT22 cells were determined by flow cytometry. Protein expression levels of B-cell lymphoma-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), and heme oxygenase-1 (HO-1) in HT22 cells were examined using Western blot. Reactive oxygen species (ROS) levels were measured with 2',7'-dichlorofluorescin diacetate (DCFH-DA). Malondialdehyde (MDA), glutathione peroxidase (GSH-Px) levels, and superoxide dismutase (SOD) enzyme activity in HT22 cells were determined using assay kits. Results: Compared to controls, OGD/R group had reduced cell viability, mitochondrial potential, Bcl-2, nuclear Nrf2, HO-1, GSH-Px levels, and SOD enzyme activity (p < 0.05), with increased apoptosis, Bax, cytoplasmic Nrf2, ROS, and MDA levels. Sevoflurane groups showed opposite trends (p < 0.05). Conclusion: Sevoflurane can mitigate oxygen-glucose deprivation/reoxygenation-induced damage in HT22 cells, and its mechanism may be related to the activation of the Keap1/Nrf2/ARE pathway to inhibit oxidative stress.
    Keywords:  HT22 cells; Keap1/Nrf2/ARE pathway; Sevoflurane; oxidative stress; oxygen-glucose deprivation/reoxygenation
    DOI:  https://doi.org/10.1080/00207454.2023.2286916
  5. J Dairy Sci. 2023 Dec 13. pii: S0022-0302(23)01215-8. [Epub ahead of print]
    Neuroprotective effect of whey protein hydrolysate containing LDIQK on HT22 cells in hydrogen peroxide-induced oxidative stress.
    Yeok B Chang, Eun-Jin Jung, Kyungae Jo, Hyung J Suh, Hyeon-Son Choi.
      This study aimed to investigate the neuroprotective effects of whey protein hydrolysate (WPH) containing the pentapeptide leucine-aspartate-isoleucine-glutamine-lysine (LDIQK). Whey protein hydrolysate (50, 100, and 200 µg/mL) demonstrated the ability to restore the viability of HT22 cells subjected to 300 µM hydrogen peroxide (H2O2)-induced oxidative stress. Furthermore, at a concentration of 200 µg/mL, it significantly reduced the increase in reactive oxygen species production and calcium ion (Ca2+) influx induced by H2O2 by 46.1% and 46.2%, respectively. Similarly, the hydrolysate significantly decreased the levels of p-tau, a hallmark of tauopathy, and BCL2 associated X (BAX), a pro-apoptosis factor, while increasing the protein levels of choline acetyltransferase (ChAT), an enzyme involved in acetylcholine synthesis, brain-derived neurotrophic factor (BDNF), a nerve growth factor, and B-cell lymphoma 2 (BCL2, an anti-apoptotic factor. Furthermore, it increased nuclear factor erythroid 2-related factor 2 (Nrf2)-hemoxygenase-1(HO-1) signaling, which is associated with the antioxidant response, while reducing the activation of mitogen-activated protein kinase (MAPK) signaling pathway components, namely phosphor-extracellular signal-regulated kinases (p-ERK), phosphor-c-Jun N-terminal kinases (p-JNK), and p-p38. Column chromatography and tandem mass spectrometry analysis identified LDIQK as a compound with neuroprotective effects in whey protein hydrolysate; it inhibited Ca2+ influx and regulated the BAX/BCL2 ratio. Collectively, whey protein hydrolysate containing LDIQK demonstrated neuroprotective effects against H2O2-induced neuronal cell damage, suggesting that whey protein hydrolysate or its active peptide, LDIQK, may serve as a potential edible agent for improving cognitive dysfunction.
    Keywords:  HT22 cell; LDIQK; neuroprotective effect; oxidative stress; whey protein hydrolysate
    DOI:  https://doi.org/10.3168/jds.2023-24284
  6. Inflammopharmacology. 2023 Dec 19.
    Neuroprotective effect of curcumin against experimental autoimmune encephalomyelitis-induced cognitive and physical impairments in mice: an insight into the role of the AMPK/SIRT1 pathway.
    Mohamed A Sadek, Mostafa A Rabie, Nesrine S El Sayed, Helmy M Sayed, Esraa A Kandil.
      Multiple sclerosis (MS) is an incurable chronic neurodegenerative disease where autoimmunity, oxidative stress, and neuroinflammation collaboration predispose myelin sheath destruction. Interestingly, curcumin, a natural polyphenol, showed a neuroprotective effect in numerous neurodegenerative diseases, including MS. Nevertheless, the influence of curcumin against MS-induced cognitive impairment is still vague. Hence, we induced experimental autoimmune encephalomyelitis (EAE) in mice using spinal cord homogenate (SCH) and complete Freund's adjuvant, which eventually mimic MS. This study aimed not only to evaluate curcumin efficacy against EAE-induced cognitive and motor dysfunction, but also to explore a novel mechanism of action, by which curcumin exerts its beneficial effects in MS. Curcumin (200 mg/kg/day) efficacy was evaluated by behavioral tests, histopathological examination, and biochemical tests. Concisely, curcumin amended EAE-induced cognitive and motor impairments, as demonstrated by the behavioral tests and histopathological examination of the hippocampus. Interestingly, curcumin activated the adenosine monophosphate (AMP)-activated protein kinase/silent mating type information regulation 2 homolog 1 (AMPK/SIRT1) axis, which triggered cyclic AMP response element-binding protein/brain-derived neurotrophic factor/myelin basic protein (CREB/BDNF/MBP) pathway, hindering demyelination of the corpus callosum. Furthermore, AMPK/SIRT1 activation augmented nuclear factor erythroid 2-related factor 2 (Nrf2), a powerful antioxidant, amending EAE-induced oxidative stress. Additionally, curcumin abolished EAE-induced neuroinflammation by inhibiting Janus kinase 2 /signal transducers and activators of transcription 3 (JAK2/STAT3) axis, by various pathways, including AMPK/SIRT1 activation. JAK2/STAT3 inhibition halts inflammatory cytokines synthesis. In conclusion, curcumin's neuroprotective effect in EAE is controlled, at least in part, by AMPK/SIRT1 activation, which ultimately minimizes EAE-induced neuronal demyelination, oxidative stress, and neuroinflammation. Graphical illustration of putative molecular pathways implicated in the management of EAE by curcumin. Curcumin activates AMPK/SIRT1, which in turn activates multiple pathways that hinder neurodegeneration, oxidative stress, and neuroinflammation. Moreover, curcumin conquers the inflammatory pathway JAK2/STAT3/NF-kβ.
    Keywords:  AMPK/SIRT1; Cognition; Curcumin; EAE; Multiple sclerosis; Nrf2
    DOI:  https://doi.org/10.1007/s10787-023-01399-3
  7. Ecotoxicol Environ Saf. 2023 Dec 20. pii: S0147-6513(23)01357-X. [Epub ahead of print]270 115853
    Combined exposure to manganese and iron decreases oxidative stress-induced nerve damage by increasing Nrf2/HO-1/NQO1 expression.
    Yuan-Yuan Fang, Meng-Jun Teng, Jian-Chao Peng, Xiao-Wei Zheng, Ya-Qi Mo, Thanh-Tung Ho, Jun-Jie Lin, Jing-Jing Luo, Michael Aschner, Yue-Ming Jiang.
       BACKGROUND: Manganese (Mn) and iron (Fe) are essential trace elements for humans, yet excessive exposure to Mn or Fe can accumulate in the central nervous system (CNS) and cause neurotoxicity. The purpose of this study was to investigate the effects of Mn and Fe exposure, alone or in combination, on inducing oxidative stress-induced neurological damage in rat cortical and SH-SY5Y cells, and to determine whether combined exposure to these metals increases their individual toxicity.
    METHODS: SH-SY5Y cells and male Sprague-Dawley rats were used to observe the effects of oxidative stress-induced neurological damage induced by exposure to manganese and iron alone or in combination. To detect the expression of anti-oxidative stress-related proteins, Nrf2, HO-1, and NQO1, and the apoptosis-related proteins, Bcl2 and Bax, and the neurological damage-related protein, α-syn. To detect reactive oxygen species generation and apoptosis. To detect the expression of the rat cortical protein Nrf2. To detect the production of proinflammatory cytokines.
    RESULTS: We demonstrate that juvenile developmental exposure to Mn and Fe and their combination impairs cognitive performance in rats by inducing oxidative stress causing neurodegeneration in the cortex. Mn, Fe, and their combined exposure increased the expression of ROS, Bcl2, Bax, and α-syn, activated the inflammatory factors IL-6 and IL-12, inhibited the activities of SOD and GSH, and induced oxidative stress-induced neurodegeneration both in rats and SH-SY5Y cells. Combined Mn-Fe exposure attenuated the oxidative stress induced by Mn and Fe exposure alone by increasing the expression of antioxidant factors Nrf2, HO-1, and NQO1.
    CONCLUSION: In both in vivo and in vitro studies, manganese and iron alone or in combination induced oxidative stress, leading to neuronal damage. In contrast, combined exposure to manganese and iron mitigated the oxidative stress induced by exposure to manganese and iron alone by increasing the expression of antioxidant factors. Therefore, studies to elucidate the main causes of toxicity and establish the molecular mechanisms of toxicity should help to develop more effective therapeutic modalities in the future.
    Keywords:  Combined exposure; Iron; Manganese; Nrf2; Oxidative stress; ROS
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.115853
  8. Int J Mol Sci. 2023 Dec 07. pii: 17223. [Epub ahead of print]24(24):
    Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation.
    Dimitar Tonev, Albena Momchilova.
      The pathogenesis of multiple sclerosis (MS) suggests that, in genetically susceptible subjects, T lymphocytes undergo activation in the peripheral compartment, pass through the BBB, and cause damage in the CNS. They produce pro-inflammatory cytokines; induce cytotoxic activities in microglia and astrocytes with the accumulation of reactive oxygen species, reactive nitrogen species, and other highly reactive radicals; activate B cells and macrophages and stimulate the complement system. Inflammation and neurodegeneration are involved from the very beginning of the disease. They can both be affected by oxidative stress (OS) with different emphases depending on the time course of MS. Thus, OS initiates and supports inflammatory processes in the active phase, while in the chronic phase it supports neurodegenerative processes. A still unresolved issue in overcoming OS-induced lesions in MS is the insufficient endogenous activation of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway, which under normal conditions plays an essential role in mitochondria protection, OS, neuroinflammation, and degeneration. Thus, the search for approaches aiming to elevate endogenous Nrf2 activation is capable of protecting the brain against oxidative damage. However, exogenous Nrf2 activators themselves are not without drawbacks, necessitating the search for new non-pharmacological therapeutic approaches to modulate OS. The purpose of the present review is to provide some relevant preclinical and clinical examples, focusing on certain exogenous and endogenous Nrf2 activators and the modulation of therapeutic plasma exchange (TPE). The increased plasma levels of nerve growth factor (NGF) in response to TPE treatment of MS patients suggest their antioxidant potential for endogenous Nrf2 enhancement via NGF/TrkA/PI3K/Akt and NGF/p75NTR/ceramide-PKCζ/CK2 signaling pathways.
    Keywords:  Nuclear Factor Erythroid 2-Related Factor 2 pathway activation; endogenous; exogenous; multiple sclerosis; nerve growth factor; oxidative stress modulation; therapeutic plasma exchange
    DOI:  https://doi.org/10.3390/ijms242417223
  9. Exp Neurol. 2023 Dec 17. pii: S0014-4886(23)00340-0. [Epub ahead of print]373 114655
    Crosstalk between Nrf2 signaling pathway and inflammation in ischemic stroke: Mechanisms of action and therapeutic implications.
    Negar Khassafi, Abolfazl Azami Tameh, Hamed Mirzaei, Ali Rafat, Shirin Barati, Negin Khassafi, Zeinab Vahidinia.
      One of the major causes of long-term disability and mortality is ischemic stroke that enjoys limited treatment approaches. On the one hand, oxidative stress, induced by excessive generation of reactive oxygen species (ROS), plays a critical role in post-stroke inflammatory response. Increased ROS generation is one of the basic factors in the progression of stroke-induced neuroinflammation. Moreover, intravenous (IV) thrombolysis using recombinant tissue plasminogen activator (rtPA) as the only medication approved for patients with acute ischemic stroke who suffer from some clinical restrictions it could not cover the complicated episodes that happen after stroke. Thus, identifying novel therapeutic targets is crucial for successful preparation of new medicines. Recent evidence indicates that the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) contributes significantly to regulating the antioxidant production in cytosol, which causes antiinflammatory effects on neurons. New findings have shown a relationship between activation of the Nrf2 and glial cells, nuclear factor kappa B (NF-κB) pathway, the nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, and expression of inflammatory markers, suggesting induction of Nrf2 activation can represent a promising therapeutic alternative as the modulators of Nrf2 dependent pathways for targeting inflammatory responses in neural tissue. Hence, this review addresses the relationship of Nrf2 signaling with inflammation and Nrf2 activators' potential as therapeutic agents. This review helps to improve required knowledge for focused therapy and the creation of modern and improved treatment choices for patients with ischemic stroke.
    Keywords:  Glial cells; Inflammation; Ischemic stroke; Nrf2; Oxidative stress; tBHQ
    DOI:  https://doi.org/10.1016/j.expneurol.2023.114655
  10. Brain Sci. 2023 Dec 14. pii: 1717. [Epub ahead of print]13(12):
    Differential Effects of Paraquat, Rotenone, and MPTP on Cellular Bioenergetics of Undifferentiated and Differentiated Human Neuroblastoma Cells.
    Ekramy Elmorsy, Ayat Al-Ghafari, Huda Al Doghaither, Sara Hashish, Mohamed Salama, Anusha W Mudyanselage, Lipta James, Wayne G Carter.
      Paraquat (PQ), rotenone (RO), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are neurotoxicants that can damage human health. Exposure to these neurotoxicants has been linked to neurodegeneration, particularly Parkinson's disease. However, their mechanisms of action have not been fully elucidated, nor has the relative vulnerability of neuronal subtypes to their exposures. To address this, the current study investigated the cytotoxic effects of PQ, RO, and MPTP and their relative effects on cellular bioenergetics and oxidative stress on undifferentiated human neuroblastoma (SH-SY5Y) cells and those differentiated to dopaminergic (DA) or cholinergic (CH) phenotypes. The tested neurotoxicants were all cytotoxic to the three cell phenotypes that correlated with both concentration and exposure duration. At half-maximal effective concentrations (EC50s), there were significant reductions in cellular ATP levels and reduced activity of the mitochondrial complexes I and III, with a parallel increase in lactate production. PQ at 10 µM significantly decreased ATP production and mitochondrial complex III activity only in DA cells. RO was the most potent inhibitor of mitochondrial complex 1 and did not inhibit mitochondrial complex III even at concentrations that induced a 50% loss of cell viability. MPTP was the most potent toxicant in undifferentiated cells. All neurotoxicants significantly increased reactive oxygen species, lipid peroxidation, and nuclear expression of Nrf2, with a corresponding inhibition of the antioxidant enzymes catalase and superoxide dismutase. At a 10 µM exposure to PQ or RO, oxidative stress biomarkers were significant in DA cells. Collectively, this study underscores the importance of mitochondrial dysfunction and oxidative stress in PQ, RO, and MPTP-induced cytotoxicity and that neuronal phenotypes display differential vulnerability to these neurotoxicants.
    Keywords:  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); mitochondrial damage; neurotoxicity; oxidative stress; paraquat; pesticides; rotenone
    DOI:  https://doi.org/10.3390/brainsci13121717
  11. Exp Ther Med. 2024 Jan;27(1): 26
    Breviscapine attenuates lead‑induced myocardial injury by activating the Nrf2 signaling pathway.
    Dexuan Li, Zhengliang Xu, Yashan Li, Yanmei Huang, Jiali Yin, Hongjuan Li, Beiji Zhang.
      The present study investigated the therapeutic potential of breviscapine (Bre) in mitigating lead (Pb)-induced myocardial injury through activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway. Rat cardiomyocytes (H9C2 cells) were exposed to Pb to model Pb poisoning, and various parameters, including cell viability, apoptosis and reactive oxygen species (ROS) production, were assessed using Cell Counting Kit-8, flow cytometry and 2',7'-dichlorfluoresceindiacetate assays, respectively. Additionally, a rat model of Pb poisoning was established in which blood Pb levels were measured using a graphite furnace atomic absorption spectrophotometer, and alterations in myocardial tissue, oxidative stress markers, inflammatory indicators, protein expression related to apoptosis and the Nrf2 pathway were evaluated via histopathology, ELISA and western blotting. The results showed that Bre treatment enhanced cell viability, decreased apoptosis, and reduced ROS production in Pb-exposed H9C2 cells. Moreover, Bre modulated oxidative stress markers and inflammatory factors while enhancing the expression of proteins in the Nrf2 pathway. In a rat model, Bre mitigated the lead-induced increase in blood Pb levels and myocardial injury biomarkers, and reversed the downregulation of Nrf2 pathway proteins. In conclusion, the current findings suggested that Bre mitigates Pb-induced myocardial injury by activating the Nrf2 signaling pathway, highlighting its potential as a therapeutic agent for protecting the heart from the harmful effects of Pb exposure. Further research is required to elucidate the exact mechanisms and explore the clinical applicability of Bre in mitigating Pb-induced myocardial damage.
    Keywords:  Bre; Nrf2 signaling pathway; lead; myocardial injury; oxidative stress
    DOI:  https://doi.org/10.3892/etm.2023.12314
  12. Neural Regen Res. 2024 Aug 01. 19(8): 1828-1834
    A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.
    Yongjiang Zhang, Shiyi Yin, Run Song, Xiaoyi Lai, Mengmeng Shen, Jiannan Wu, Junqiang Yan.
      JOURNAL/nrgr/04.03/01300535-202408000-00037/figure1/v/2023-12-16T180322Z/r/image-tiff Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson's disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson's disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson's disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson's disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson's disease by interacting with endoplasmic reticulum stress and Parkin.
    DOI:  https://doi.org/10.4103/1673-5374.389356
  13. Zool Res. 2024 Jan 18. pii: 2095-8137(2024)01-0108-17. [Epub ahead of print]45(1): 108-124
    Cath-KP, a novel peptide derived from frog skin, prevents oxidative stress damage in a Parkinson's disease model.
    Huanpeng Lu, Jinwei Chai, Zijian Xu, Jiena Wu, Songzhe He, Hang Liao, Peng Huang, Xiaowen Huang, Xi Chen, Haishan Jiang, Shaogang Qu, Xueqing Xu.
      Parkinson's disease (PD) is a neurodegenerative condition that results in dyskinesia, with oxidative stress playing a pivotal role in its progression. Antioxidant peptides may thus present therapeutic potential for PD. In this study, a novel cathelicidin peptide (Cath-KP; GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV) was identified from the skin of the Asiatic painted frog ( Kaloula pulchra). Structural analysis using circular dichroism and homology modeling revealed a unique αββ conformation for Cath-KP. In vitro experiments, including free radical scavenging and ferric-reducing antioxidant analyses, confirmed its antioxidant properties. Using the 1-methyl-4-phenylpyridinium ion (MPP +)-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, Cath-KP was found to penetrate cells and reach deep brain tissues, resulting in improved MPP +-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1 (Sirt1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Both focal adhesion kinase (FAK) and p38 were also identified as regulatory elements. In the MPTP-induced PD mice, Cath-KP administration increased the number of tyrosine hydroxylase (TH)-positive neurons, restored TH content, and ameliorated dyskinesia. To the best of our knowledge, this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress. These findings expand the known functions of cathelicidins, and hold promise for the development of therapeutic agents for PD.
    Keywords:  Cath-KP; Neuroprotection; Oxidative stress; Parkinson’s disease; Peptide
    DOI:  https://doi.org/10.24272/j.issn.2095-8137.2023.101
  14. Molecules. 2023 Dec 05. pii: 7955. [Epub ahead of print]28(24):
    Palmatine Protects PC12 Cells and Mice from Aβ25-35-Induced Oxidative Stress and Neuroinflammation via the Nrf2/HO-1 Pathway.
    Yu Wang, Hongyan Pei, Weijia Chen, Rui Du, Jianming Li, Zhongmei He.
      Alzheimer's disease is a common degenerative disease which has a great impact on people's daily lives, but there is still a certain market gap in the drug research about it. Palmatine, one of the main components of Huangteng, the rattan stem of Fibraurea recisa Pierre (Menispermaceae), has potential in the treatment of Alzheimer's disease. The aim of this study was to evaluate the neuroprotective effect of palmatine on amyloid beta protein 25-35-induced rat pheochromocytoma cells and AD mice and to investigate its mechanism of action. CCK8 assays, ELISA, the Morris water maze assay, fluorescent probes, calcein/PI staining, immunofluorescent staining and Western blot analysis were used. The experimental results show that palmatine can increase the survival rate of Aβ25-35-induced PC12 cells and mouse hippocampal neurons, reduce apoptosis, reduce the content of TNF-α, IL-1β, IL-6, GSH, SOD, MDA and ROS, improve the learning and memory ability of AD mice, inhibit the expression of Keap-1 and Bax, and promote the expression of Nrf2, HO-1 and Bcl-2. We conclude that palmatine can ameliorate oxidative stress and neuroinflammation produced by Aβ25-35-induced PC12 cells and mice by modulating the Nrf2/HO-1 pathway. In conclusion, our results suggest that palmatine may have a potential therapeutic effect on AD and could be further investigated as a promising therapeutic agent for AD. It provides a theoretical basis for the development of related drugs.
    Keywords:  Aβ25-35-induced Alzheimer’s disease; Nrf2/HO-1 pathway; neuroinflammation; oxidative stress; palmatine
    DOI:  https://doi.org/10.3390/molecules28247955
  15. BMC Pharmacol Toxicol. 2023 Dec 21. 24(1): 82
    Amlodipine alleviates renal ischemia/reperfusion injury in rats through Nrf2/Sestrin2/PGC-1α/TFAM Pathway.
    Hadi Shirzad, Seyed Amin Mousavinezhad, Mohammad Panji, Moin Ala.
       BACKGROUND: Previously, observational studies showed that amlodipine can mitigate calcineurin inhibitor- and contrast-induced acute kidney injury (AKI). Herein, we aimed to measure the effect of amlodipine on renal ischemia/reperfusion (I/R) injury and find the underlying mechanisms.
    MATERIALS AND METHODS: Bilateral renal I/R was induced by clamping the hilum of both kidneys for 30 min. The first dose of amlodipine 10 mg/kg was gavaged before anesthesia. The second dose of amlodipine was administered 24 h after the first dose. Forty-eight hours after I/R, rats were anesthetized, and their blood and tissue specimens were collected.
    RESULTS: Amlodipine significantly decreased the elevated serum levels of creatinine and blood urea nitrogen (BUN) and mitigated tissue damage in hematoxylin & eosin (H&E) staining. Amlodipine strongly reduced the tissue levels of malondialdehyde (MDA), interleukin 1β (IL1β), and tumor necrosis factor α (TNF-α). Amlodipine enhanced antioxidant defense by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2. Furthermore, amlodipine significantly improved mitochondrial biogenesis by promoting Sestrin2/peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α)/mitochondrial transcription factor A (TFAM) pathway. It also enhanced autophagy and attenuated apoptosis, evidenced by increased LC3-II/LC3-I and bcl2/bax ratios after renal I/R.
    CONCLUSION: These findings suggest that amlodipine protects against renal I/R through Nrf2/Sestrin2/PGC-1α/TFAM Pathway.
    Keywords:  Amlodipine; Nrf2; PGC-1α; Renal ischemia/reperfusion; Sestrin2
    DOI:  https://doi.org/10.1186/s40360-023-00722-6
  16. Biochem Biophys Res Commun. 2023 Nov 25. pii: S0006-291X(23)01418-3. [Epub ahead of print]693 149324
    Puerarin reduces cell damage from cerebral ischemia-reperfusion by inhibiting ferroptosis.
    Changxuan Li, Yu Liu.
      This study explores the protective effects of Puerarin, a compound derived from the traditional Chinese herb Pueraria, against cellular damage induced by Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) in PC12 cells. The research focuses on understanding how Puerarin influences the mechanisms of ferroptosis and oxidative stress, key factors in ischemia-reperfusion injury relevant to neurodegenerative diseases. In our in vitro model, we identified the optimal OGD duration to induce significant cell stress and confirmed the non-toxicity of Puerarin up to 100uM. The results reveal that Puerarin substantially mitigates the detrimental effects of OGD/R, including improvements in cell viability, mitochondrial integrity, and reductions in oxidative stress markers like ROS and lipid peroxidation. Notably, Puerarin modulates key proteins in the autophagy process and the Nrf2 pathway, crucial in cellular stress responses. Further, the use of 3-Methyladenine, an autophagy inhibitor, underscores the significance of autophagy in managing OGD/R-induced stress. These findings suggest Puerarin's potential as a therapeutic agent for conditions characterized by ischemic cellular damage, highlighting the need for further clinical exploration.
    Keywords:  Autophahy; Ferroptosis; Oxygen-glucose deprivation/reperfusion; Puerarin; Ubiquitination
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149324
  17. Antioxidants (Basel). 2023 Nov 21. pii: 2022. [Epub ahead of print]12(12):
    Elamipretide(SS-31) Attenuates Idiopathic Pulmonary Fibrosis by Inhibiting the Nrf2-Dependent NLRP3 Inflammasome in Macrophages.
    Yunjuan Nie, Jiao Li, Xiaorun Zhai, Zhixu Wang, Junpeng Wang, Yaxian Wu, Peng Zhao, Gen Yan.
      Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disease with a limited therapeutic strategy. Mitochondrial oxidative stress in macrophages is directly linked to IPF. Elamipretide(SS-31) is a mitochondrion-targeted peptide that has been shown to be safe and beneficial for multiple diseases. However, whether SS-31 alleviates IPF is unclear. In the present study, we used a bleomycin (BLM)-induced mouse model followed by SS-31 injection every other day to investigate its role in IPF and explore the possible mechanism. Our results showed that SS-31 treatment significantly suppressed BLM-induced pulmonary fibrosis and inflammation, with improved histological change, and decreased extracellular matrix deposition and inflammatory cytokines release. Impressively, the expression percentage of IL-1β and IL-18 was downregulated to lower than half with SS-31 treatment. Mechanistically, SS-31 inhibited IL-33- or lipopolysaccharide(LPS)/IL-4-induced production of IL-1β and IL-18 in macrophages by suppressing NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome activation. Nuclear factor erythroid 2-related factor 2(Nrf2) was dramatically upregulated along with improved mitochondrial function after SS-31 treatment in activated macrophages and BLM-induced mice. Conversely, there was no significant change after SS-31 treatment in Nrf2-/- mice and macrophages. These findings indicated that SS-31 protected against pulmonary fibrosis and inflammation by inhibiting the Nrf2-mediated NLRP3 inflammasome in macrophages. Our data provide initial evidence for the therapeutic efficacy of SS-31 in IPF.
    Keywords:  IPF; NLRP3 inflammasome; Nrf2; SS-31; macrophage
    DOI:  https://doi.org/10.3390/antiox12122022
  18. Exp Ther Med. 2024 Jan;27(1): 37
    Melatonin exerts neuroprotective effects in mice with spinal cord injury by activating the Nrf2/Keap1 signaling pathway via the MT2 receptor.
    Liyan Yan, Xiaonan Han, Mingkang Zhang, Hongwei Kou, Hongjian Liu, Tian Cheng.
      Spinal cord injury (SCI) is a devastating event that often leads to severe disability, and effective treatments for SCI are currently limited. The present study investigated the potential effects and specific mechanisms of melatonin treatment in SCI. Mice were divided into Sham (Sham), Vehicle (Veh), Melatonin (Mel), and Melatonin + 4-phenyl-2-propionamidotetralin (4P-PDOT) (Mel + 4PP) groups based on randomized allocation. The expression of MT2 and the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Keap1 signaling pathways were examined, along with oxidative stress indicators, inflammatory factors and GFAP-positive cells near the injury site. The polarization of microglial cells in different inflammatory microenvironments was also observed. Cell survival, motor function recovery and spinal cord tissue morphology were assessed using staining and Basso Mouse Scale scores. On day 7 after SCI, the results revealed that melatonin treatment increased MT2 protein expression and activated the Nrf2/Keap1 signaling pathway. It also reduced GFAP-positive cells, mitigated oxidative stress, and suppressed inflammatory responses around the injury site. Furthermore, melatonin treatment promoted the polarization of microglia toward the M2 type, increased the number of neutrophil-positive cells, and modulated the transcription of Bax and Bcl2 in the injured spinal cord. Melatonin treatment alleviated the severity of spinal injuries and facilitated functional recovery in mice with SCI. Notably, blocking MT2 with 4P-PDOT partially reversed the neuroprotective effects of melatonin in SCI, indicating that the activation of the MT2/Nrf2/Keap1 signaling pathway contributes to the neuroprotective properties of melatonin in SCI. The therapeutic and translational potentials of melatonin in SCI warrant further investigation.
    Keywords:  MT2; melatonin; neuroprotection; nuclear factor-erythroid 2-related factor 2; spinal cord injury
    DOI:  https://doi.org/10.3892/etm.2023.12325
  19. Brain Res. 2023 Dec 16. pii: S0006-8993(23)00495-X. [Epub ahead of print]1825 148724
    Upregulation of mitochondrial PGK1 by ROS-TBC1D15 pathway promotes neuronal death after oxygen-glucose deprivation/reoxygenation injury.
    Songfeng Chen, Hui Wang, Juan Chen, Jing Cheng, Jingchen Gao, Shujun Chen, Xujin Yao, Jiangdong Sun, Jinyang Ren, Shifang Li, Fengyuan Che, Qi Wan.
      Phosphoglycerate kinase 1 (PGK1) is extensively located in the cytosol and mitochondria. The role of PGK1 in ischemic neuronal injury remains elusive. In the in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R), we showed that PGK1 expression was increased in cortical neurons. Knockdown of PGK1 led to a reduction of OGD/R-induced neuronal death. The expression of cytosolic PGK1 was reduced, but the levels of mitochondrial PGK1 were increased in OGD/R-insulted neurons. Inhibiting the activity of mitochondrial PGK1 alleviated the neuronal injury after OGD/R insult. We further showed that the protein levels of TBC domain family member 15 (TBC1D15) were decreased in OGD/R-insulted neurons. Knockdown of TBC1D15 led to increased levels of mitochondrial PGK1 after OGD/R insult in cortical neurons. Moreover, increased reactive oxygen species (ROS) resulted in a reduction of TBC1D15 in OGD/R-insulted neurons. These results suggest that the upregulation of mitochondrial PGK1 by ROS-TBC1D15 signaling pathway promotes neuronal death after OGD/R injury. Mitochondrial PGK1 may act as a regulator of neuronal survival and interventions in the PGK1-dependent pathway may be a potential therapeutic strategy.
    Keywords:  Mitochondria; Oxygen-glucose deprivation/reoxygenation; Phosphoglycerate Kinase 1; Reactive oxygen species; TBC domain family member 15
    DOI:  https://doi.org/10.1016/j.brainres.2023.148724
  20. Anesth Analg. 2023 Dec 18.
    Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia.
    Hee Kee Kim, Qi Wang, Seon-Hee Hwang, Patrick M Dougherty, Jing Wang, Salahadin Abdi.
       BACKGROUND: Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP.
    METHODS: CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, mechanical hyperalgesia, levels of inflammatory mediators and pNrf2, and location of pNrf2 in the dorsal root ganglia (DRG) were measured by RNA sequencing, von Frey filaments, Western blotting, and immunohistochemistry in rats and human DRG samples. In addition, the mitochondrial functions in 50B11 DRG neuronal cells were measured by fluorescence assay.
    RESULTS: Our RNA transcriptome of CINP rats showed a downregulated Nrf2 pathway in the pain condition. Importantly, single and repeated systemic injections of BM ameliorated CINP. Paclitaxel increased inflammatory mediators, but BM decreased them and increased pNrf2 in the DRG. In addition, paclitaxel decreased mitochondrial membrane potential and increased mitochondrial volume in 50B11 cells, but BM restored them. Furthermore, pNrf2 was expressed in neurons and satellite cells in rat and human DRG.
    CONCLUSIONS: Our results demonstrate the analgesic effects of BM by Nrf2 activation and the fundamental role of pNrf2 on CINP, suggesting a target for CINP and a therapeutic strategy for patients.
    DOI:  https://doi.org/10.1213/ANE.0000000000006736
  21. Int Immunopharmacol. 2023 Dec 14. pii: S1567-5769(23)01637-5. [Epub ahead of print]127 111310
    Exosomal OIP5-AS1 attenuates cerebral ischemia-reperfusion injury by negatively regulating TXNIP protein stability and inhibiting neuronal pyroptosis.
    Zhongchen Li, Yuejiu Pang, Lei Hou, Xiaohui Xing, Fuhua Yu, Mingxu Gao, Jiyue Wang, Xueyuan Li, Liyong Zhang, Yilei Xiao.
       BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) can cause neuronal apoptosis and lead to irreversible brain injury. Numerous lncRNAs have been reported to play important roles in CIRI, but it is unclear whether these lncRNAs can function through exosomes.
    METHODS: In this study, we utilized the middle cerebral artery occlusion/reperfusion (MCAO/R) animal model and the oxygen-glucose deprivation/ reoxygenation (OGD/R) cell model. RNA sequencing was performed to screen for differentially expressed lncRNAs in M2 microglia-derived exosomes (M2-Exos). RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation and ubiquitination assays were used to explore the molecular mechanism of OIP5-AS1 in alleviating CIRI.
    RESULTS: M2-Exos could alleviate nerve injury and pyroptosis after CIRI in vitro and in vivo. OIP5-AS1 was found to be significantly up-regulated in M2-Exos and down-regulated in OGD/R neurons, MCAO/R mice and ischemic stroke patients. In MCAO/R mice, OIP5-AS1 could reduce cerebral infarct size, cerebral edema and mNSS scores, and inhibit the expression levels of pyroptosis-related proteins in brain tissue. TXNIP was confirmed to be a reliable binding protein of OIP5-AS1. OIP5-AS1 overexpression significantly attenuated MCAO/R-induced upregulation of TXNIP at the protein level, but not at the mRNA level. OIP5-AS1 promoted the TXNIP degradation process and increased the ubiquitination of TXNIP. ITCH could bind to TXNIP. ITCH overexpression or knockdown did not alter the mRNA level of TXNIP, but negatively regulated TXNIP expression at the protein level. ITCH accelerated the degradation and ubiquitination of TXNIP, which could be attenuated by OIP5-AS1 knockdown. OIP5-AS1 could improve neuronal damage and inhibit neuronal pyroptosis through TXNIP.
    CONCLUSIONS: M2-Exo-derived OIP5-AS1 can induce TXNIP ubiquitination and degradation by recruiting ITCH, negatively regulate TXNIP protein stability, inhibit neuronal pyroptosis, and attenuate CIRI.
    Keywords:  Cerebral ischemia reperfusion injury; M2 microglial exosomes; OIP5-AS1; Pyroptosis; TXNIP
    DOI:  https://doi.org/10.1016/j.intimp.2023.111310
  22. Neural Regen Res. 2024 Aug 01. 19(8): 1660-1670
    Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system injuries.
    Li Zhang, Zhigang Hu, Zhenxing Li, Yixing Lin.
      Central nervous system injuries have a high rate of resulting in disability and mortality; however, at present, effective treatments are lacking. Programmed cell death, which is a genetically determined form of active and ordered cell death with many types, has recently attracted increasing attention due to its functions in determining the fate of cell survival. A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage. In this review, we provide an overview of the role of programmed cell death in central nervous system injuries, including the pathways involved in mitophagy, pyroptosis, ferroptosis, and necroptosis, and the underlying mechanisms by which mitophagy regulates pyroptosis, ferroptosis, and necroptosis. We also discuss the new direction of therapeutic strategies targeting mitophagy for the treatment of central nervous system injuries, with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury. In conclusion, based on these properties and effects, interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients.
    DOI:  https://doi.org/10.4103/1673-5374.389361
  23. PLoS One. 2023 ;18(12): e0295903
    Notoginsenoside R1 attenuates brain injury in rats with traumatic brain injury: Possible mediation of apoptosis via ERK1/2 signaling pathway.
    Xiaoxian Pei, Ling Zhang, Dan Liu, Yajuan Wu, Xiaowei Li, Ying Cao, Xiangdong Du.
      Traumatic brain injury (TBI) occurs worldwide and is associated with high mortality and disability rate. Apoptosis induced by TBI is one of the important causes of secondary injury after TBI. Notoginsenoside R1 (NGR1) is the main phytoestrogen extracted from Panax notoginseng. Many studies have shown that NGR1 has potent neuroprotective, anti-inflammatory, and anti-apoptotic properties and is effective in ischemia-reperfusion injury. Therefore, we investigated the potential neuroprotective effects of NGR1 after TBI and explored its molecular mechanism of action. A rat model of TBI was established using the controlled cortical impact (CCI) method. The expression levels of Bcl-2, Bax, caspase 3, and ERK1/2-related molecules in the downstream pathway were also detected by western blotting. The expression levels of pro-inflammatory cytokines were detected by real-time quantitative PCR. Nissl staining was used to clarify the morphological changes around the injury foci in rats after TBI. Fluoro-Jade B (FJB) and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) fluorescence staining were used to detect the apoptosis of neural cells in each group of rats. The results showed that NGR1 administration reduced neurological deficits after TBI, as well as brain edema and brain tissue apoptosis. It also significantly inhibited the expression of pro-inflammatory cytokines. Furthermore, NGR1 decreased the expression levels of extracellular signal-regulated kinase (ERK) and p-RSK1, which are phosphorylated after trauma. This study suggests that NGR1 can improve neuronal apoptosis in brain injury by inhibiting the ERK signaling pathway. NGR1 is a potential novel neuroprotective agent for the treatment of secondary brain injury after TBI.
    DOI:  https://doi.org/10.1371/journal.pone.0295903
  24. Pharmaceuticals (Basel). 2023 Dec 11. pii: 1714. [Epub ahead of print]16(12):
    Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders.
    Laura Mihaela Isop, Andrea Elena Neculau, Radu Dan Necula, Cristian Kakucs, Marius Alexandru Moga, Lorena Dima.
      Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer's, Parkinson's, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin's mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as "metformin", "neuroprotection", and "neurodegenerative diseases", with data up to September 2023. Recent research on metformin's glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1-AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions.
    Keywords:  Alzheimer; Parkinson disease; antiaging; cognitive impairment; diabetes; epilepsy; metformin; neurodegenerative; neuroprotection
    DOI:  https://doi.org/10.3390/ph16121714
  25. Saudi Pharm J. 2023 Dec;31(12): 101871
    The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells.
    Azza Ramadan, Abuelnor Mohammed, Asim Ahmed Elnour, Adel Sadeq, Nadia Al Mazrouei, Maisoun Alkaabi, Khalid Awad Al-Kubaisi, Semira Abdi Beshir, Vineetha Menon, Abdulla AlAmoodi, Kishore Ganana Sam, Ali Awadallah Ali Mohamed Saeed, Sami Fatehi Abdalla, Samah Mohammed Hussein.
       Background: Huntington's disease is an inherited progressive neurodegenerative disorder caused by an expansion of the polyglutamine tract leading to malformation and aggregation of the mutant huntingtin protein in the cell cytoplasm and nucleus of affected brain regions. The development of neuroprotective agents from plants has received considerable research attention.
    Objective: Our study aims to investigate the neuroprotective effects of luteolin and the mechanisms that underline its potential mediated protection in the mutant htt neuroblastoma cells.
    Methods: The mutant htt neuroblastoma cells were transfected with 160Q, and the control wild-type neuroblastoma cells were transfected with 20Q htt for 24 h and later treated with luteolin. Cell viability was determined by MTT and PI staining in both groups, while western blotting was used to evaluate caspase 3 protein expression. Aggregation formation was assessed via immunofluorescence microscopy. Also, western blotting was utilized to measure the protein expression of mutant htt aggregated and soluble protein, Nrf2 and HO-1. The impact of Nrf2 on luteolin-treated neuroblastoma cells was assessed using small interfering RNAs.
    Results: Our study reports that luteolin can protect cultured cells from mutant huntingtin cytotoxicity, evidenced by increased viability and decreased apoptosis. Also, luteolin reduced the accumulation of soluble and insoluble mutant huntingtin aggregates in mutant htt neuroblastoma cells transfected with 160Q compared to the control wild-type. The mutant htt aggregate reduction mediated by luteolin appeared to be independent of the Nrf2 -HO-1 antioxidant pathway.
    Conclusion: Luteolin presents a new potential therapeutic and protective agent for the treatment and decreasing the cytotoxicity in neurodegenerative diseases such as Huntington's disease.
    Keywords:  Aggregation; Huntington’s disease; Luteolin, misfolded protein; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.jsps.2023.101871
  26. Eur J Pharmacol. 2023 Dec 18. pii: S0014-2999(23)00778-1. [Epub ahead of print]963 176264
    Quercetin attenuates cerebral ischemic injury by inhibiting ferroptosis via Nrf2/HO-1 signaling pathway.
    Caiwang Peng, Qidi Ai, Fengyan Zhao, Hengli Li, Yang Sun, Keyan Tang, Yantao Yang, Naihong Chen, Fang Liu.
       AIMS: Ischemic stroke is a severe cerebrovascular disease in which neuronal death continually occurs through multiple forms, including apoptosis, autophagy, pyroptosis and ferroptosis. Quercetin (QRC), as a natural flavonoid compound, has been reported to have pharmacological effects on ischemic injury accompanied by unclear anti-ferroptotic mechanisms. This study is designed to investigate the therapeutic effects of QRC against ferroptosis in ischemic stroke.
    MATERIALS AND METHODS: In vivo, the model of MCAO rats were used to assess the protective effect of QRC on cerebral ischemic. Additionally, we constructed oxidative stressed and ferroptotic cell models to explore the effects and mechanisms of QRC on ferroptosis. The related proteins were analysed by western blotting, immunohistochemical and immunofluorescence techniques.
    RESULTS: The experiments demonstrated that QRC improves neurological deficits, infarct volume, and pathological features in MCAO rats, also increased the viability of HT-22 cells exposed to H2O2 and erastin. These results, including MDA, SOD, GSH, ROS levels and iron accumulation, indicated that QRC suppresses the generation of lipid peroxides and may involve in the regulatory of ferroptosis. Both in vitro and in vivo, QRC was found to inhibit ferroptosis by up-regulating GPX4 and FTH1, as well as down-regulating ACSL4. Furthermore, we observed that QRC enhances the nuclear translocation of Nrf2 and activates the downstream antioxidative proteins. Importantly, the effect of QRC on ferroptosis can be reversed by the Nrf2 inhibitor ML385.
    CONCLUSIONS: This study provides evidence that QRC has a neuroprotective effect by inhibiting ferroptosis, demonstrating the therapeutic potential for cerebral ischemic stroke.
    Keywords:  Cerebral ischaemia; Ferroptosis; Nrf2/HO-1 signalling pathway; Quercetin
    DOI:  https://doi.org/10.1016/j.ejphar.2023.176264
  27. Sci Total Environ. 2023 Dec 13. pii: S0048-9697(23)07858-0. [Epub ahead of print]912 169228
    Polystyrene micro- and nanoplastics induce gastric toxicity through ROS mediated oxidative stress and P62/Keap1/Nrf2 pathway.
    Rongli Sun, Manman Liu, Fei Xiong, Kai Xu, Jiawei Huang, Jinyan Liu, Daqin Wang, Yuepu Pu.
      Microplastics (MPs) exist widely in the environment and can enter the human body indirectly through the food chain or directly through inhalation or ingestion. The primary organ that MPs contaminated food or water enters the human body through the digestive tract is the stomach. However, at present, the effects of MPs on the stomach and the related mechanism remain unclear. In this study, our results indicated that 50 nm and 250 nm polystyrene MPs (PS-MPs) at environmental related dose significantly decreased stomach organ coefficient, inhibited gastric juice secretion and mucus secretion, disrupted gastric barrier function and suppressed antioxidant ability in mice. In vitro experiments showed that PS-MPs inhibited cell viability, increased ROS generation, and induced apoptosis through mitochondria-dependent pathway. Simultaneously, PS-MPs also decreased mitochondrial membrane potential, ATP level, disrupted mitochondrial kinetic homeostasis, and activated P62 / Nrf2 / Keap1 pathway. Furthermore, blocking ROS (NAC) partially alleviated ROS and apoptosis caused by PS-MPs. Based on above findings, the potential adverse outcome pathway (AOP) of PS-MPs-caused gastric toxicity was proposed which provides a new insight into the risk assessment of MP related gastric damage. Our study unveils the gastric injury induced by PS MPs is dependent on ROS - mediated P62 / Nrf2 / Keap1 signaling pathway, and provides scientific basis for further exploration the mechanism of gastric toxicity of PS MPs.
    Keywords:  Adverse outcome pathway; Gastric toxicity; Microplastics; Nuclear factor-E2-related factor 2; ROS
    DOI:  https://doi.org/10.1016/j.scitotenv.2023.169228
  28. Eur J Neurosci. 2023 Dec 17.
    Overexpression of SESN1 improves mitochondrial damage and mitophagy, a potential therapeutic strategy for cognitive dysfunction after anaesthesia.
    Li Sun, Xiaoya Hong, Daliang Wang, Yangyang Li.
      Postoperative cognitive dysfunction (POCD) is a prevalent central nervous system complication predominantly observed in elderly patients. Sevoflurane, a general anaesthetic agent, has been implicated in the development of POCD, yet the underlying regulatory mechanisms potentially involving Sestrin1 (SESN1), a stress-responsive protein that plays a critical role in cellular homeostasis and protection against stress-induced damage, including oxidative stress and DNA damage, remain elusive. This study endeavoured to elucidate the impact of SESN1 on sevoflurane-induced cognitive impairment in rats. Employing a model in which SESN1 was transfected into SD male rats and cognitive dysfunction was induced by sevoflurane. The Morris Water Maze test was used for behavioural evaluation, Enzyme-Linked Immunosorbent Assay, Western blotting and immunofluorescence were applied to assess the influence of SESN1 on the inflammatory response and mitophagy in the rat hippocampus. The study further aimed to uncover the putative mechanism by which SESN1, through SIRT1, might modulate cognitive function. Concurrently, levels of malondialdehyde, superoxide dismutase and mitochondrially produced ATP within the rat hippocampus were quantified. Experimental outcomes suggested that SESN1 overexpression significantly mitigated the deleterious effects of sevoflurane anaesthesia, ameliorated neuroinflammation and inflammasome activation, modified mitochondrial function and facilitated mitophagy. Additionally, SESN1, via the activation of SIRT1, may suppress inflammasome activation and mitochondrial dysfunction. Collectively, these findings underscore SESN1's integral role in counteracting sevoflurane-induced cognitive impairment, impeding inflammasome activation, enhancing mitochondrial function and fostering mitophagy, which appear to be intricately linked to SESN1-mediated SIRT1 activation. SESN1 is a novel therapeutic target for POCD, potentially advancing neuroprotective strategies in clinical settings.
    Keywords:  SESN1; SIRT1; postoperative cognitive dysfunction; sevoflurane
    DOI:  https://doi.org/10.1111/ejn.16218
  29. Expert Opin Drug Discov. 2023 Dec 19. 1-14
    The SH-SY5Y cell line: a valuable tool for Parkinson's disease drug discovery.
    Manisha Pandey, Varnita Karmakar, Ankit Majie, Monika Dwivedi, Shadab Md, Bapi Gorain.
       INTRODUCTION: Owing to limited efficient treatment strategies for highly prevalent and distressing Parkinson's disease (PD), an impending need emerged for deciphering new modes and mechanisms for effective management. SH-SY5Y-based in vitro neuronal models have emerged as a new possibility for the elucidation of cellular and molecular processes in the pathogenesis of PD. SH-SY5Y cells are of human origin, adhered to catecholaminergic neuronal attributes, which consequences in imparting wide acceptance and significance to this model over conventional in vitro PD models for high-throughput screening of therapeutics.
    AREAS COVERED: Herein, the authors review the SH-SY5Y cell line and its value to PD research. The authors also provide the reader with their expert perspectives on how these developments can lead to the development of new impactful therapeutics.
    EXPERT OPINION: Encouraged by recent research on SH-SY5Y cell lines, it was envisaged that this in vitro model can serve as a primary model for assessing efficacy and toxicity of new therapeutics as well as for nanocarriers' capacity in delivering therapeutic agents across BBB. Considering the proximity with human neuronal environment as in pathogenic PD conditions, SH-SY5Y cell lines vindicated consistency and reproducibility in experimental results. Accordingly, exploitation of this standardized SH-SY5Y cell line can fast-track the drug discovery and development path for novel therapeutics.
    Keywords:  Parkinson’s disease; SH-SY5Y cell line; genetic relationship; in vitro model; molecular environment; nanotechnology
    DOI:  https://doi.org/10.1080/17460441.2023.2293158
  30. Antioxidants (Basel). 2023 Nov 23. pii: 2033. [Epub ahead of print]12(12):
    Antioxidant Capacity of Free and Bound Phenolics from Olive Leaves: In Vitro and In Vivo Responses.
    Ting Li, Wenjun Wu, Jianming Zhang, Qinghang Wu, Shenlong Zhu, Erli Niu, Shengfeng Wang, Chengying Jiang, Daqun Liu, Chengcheng Zhang.
      Olive leaves are rich in phenolic compounds. This study explored the chemical profiles and contents of free phenolics (FPs) and bound phenolics (BPs) in olive leaves, and further investigated and compared the antioxidant properties of FPs and BPs using chemical assays, cellular antioxidant evaluation systems, and in vivo mouse models. The results showed that FPs and BPs have different phenolic profiles; 24 free and 14 bound phenolics were identified in FPs and BPs, respectively. Higher levels of phenolic acid (i.e., sinapinic acid, 4-coumaric acid, ferulic acid, and caffeic acid) and hydroxytyrosol were detected in the BPs, while flavonoids, triterpenoid acids, and iridoids were more concentrated in the free form. FPs showed a significantly higher total flavonoid content (TFC), total phenolic content (TPC), and chemical antioxidant properties than those of BPs (p < 0.05). Within the range of doses (20-250 μg/mL), both FPs and BPs protected HepG2 cells from H2O2-induced oxidative stress injury, and there was no significant difference in cellular antioxidant activity between FPs and BPs. The in vivo experiments suggested that FP and BP treatment inhibited malondialdehyde (MDA) levels in a D-galactose-induced oxidation model in mice, and significantly increased antioxidant enzyme activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and the total antioxidant capacity (T-AOC). Mechanistically, FPs and BPs exert their antioxidant activity in distinct ways; FPs ameliorated D-galactose-induced oxidative stress injury partly via the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway, while the BP mechanisms need further study.
    Keywords:  antioxidant properties; bound phenolics; free phenolics; olive leaves; oxidative stress
    DOI:  https://doi.org/10.3390/antiox12122033
  31. Antioxidants (Basel). 2023 Nov 30. pii: 2062. [Epub ahead of print]12(12):
    Hydrogen: A Rising Star in Gas Medicine as a Mitochondria-Targeting Nutrient via Activating Keap1-Nrf2 Antioxidant System.
    Danyu Cheng, Jiangang Long, Lin Zhao, Jiankang Liu.
      The gas molecules O2, NO, H2S, CO, and CH4, have been increasingly used for medical purposes. Other than these gas molecules, H2 is the smallest diatomic molecule in nature and has become a rising star in gas medicine in the past few decades. As a non-toxic and easily accessible gas, H2 has shown preventive and therapeutic effects on various diseases of the respiratory, cardiovascular, central nervous system, and other systems, but the mechanisms are still unclear and even controversial, especially the mechanism of H2 as a selective radical scavenger. Mitochondria are the main organelles regulating energy metabolism in living organisms as well as the main organelle of reactive oxygen species' generation and targeting. We propose that the protective role of H2 may be mainly dependent on its unique ability to penetrate every aspect of cells to regulate mitochondrial homeostasis by activating the Keap1-Nrf2 phase II antioxidant system rather than its direct free radical scavenging activity. In this review, we summarize the protective effects and focus on the mechanism of H2 as a mitochondria-targeting nutrient by activating the Keap1-Nrf2 system in different disease models. In addition, we wish to provide a more rational theoretical support for the medical applications of hydrogen.
    Keywords:  Keap1-Nrf2; Nrf2 activator; antioxidant; gas medicine; hydrogen; mitochondria
    DOI:  https://doi.org/10.3390/antiox12122062
  32. Heliyon. 2023 Nov;9(11): e21894
    Multifunctional effect of flavonoids from Millettia brandisiana against Alzheimer's disease pathogenesis.
    Puguh Novi Arsito, Pornthip Waiwut, Chavi Yenjai, Supakorn Arthan, Orawan Monthakantirat, Natsajee Nualkaew, Pitchayakarn Takomthong, Chantana Boonyarat.
      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuronal death. Fifteen flavonoids from Millettia brandisiana were evaluated for the multifunctional effect against AD pathogenesis, including butyrylcholine esterase (BuChE) inhibition, anti-amyloid beta (Aβ) aggregation and neuroprotection against hydrogen peroxide (H2O2) toxicity in differentiated human neuroblastoma SH-SY5Y cell. To understand the mechanism and structure-activity relationship, binding interactions between flavonoids and the BuChE and Aβ were investigated in silico. Furthermore, drug-likeness properties and ADMET parameters were evaluated in silico using SwissADME and pKCSM tools. All flavonoids exhibit a good drug-likeness profile. Six flavonoids have potency in BuChE inhibition, and four flavonoids show potency in anti-Aβ aggregation. Flavonoids with the 6″,6″-dimethylchromeno- [2″,3″:7,8]-flavone structure show a favorable multifunctional effect. In silico analysis showed that flavonoids can bind in various positions to the catalytic triad, anionic site, and acyl pocket. In Aβ1-42, potential flavonoids can attach to the central hydrophobic region and the C terminal hydrophobic and interfere with Aβ interchain hydrogen binding. When compared together, it can inhibit multifunctional action with a favorable ADMET parameter and drug-likeness profile. In addition, candidine can prevent neuronal damage in differentiated SH-SY5Y neuroblastoma cells induced by H2O2 in a dose-dependent manner.
    Keywords:  ADMET; Amyloid beta; Butyrylcholine esterase; Drug-likeness properties; Molecular docking; Multi-mode of action; Neuroprotection; Structure-activity relationship
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e21894
  33. Biol Trace Elem Res. 2023 Dec 22.
    Carvacrol Reduces Mercuric Chloride-Induced Testicular Toxicity by Regulating Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Histopathological Changes.
    Hasan Şimşek, Cihan Gür, Sefa Küçükler, Mustafa İleritürk, Nurhan Akaras, Mehmet Öz, Fatih Mehmet Kandemir.
      Mercuric chloride (HgCl2) is a heavy metal that is toxic to the human body. Carvacrol (CAR) is a flavonoid found naturally in plants and has many biological and pharmacological activities including anti-inflammatory, antioxidant, and anticancer activities. This study aimed to investigate the efficacy of CAR in HgCl2-induced testicular tissue damage. HgCl2 was administered intraperitoneally at a dose of 1.23 mg/kg body weight alone or in combination with orally administered CAR (25 mg/kg and 50 mg/kg body weight) for 7 days. Biochemical and histological methods were used to investigate oxidative stress, inflammation, apoptosis, and autophagy pathways in testicular tissue. CAR treatment increased HgCl2-induced decreased antioxidant enzyme (SOD, CAT, and GPx) activities and GSH levels. In addition, CAR reduced MDA levels, a marker of lipid peroxidation. CAR decreased the levels of inflammatory mediators NF-κB, TNF-α, IL-1β, COX-2, iNOS, MAPK14, MAPK15, and JNK. The increases in apoptotic Bax and Caspase-3 with HgCl2 exposure decreased with CAR, while the decreased antiapoptotic Bcl-2 level increased. CAR reduced HgCl2-induced autophagy damage by increasing Beclin-1, LC3A, and LC3B levels. Overall, the data from this study suggested that testicular tissue damage associated with HgCl2 toxicity can be mitigated by CAR administration.
    Keywords:  Apoptosis; Carvacrol; Inflammation; Mercuric chloride; Oxidative stress; Testicular toxicity
    DOI:  https://doi.org/10.1007/s12011-023-04022-2
  34. Antioxidants (Basel). 2023 Nov 23. pii: 2034. [Epub ahead of print]12(12):
    Hyperbaric Oxygen Therapy Alleviates Memory and Motor Impairments Following Traumatic Brain Injury via the Modulation of Mitochondrial-Dysfunction-Induced Neuronal Apoptosis in Rats.
    Reem Sakas, Katya Dan, Doron Edelman, Saher Abu-Ata, Aviv Ben-Menashe, Yaseen Awad-Igbaria, Jean Francois-Soustiel, Eilam Palzur.
      Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young adults, characterized by primary and secondary injury. Primary injury is the immediate mechanical damage, while secondary injury results from delayed neuronal death, often linked to mitochondrial damage accumulation. Hyperbaric oxygen therapy (HBOT) has been proposed as a potential treatment for modulating secondary post-traumatic neuronal death. However, the specific molecular mechanism by which HBOT modulates secondary brain damage through mitochondrial protection remains unclear. Spatial learning, reference memory, and motor performance were measured in rats before and after Controlled Cortical Impact (CCI) injury. The HBOT (2.5 ATA) was performed 4 h following the CCI and twice daily (12 h intervals) for four consecutive days. Mitochondrial functions were assessed via high-resolution respirometry on day 5 following CCI. Moreover, IHC was performed at the end of the experiment to evaluate cortical apoptosis, neuronal survival, and glial activation. The current result indicates that HBOT exhibits a multi-level neuroprotective effect. Thus, we found that HBOT prevents cortical neuronal loss, reduces the apoptosis marker (cleaved-Caspase3), and modulates glial cell proliferation. Furthermore, HBO treatment prevents the reduction in mitochondrial respiration, including non-phosphorylation state, oxidative phosphorylation, and electron transfer capacity. Additionally, a superior motor and spatial learning performance level was observed in the CCI group treated with HBO compared to the CCI group. In conclusion, our findings demonstrate that HBOT during the critical period following the TBI improves cognitive and motor damage via regulating glial proliferation apoptosis and protecting mitochondrial function, consequently preventing cortex neuronal loss.
    Keywords:  apoptosis; hyperbaric oxygen therapy (HBOT); mitochondria respiration; secondary brain injury; traumatic brain injury
    DOI:  https://doi.org/10.3390/antiox12122034
  35. Molecules. 2023 Dec 07. pii: 7988. [Epub ahead of print]28(24):
    Neuroprotective Effects of Aldehyde-Reducing Composition in an LPS-Induced Neuroinflammation Model of Parkinson's Disease.
    Sora Kang, Youngjin Noh, Seung Jun Oh, Hye Ji Yoon, Suyeol Im, Hung Taeck Kwon, Youngmi Kim Pak.
      Parkinson's disease (PD) is a complex neurodegenerative disease in which neuroinflammation and oxidative stress interact to contribute to pathogenesis. This study investigates the in vivo neuroprotective effects of a patented yeast extract lysate in a lipopolysaccharide (LPS)-induced neuroinflammation model. The yeast extract lysate, named aldehyde-reducing composition (ARC), exhibited potent antioxidant and anti-aldehyde activities in vitro. Oral administration of ARC at 10 or 20 units/kg/day for 3 days prior to intraperitoneal injection of LPS (10 mg/kg) effectively preserved dopaminergic neurons in the substantia nigra (SN) and striatum by preventing LPS-induced cell death. ARC also normalized the activation of microglia and astrocytes in the SN, providing further evidence for its neuroprotective properties. In the liver, ARC downregulated the LPS-induced increase in inflammatory cytokines and reversed the LPS-induced decrease in antioxidant-related genes. These findings indicate that ARC exerts potent antioxidant, anti-aldehyde, and anti-inflammatory effects in vivo, suggesting its potential as a disease-modifying agent for the prevention and treatment of neuroinflammation-related diseases, including Parkinson's disease.
    Keywords:  ALDH; Parkinson’s disease; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3390/molecules28247988
  36. Cell Commun Signal. 2023 Dec 15. 21(1): 357
    Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis.
    Wenxin Tang, Chaoying Yan, Shuxuan He, Mengyu Du, Bo Cheng, Bin Deng, Shan Zhu, Yansong Li, Qiang Wang.
       BACKGROUND: Type 2 diabetes mellitus (T2DM) induced diabetes-associated cognitive dysfunction (DACD) that seriously affects the self-management of T2DM patients, is currently one of the most severe T2DM-associated complications, but the mechanistic basis remains unclear. Mitochondria are highly dynamic organelles, whose function refers to a broad spectrum of features such as mitochondrial dynamics, mitophagy and so on. Mitochondrial abnormalities have emerged as key determinants for cognitive function, the relationship between DACD and mitochondria is not well understood.
    METHODS: Here, we explored the underlying mechanism of mitochondrial dysfunction of T2DM mice and HT22 cells treated with high glucose/palmitic acid (HG/Pal) focusing on the mitochondrial fission-mitophagy axis with drug injection, western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of caveolin-1 (cav-1) in T2DM induced mitochondrial dysfunction and synaptic alteration through viral transduction.
    RESULTS: As previously reported, T2DM condition significantly prompted hippocampal mitochondrial fission, whereas mitophagy was blocked rather than increasing, which was accompanied by dysfunctional mitochondria and impaired neuronal function. By contrast, Mdivi-1 (mitochondrial division inhibitor) and urolithin A (mitophagy activator) ameliorated mitochondrial and neuronal function and thereafter lead to cognitive improvement by inhibiting excessive mitochondrial fission and giving rise to mitophagy, respectively. We have previously shown that cav-1 can significantly improve DACD by inhibiting ferroptosis. Here, we further demonstrated that cav-1 could not only inhibit mitochondrial fission via the interaction with GSK3β to modulate Drp1 pathway, but also rescue mitophagy through interacting with AMPK to activate PINK1/Parkin and ULK1-dependent signlings.
    CONCLUSIONS: Overall, our data for the first time point to a mitochondrial fission-mitophagy axis as a driver of neuronal dysfunction in a phenotype that was exaggerated by T2DM, and the protective role of cav-1 in DACD. Graphic Summary Illustration. In T2DM, excessive mitochondrial fission and impaired mitophagy conspire to an altered mitochondrial morphology and mitochondrial dysfunction, with a consequent neuronal damage, overall suggesting an unbalanced mitochondrial fission-mitophagy axis. Upon cav-1 overexpression, GSK3β and AMPK are phosphorylated respectively to activate Drp1 and mitophagy-related pathways (PINK1 and ULKI), ultimately inhibits mitochondrial fission and enhances mitophagy. In the meantime, the mitochondrial morphology and neuronal function are rescued, indicating the protective role of cav-1 on mitochondrial fission-mitophagy axis. Video Abstract.
    Keywords:  Caveolin-1; Diabetes-associated cognitive dysfunction; Mitochondrial fission; Mitophagy
    DOI:  https://doi.org/10.1186/s12964-023-01328-5
  37. Neuropharmacology. 2023 Dec 15. pii: S0028-3908(23)00404-5. [Epub ahead of print]245 109814
    Defective autophagy contributes to bupivacaine-induced aggravation of painful diabetic neuropathy in db/db mice.
    Keke Fan, Qinming Liao, Pengfei Yuan, Rui Xu, Zhongjie Liu.
      Current evidence suggests that hyperactivated or impaired autophagy can lead to neuronal death. The effect of local anesthetics on painful diabetic neuropathy (PDN) and the role of autophagy in the above pathological process remain unclear, warranting further studies. So, PDN models were established by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in leptin gene-mutation (db/db) mice. Wild type (WT) and PDN mice received intrathecal 0.75% bupivacaine or/with intraperitoneal drug treatment (rapamycin or bafilomycin A1). Subsequently, the PWT and PWL were measured to assess hyperalgesia at 6 h, 24 h, 30 h, and 48 h after intrathecal bupivacaine. Also, sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) were measured before and 48 h after intrathecal bupivacaine treatment. The spinal cord tissue of L4-L6 segments and serum were harvested to evaluate the change of autophagy, oxidative stress, oxidative injury, and apoptosis. We found that bupivacaine induced the activation of autophagy but did not affect the pain threshold, SNCV and MNCV in WT mice at predefined time points. Conversely, bupivacaine lowered autophagosome generation and degradation, slowed SNCV and aggravated spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. The autophagy activator (rapamycin) could decrease spinal dorsal horn neuron oxidative injury, alleviate the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Meanwhile, the autophagy inhibitor (bafilomycin A1) could exacerbate spinal dorsal horn neuron oxidative injury, the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Our results showed that bupivacaine could induce defective autophagy, slowed SNCV and aggravate spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. Restoring autophagy may represent a potential therapeutic approach against nerve injury in PDN patients with local anesthesia and analgesia.
    Keywords:  Anesthetic drugs; Autophagy; Bupivacaine; Diabetes mellitus; Neuropathic pain; Oxidative stress
    DOI:  https://doi.org/10.1016/j.neuropharm.2023.109814
  38. J Pharm Pharmacol. 2023 Dec 16. pii: rgad114. [Epub ahead of print]
    Arctigenin attenuated spatial memory impairment in pR5 mice by regulating mitochondrial energy metabolism.
    Chao Yang, Ding Dan, Jia Xu, Chaoming Qiu, Kaiwu He, Chang-E Zhang, Shangming Li, Xifei Yang, Pingyi Xu, Feiqi Zhu.
       OBJECTIVES: Arctigenin (ATG) is a natural product with a variety of biological activity, which can improve the pathological changes of Alzheimer's disease (AD) model mice through multiple mechanisms. This study aims to further elucidate the potential mechanism by which ATG improves memory impairment in AD mice.
    METHODS: Here, we used pR5 mice as an experimental model, and ATG was administered continuously for 90 days. Novel object recognition, Y-maze, and Morris water maze were used to evaluate the therapeutic effect of ATG on memory impairment in AD mice. Immunohistochemical and immunofluorescence analyses were used to evaluate the effects of ATG on tau hyperphosphorylation and neuroinflammation, respectively. Finally, proteomics techniques were used to explore the possible mechanism of ATG.
    KEY FINDINGS: ATG significantly improved memory impairment in pR5 mice and inhibited tau phosphorylation in the hippocampus and neuroinflammation in the cortex. According to the proteomic analysis, the altered cognitive function of ATG was associated with the proteins of the tricarboxylic acid cycle and the electron transport chain.
    CONCLUSION: These results suggest that ATG is a potential therapeutic agent for diseases related to aberrant energy metabolism that can treat AD by improving mitochondrial function.
    Keywords:  Alzheimer’s disease; aberrant energy metabolism; arctigenin; mitochondria; proteomics
    DOI:  https://doi.org/10.1093/jpp/rgad114
  39. Neuroreport. 2023 Dec 22.
    Naringenin alleviates cognitive dysfunction in rats with cerebral ischemia/reperfusion injury through up-regulating hippocampal BDNF-TrkB signaling: involving suppression in neuroinflammation and oxidative stress.
    Xiao-Qin Zhu, Dong Gao.
      Cognitive dysfunction is one of the common complications of cerebral ischemia-reperfusion (CI/R) injury after ischemic stroke. Neuroinflammation and oxidative stress are the core pathological mechanism of CI/R injury. The activation of brain derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling antagonize cognitive dysfunction in a series of neuropathy. Naringenin (NAR) improves cognitive function in many diseases, but the role of NAR in CI/R injury-induced cognitive dysfunction remains unexplored. The study aimed to explore the potential protective effects of NAR in CI/R injury-induced cognitive dysfunction and underlying mechanism. The rats were exposed to transient middle cerebral artery occlusion (MCAO) and then treated with distilled water or NAR (50 or 100 mg/kg/day, p.o.) for 30 days. The Y-maze test, Novel object recognition test and Morris water maze test were performed to assess cognitive function. The levels of oxidative stress and inflammatory cytokines were measured by ELISA. The expressions of BDNF/TrkB signaling were detected by Western blot. NAR prevented cognitive impairment in MCAO-induced CI/R injury rats. Moreover, NAR inhibited oxidative stress (reduced levels of malondialdehyde and 4-hydroxynonenal, increased activities of superoxide dismutase and Glutathione peroxidase) and inflammatory cytokines (reduced levels of tumor necrosis factor-α, Interleukin-1β and Interleukin-6), up-regulated the expressions of BDNF and p-TrkB in hippocampus of MCAO-induced CI/R rats. NAR ameliorated cognitive dysfunction of CI/R rats via inhibiting oxidative stress, reducing inflammatory response, and up-regulating BDNF/TrkB signaling pathways in the hippocampus.
    DOI:  https://doi.org/10.1097/WNR.0000000000001989
  40. Cells. 2023 Dec 12. pii: 2821. [Epub ahead of print]12(24):
    Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia.
    Natali Joma, Issan Zhang, Germanna L Righetto, Laura McKay, Evan Rizzel Gran, Ashok Kakkar, Dusica Maysinger.
      The tumor microenvironment (TME) has emerged as a valuable therapeutic target in glioblastoma (GBM), as it promotes tumorigenesis via an increased production of reactive oxygen species (ROS). Immune cells such as microglia accumulate near the tumor and its hypoxic core, fostering tumor proliferation and angiogenesis. In this study, we explored the therapeutic potential of natural polyphenols with antioxidant and anti-inflammatory properties. Notably, flavonoids, including fisetin and quercetin, can protect non-cancerous cells while eliminating transformed cells (2D cultures and 3D tumoroids). We tested the hypothesis that fisetin and quercetin are modulators of redox-responsive transcription factors, for which subcellular location plays a critical role. To investigate the sites of interaction between natural compounds and stress-responsive transcription factors, we combined molecular docking with experimental methods employing proximity ligation assays. Our findings reveal that fisetin decreased cytosolic acetylated high mobility group box 1 (acHMGB1) and increased transcription factor EB (TFEB) abundance in microglia but not in GBM. Moreover, our results suggest that the most powerful modulator of the Nrf2-KEAP1 complex is fisetin. This finding is in line with molecular modeling and calculated binding properties between fisetin and Nrf2-KEAP1, which indicated more sites of interactions and stronger binding affinities than quercetin.
    Keywords:  fisetin; glioblastoma; microglia; natural polyphenols; oxidative stress; quercetin; reactive oxygen species; redox-responsive transcription factors; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells12242821
  41. Neuron. 2023 Dec 20. pii: S0896-6273(23)00836-X. [Epub ahead of print]111(24): 3901-3903
    Human-specific translational control of neuronal mitochondria and excitability.
    Alicia R Lane, Meghan E Wynne, Victor Faundez.
      How are human-specific brain bioenergetics and excitability connected? In this Neuron issue, Shen et al.1 reveal a human-specific interaction between RACK1 mRNA and FMRP. Reducing RACK1 mimics FMRP-dependent excitability and mitochondrial phenotypes, which can be reversed with mitochondrial-protective drugs. These findings suggest that FMRP-mediated translation adapts mitochondria to excitability energy demands.
    DOI:  https://doi.org/10.1016/j.neuron.2023.10.031
  42. Brain Res Bull. 2023 Dec 18. pii: S0361-9230(23)00263-0. [Epub ahead of print] 110838
    Electroacupuncture ameliorates chronic unpredictable mild stress-induced depression-like behavior and cognitive impairment through suppressing oxidative stress and neuroinflammation in rats.
    Tao Tong, Chongyao Hao, Junliang Shen, Siyu Liu, Simin Yan, Muhammad Shahzad Aslamc, Yiping Chen, Wenjie Chen, Jianguo Li, Yuhan Li, Jingyu Zeng, Meng Li, Zhuoran You, Tuergong Gulizhaerkezi, Simiao Wei, Anning Zhu, Xianjun Meng.
       BACKGROUND: Depression is associated with lowered mood, anxiety, anhedonia, cognitive impairments, and even suicidal tendencies in severe cases. Yet few studies have directed acupuncture's mechanism toward enhancing axonal repair correlated with synaptic plasticity and anti-inflammatory effects related to oxidative stress in the hippocampus.
    METHODS: Male Sprague-Dawley (SD) rats were randomly divided into control group (CON), chronic unpredictable mild stress (CUMS) group, CUMS + electroacupuncture group (EA), and CUMS + fluoxetine group (FLX) (n=10/group). Rats were given a 28-day treatment at the Shangxing (GV23) and Fengfu (GV16) acupoints with electroacupuncture or fluoxetine (2.1mg/kg).
    RESULTS: Rats exposed to CUMS induced depression-like behaviors and spatial learning-memory impairment, changed the ionized calcium binding adaptor molecule 1 (IBA-1), Vglut1, myelin basic protein (MBP), and postsynaptic density protein 95 (PSD95) level of hippocampal, increased the Nod-like receptor protein 3 (NLRP3), atypical squamous cell (ASC), Caspase level and hippocampal reactive oxygen species (ROS), and prompted the activation of Epha4-mediated signaling and an inflammatory response. Conversely, electroacupuncture administration reduced these changes and prevented depression-like behaviors and cognitive impairment. Electroacupuncture also promoted hippocampal expression of Sirtuin1(SIRT1), Nuclear factor erythroid 2-like (Nrf2), Heme oxygenase-1 (HO-1); reduced the expression of interleukin-1β (IL-1β), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-α); and prevented neural damage, particularly the synaptic myelin sheath, and neuroinflammation by regulating Eph receptor A4 (EphA4) in the hippocampal.
    CONCLUSION: These results indicate that electroacupuncture prevents depression-like behaviors with cognitive impairment and synaptic and neuronal damage, probably by reducing EphA4, which mediates ROS hyperfunction and the inflammatory response.
    Keywords:  Chronic unpredictable mild stress; Depression; Electroacupuncture; EphA4; Synaptic plasticity; Y-maze
    DOI:  https://doi.org/10.1016/j.brainresbull.2023.110838
  43. Biomolecules. 2023 Dec 13. pii: 1789. [Epub ahead of print]13(12):
    Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.
    Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Jose Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Mónica Álvarez-Córdoba, Manuel Munuera-Cabeza, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Ana Romero-González, Jose Antonio Sánchez-Alcázar.
      Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.
    Keywords:  ageing; mitochondria; mitochondrial biogenesis; mitochondrial diseases; mitochondrial dynamics; mitochondrial quality control mechanisms; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases; therapeutic target
    DOI:  https://doi.org/10.3390/biom13121789
  44. Acta Biomater. 2023 Dec 16. pii: S1742-7061(23)00725-0. [Epub ahead of print]
    A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease.
    Liling Ou, Zixia Wu, Xiao Hu, Jinyi Huang, Zhiqi Yi, Zehua Gong, Huaqiong Li, Ke Peng, Chang Shu, Leo H Koole.
      Dry eye disease (DED) is currently the most prevalent condition seen in ophthalmology outpatient clinics, representing a significant public health issue. The onset and progression of DED are closely associated with oxidative stress-induced inflammation and damage. To address this, an aldehyde-functionalized F127 (AF127) hydrogel eye drop delivering multifunctional antioxidant Cu2-xSe nanoparticles (Cu2-xSe NPs) was designed. The research findings revealed that the Cu2-xSe nanoparticles exhibit unexpected capabilities in acting as superoxide dismutase and glutathione peroxidase. Additionally, Cu2-xSe NPs possess remarkable efficacy in scavenging reactive oxygen species (ROS) and mitigating oxidative damage. Cu2-xSe NPs displayed promising therapeutic effects in a mouse model of dry eye. Detailed investigation revealed that the nanoparticles exert antioxidant, anti-apoptotic, and inflammation-mitigating effects by modulating the NRF2 and p38 MAPK signalling pathways. The AF127 hydrogel eye drops exhibit good adherence to the ocular surface through the formation of Schiff-base bonds. These findings suggest that incorporating antioxidant Cu2-xSe nanoparticles into a tissue-adhesive hydrogel could present a highly effective therapeutic strategy for treating dry eye disease and other disorders associated with reactive oxygen species. STATEMENT OF SIGNIFICANCE: A new formulation for therapeutic eye drops to be used in the treatment of dry eye disease (DED) was developed. The formulation combines copper-selenium nanoparticles (Cu2-xSe NPs) with aldehyde-functionalized Pluronic F127 (AF127). This is the first study to directly examine the effects of Cu2-xSe NPs in ophthalmology. The NPs exhibited antioxidant capabilities and enzyme-like properties. They effectively eliminated reactive oxygen species (ROS) and inhibited apoptosis through the NRF2 and p38 MAPK signalling pathways. Additionally, the AF127 hydrogel enhanced tissue adhesion by forming Schiff-base links. In mouse model of DED, the Cu2-xSe NPs@AF127 eye drops demonstrated remarkable efficacy in alleviating symptoms of DED. These findings indicate the potential of Cu2-xSe NPs as a readily available and user-friendly medication for the management of DED.
    Keywords:  Antioxidant; Cu(2−x)Se nanoparticles; Dry eye disease; F127; Ocular adhesive
    DOI:  https://doi.org/10.1016/j.actbio.2023.12.021
  45. Sci Rep. 2023 Dec 18. 13(1): 22540
    Renoprotective effects of extracellular fibroblast specific protein 1 via nuclear factor erythroid 2-related factor-mediated antioxidant activity.
    Naoki Takahashi, Seiji Yokoi, Hideki Kimura, Hironobu Naiki, Taiji Matsusaka, Yasuhiko Yamamoto, Kimihiko Nakatani, Kenji Kasuno, Masayuki Iwano.
      Podocyte expression of fibroblast specific protein 1 (FSP1) is observed in various types of human glomerulonephritis. Considering that FSP1 is secreted extracellularly and has been shown to have multiple biological effects on distant cells, we postulated that secreted FSP1 from podocytes might impact renal tubules. Our RNA microarray analysis in a tubular epithelial cell line (mProx) revealed that FSP1 induced the expression of heme oxygenase 1, sequestosome 1, solute carrier family 7, member 11, and cystathionine gamma-lyase, all of which are associated with nuclear factor erythroid 2-related factor (Nrf2) activation. Therefore, FSP1 is likely to exert cytoprotective effects through Nrf2-induced antioxidant activity. Moreover, in mProx, FSP1 facilitated Nrf2 translocation to the nucleus, increased levels of reduced glutathione, inhibited the production of reactive oxygen species (ROS), and reduced cisplatin-induced cell death. FSP1 also ameliorated acute tubular injury in mice with cisplatin nephrotoxicity, which is a representative model of ROS-mediated tissue injury. Similarly, in transgenic mice that express FSP1 specifically in podocytes, tubular injury associated with cisplatin nephrotoxicity was also mitigated. Extracellular FSP1 secreted from podocytes acts on downstream tubular cells, exerting renoprotective effects through Nrf2-mediated antioxidant activity. Consequently, podocytes and tubular epithelial cells have a remote communication network to limit injury.
    DOI:  https://doi.org/10.1038/s41598-023-49863-y
  46. Brain Sci. 2023 Nov 21. pii: 1610. [Epub ahead of print]13(12):
    Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration.
    Patrícia Marzola, Thayza Melzer, Eloisa Pavesi, Joana Gil-Mohapel, Patricia S Brocardo.
      Neuroplasticity refers to the ability of the brain to reorganize and modify its neural connections in response to environmental stimuli, experience, learning, injury, and disease processes. It encompasses a range of mechanisms, including changes in synaptic strength and connectivity, the formation of new synapses, alterations in the structure and function of neurons, and the generation of new neurons. Neuroplasticity plays a crucial role in developing and maintaining brain function, including learning and memory, as well as in recovery from brain injury and adaptation to environmental changes. In this review, we explore the vast potential of neuroplasticity in various aspects of brain function across the lifespan and in the context of disease. Changes in the aging brain and the significance of neuroplasticity in maintaining cognitive function later in life will also be reviewed. Finally, we will discuss common mechanisms associated with age-related neurodegenerative processes (including protein aggregation and accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation) and how these processes can be mitigated, at least partially, by non-invasive and non-pharmacologic lifestyle interventions aimed at promoting and harnessing neuroplasticity.
    Keywords:  aging; cognitive function; lifestyle interventions; neurodegeneration; neurodevelopment; neuroplasticity
    DOI:  https://doi.org/10.3390/brainsci13121610
  47. Toxicol Mech Methods. 2023 Dec 19. 1-21
    Eucalyptol regulates Nrf2 and NF-kB signaling and alleviates gentamicin-induced kidney injury in rats by downregulating oxidative stress, oxidative DNA damage, inflammation, and apoptosis.
    Gokhan Akcakavak, Filiz Kazak, Ozhan Karatas, Halil Alakus, Ibrahim Alakus, Omer Kirgiz, Zeynep Celik, Mehmet Zeki Yilmaz Deveci, Ozgur Ozdemir, Mehmet Tuzcu.
      Gentamicin, an aminoglycoside antibiotic, is nowadays widely used in the treatment of gram-negative microorganisms. The antimicrobial, anti-inflammatory, and antioxidant activities of eucalyptol, a type of saturated monoterpene, have been reported in many studies. The aim of this study was to examine the possible effects of eucalyptol on gentamicin-induced renal toxicity. A total of 32 rats were divided into 4 groups; Control (C), Eucalyptol (EUC), Gentamicin (GEN), and Gentamicin + Eucalyptol (GEN + EUC). In order to induce renal toxicity, 100 mg/kg gentamicin was administered intraperitoneally (i.p.) for 10 consecutive days in the GEN and GEN + EUC groups. EUC and GEN + EUC groups were given 100 mg/kg orally of eucalyptol for 10 consecutive days. Afterwards, rats were euthanized and samples were taken and subjected to histopathological, biochemical, immunohistochemical, and real-time PCR examinations. The blood urea nitrogen (BUN) and creatinine (CRE) levels were significantly decreased in the GEN + EUC group (0.76 and 0.69 fold, respectively) compared to the GEN group. The glutathione peroxidase (GPx) and and catalase (CAT) activities were significantly increased in the GEN + EUC group (1.35 and 2.67 fold, respectively) compared to the GEN group. In GEN group, Nuclear factor kappa B (NF-kB), Interleukin 1-beta (IL-1β), Inducible nitric oxide synthase (iNOS), Tumor necrosis factor-α (TNF-α), Caspase-3, 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and Nuclear factor erythroid 2-related factor (Nrf2) expression levels were found to be quite irregular. GEN + EUC group decreased the expressions of NF-kB, IL-1β, iNOS, TNF-α, Caspase-3, and 8-OHdG (0.55, 0.67, 0.54, 0.54, 0.63 and 0.67 fold, respectively), while it caused increased expression of Nrf2 (3.1 fold). In addition, eucalyptol treatment ameliorated the histopathological changes that occurred with gentamicin. The results of our study show that eucalyptol has anti-inflammatory, antioxidative, antiapoptotic, nephroprotective, and curative effects on gentamicin-induced nephrotoxicity.
    Keywords:  Gentamicin; apoptosis; eucalyptol; inflammation; nephrotoxicity; oxidative stress
    DOI:  https://doi.org/10.1080/15376516.2023.2297234
  48. Neurol Res. 2023 Dec 20. 1-11
    Minocycline mitigates tau pathology via modulating the TLR-4/NF-кβ signalling pathway in the hippocampus of neuroinflammation rat model.
    Entesar Yaseen Abdo Qaid, Zuraidah Abdullah, Rahimah Zakaria, Idris Long.
       INTRODUCTION: The neuroinflammatory response was seen to impact the formation of phosphorylated tau protein in Alzheimer's disease (AD). This study aims to investigate the molecular mechanism of minocycline in reducing phosphorylated tau protein formation in the hippocampus of lipopolysaccharide (LPS)-induced rats.
    METHODS: Fifty adult male Sprague Dawley (SD) rats were randomly allocated to 1 of 5 groups: control, LPS (5 mg/kg), LPS + minocycline (25 mg/kg), LPS + minocycline (50 mg/kg) and LPS + memantine (10 mg/kg). Minocycline and memantine were administered intraperitoneally (i.p) for two weeks, and LPS was injected i.p. once on day 5. ELISA was used to determine the level of phosphorylated tau protein in SD rats' hippocampal tissue. The density and expression of Toll-like receptor-4 (TLR-4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кβ), tumour necrosis factor-alpha (TNF-α), and cyclooxygenase (COX)-2 were determined using Western blot and immunohistochemistry.
    RESULTS: Minocycline, like memantine, prevented LPS-induced increasein phosphorylated tau protein level suggested via reduced density and expression of TLR-4, NF-кβ, TNF-αand COX-2 proteins in rat hippocampal tissue. Interestingly, higher doses were shown to be more neuroprotective than lower doses.
    CONCLUSION: This study suggests that minocycline suppresses the neuroinflammation signalling pathway and decreased phosphorylated tau protein formation induced by LPS in a dose-dependent manner. Minocycline can be used as a preventative and therapeutic drug for neuroinflammatory diseases such as AD.
    Keywords:  Lipopolysaccharide; hippocampus; memantine; minocycline; neuroinflammation
    DOI:  https://doi.org/10.1080/01616412.2023.2296754
  49. Int J Mol Sci. 2023 Dec 12. pii: 17380. [Epub ahead of print]24(24):
    Improved Glycaemic Control and Nephroprotective Effects of Empagliflozin and Paricalcitol Co-Therapy in Mice with Type 2 Diabetes Mellitus.
    Abdulrahman Mujalli, Wesam F Farrash, Ahmad A Obaid, Anmar A Khan, Riyad A Almaimani, Shakir Idris, Mohamed E Elzubier, Elshiekh Babiker A Khidir, Akhmed Aslam, Faisal Minshawi, Mohammad A Alobaidy, Adel B Alharbi, Hussain A Almasmoum, Mazen Ghaith, Khalid Alqethami, Bassem Refaat.
      Herein, we measured the antidiabetic and nephroprotective effects of the sodium-glucose cotransporter-2 inhibitor (empagliflozin; SGLT2i) and synthetic active vitamin D (paricalcitol; Pcal) mono- and co-therapy against diabetic nephropathy (DN). Fifty mice were assigned into negative (NC) and positive (PC) control, SGLT2i, Pcal, and SGLT2i+Pcal groups. Following establishment of DN, SGLT2i (5.1 mg/kg/day) and/or Pcal (0.5 µg/kg/day) were used in the designated groups (5 times/week/day). DN was affirmed in the PC group by hyperglycaemia, dyslipidaemia, polyuria, proteinuria, elevated urine protein/creatinine ratio, and abnormal renal biochemical parameters. Renal SREBP-1 lipogenic molecule, adipokines (leptin/resistin), pro-oxidant (MDA/H2O2), pro-inflammatory (IL1β/IL6/TNF-α), tissue damage (iNOS/TGF-β1/NGAL/KIM-1), and apoptosis (TUNEL/Caspase-3) markers also increased in the PC group. In contrast, renal lipolytic (PPARα/PPARγ), adiponectin, antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL10) molecules decreased in the PC group. Both monotherapies increased insulin levels and mitigated hyperglycaemia, dyslipidaemia, renal and urine biochemical profiles alongside renal lipid regulatory molecules, inflammation, and oxidative stress. While SGLT2i monotherapy showed superior effects to Pcal, their combination demonstrated enhanced remedial actions related to metabolic control alongside renal oxidative stress, inflammation, and apoptosis. In conclusion, SGLT2i was better than Pcal monotherapy against DN, and their combination revealed better nephroprotection, plausibly by enhanced glycaemic control with boosted renal antioxidative and anti-inflammatory mechanisms.
    Keywords:  INOS; KIM-1; NGAL; SGLT2 inhibitor; TGF-β; adipokines; vitamin D
    DOI:  https://doi.org/10.3390/ijms242417380
  50. Biomed Pharmacother. 2023 Dec 18. pii: S0753-3322(23)01810-3. [Epub ahead of print]170 116012
    Berberine exerts antidepressant effects in vivo and in vitro through the PI3K/AKT/CREB/BDNF signaling pathway.
    Yueheng Tang, Hao Su, Kexin Nie, Hongzhan Wang, Yang Gao, Shen Chen, Fuer Lu, Hui Dong.
       BACKGROUND: Depression, a global neuropsychiatric disorder, brings a serious burden to patients and society as its incidence continues to rise. Berberine is one of the main compounds of a variety of Chinese herbal medicines and has been shown to have multiple pharmacological effects. However, whether berberine can exert antidepressant effects in vivo and in vitro and its related mechanisms remain to be explored.
    METHODS: The chronic restraint stress (CRS) method and corticosterone (CORT) were applied to simulate depression-like behavior in vivo and neuronal apoptosis in vitro, respectively. The antidepressant effects of berberine were evaluated by behavioral tests and changes in the content of monoamine neurotransmitters. Inflammatory cytokines were detected and immunofluorescence staining was used to observe the expression levels of apoptosis-related proteins. RT-qPCR and Western blot were used to examine the mRNA and protein expression (or phosphorylation) levels of biomarkers of the PI3K/AKT/CREB/BDNF signaling pathways.
    RESULTS: Behavioral tests and levels of neurotransmitters proved that berberine could effectively ameliorate depression-like symptoms in CRS mice. Meanwhile, the results of ELISA and immunofluorescence staining showed that berberine could alleviate inflammatory status and reduce cell apoptosis in vivo and in vitro. Moreover, the changes of the PI3K/AKT/CREB/BDNF signaling pathway induced by CRS or CORT in mouse hippocampus or HT-22 cells were significantly reversed by berberine.
    CONCLUSION: Our current study suggested that berberine could exert antidepressant effects in vitro and in vivo, which may be associated with the PI3K/AKT/CREB/BDNF signaling pathway.
    Keywords:  Apoptosis; Berberine; CREB/BDNF; Depression; PI3K/AKT
    DOI:  https://doi.org/10.1016/j.biopha.2023.116012
  51. Biomed Pharmacother. 2023 Dec 19. pii: S0753-3322(23)01851-6. [Epub ahead of print]170 116053
    Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling.
    Yuqing Yang, Liang Gao, Jia Meng, Hong Li, Xiaobai Wang, Ying Huang, Jie Wu, Honglin Ma, Dongying Yan.
       BACKGROUND: Endoplasmic reticulum (ER) stress-induced nerve cell damage has been known to be a hallmark feature of Mn-induced parkinsonism pathogenesis. However, several compensatory machineries, such as unfolded protein response (UPR), autophagy, and immune response, play an essential role in this damage, and the underlying molecular mechanisms are poorly understood.
    METHODS: Neurobehavioral impairment was assessed using catwalk gait analysis and open field test. RNA-seq analyzed the differentially expressed genes (DEGs). TUNEL staining and immunohistochemical analysis evaluated the nerve cells apoptosis and microglial cell activation. Flow cytometry assay measured microglia M1/M2 polarization. Western blotting measured protein expression. Immunofluorescence staining was used to observe the target molecules' subcellular localization.
    RESULTS: The study revealed that Mn caused a reduction in motor capacity, nerve cell apoptosis, and microglia activation with an imbalance in M1/M2 polarization, coupled with NF-κB signaling and PERK signaling activation. 4-PBA pretreatment could counteract these effects, while 3-MA administration exacerbated them. Additionally, autophagy could be activated by Mn. This activation could be further upregulated by 4-PBA pretreatment, whereas it was suppressed under 3-MA administration. Mn also decreased inactive GSK-3β, increased STAT3 signaling activation, and increased colocalization of GSK-3β and STAT3. These effects were strengthened by 4-PBA pretreatment, while 3-MA administration reversed them.
    DISCUSSION: This study suggests that autophagy and M2 microglia polarization might be protective in Mn-induced ER stress damage, possibly through GSK-3β-ULK1 autophagy signaling and STAT3 signaling activation.
    Keywords:  Autophagy; ER stress; GSK-3β; Manganese; Microglia polarization; Parkinsonism
    DOI:  https://doi.org/10.1016/j.biopha.2023.116053
  52. J Neuroimmune Pharmacol. 2023 Dec 19.
    Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson's Disease.
    Pranay Srivastava, Shuhei Nishiyama, Fang Zhou, Sonia H Lin, Akriti Srivastava, Chienwen Su, Yuehang Xu, Weiyi Peng, Michael Levy, Michael Schwarzschild, Xiqun Chen.
       BACKGROUND: Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson's disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable central nervous system (CNS) permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells. The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD.
    METHODS: C57BL/6 mice were treated systemically with MPTP.HCl (20 mg/kg) and LPS (1 mg/kg) from day 1 to day 4 and NDP-MSH (400 µg/kg) or vehicle from day 1 to day 12 following which the mice were sacrificed. Peripheral and CNS immune cells were phenotyped and inflammatory markers were measured. The nigrostriatal dopaminergic system was assessed behaviorally, chemically, immunologically, and pathologically. To understand the role of regulatory T cells (Tregs) in this model, CD25 monoclonal antibody was used to deplete CD25 + Tregs.
    RESULTS: Systemic NDP-MSH administration significantly attenuated striatal dopamine depletion and nigral dopaminergic neuron loss induced by MPTP + LPS. It improved the behavioral outcomes in the pole test. Mc1r mutant mice injected with NDP-MSH in the MPTP and LPS paradigm showed no changes in striatal dopamine levels suggesting that the NDP-MSH acts through the MC1R pathway. Although no NDP-MSH was detected in the brain, peripheral, NDP-MSH attenuated neuroinflammation as observed by diminished microglial activation in the nigral region, along with reduced TNF-α and IL1β levels in the ventral midbrain. Depletion of Tregs was associated with diminished neuroprotective effects of NDP-MSH.
    CONCLUSIONS: Our study demonstrates that peripherally acting NDP-MSH confers protection on dopaminergic nigrostriatal neurons and reduces hyperactivated microglia. NDP-MSH modulates peripheral immune responses, and Tregs may be involved in the neuroprotective effect of NDP-MSH.
    Keywords:  BBB; LPS; MPTP; Melanocortin 1 Receptor; Parkinson’s Disease; Regulatory T Cells (Tregs)
    DOI:  https://doi.org/10.1007/s11481-023-10094-7
  53. J Ethnopharmacol. 2023 Dec 20. pii: S0378-8741(23)01508-8. [Epub ahead of print] 117638
    Gynura divaricata (L.) DC. promotes diabetic wound healing by activating Nrf2 signaling in diabetic rats.
    Caimin Xu, Lixin Hu, Jing Zeng, Anguo Wu, Shilong Deng, Zijuan Zhao, Kang Geng, Jiesi Luo, Long Wang, Xiaogang Zhou, Wei Huang, Yang Long, Jianying Song, Silin Zheng, Jianming Wu, Qi Chen.
       THE ETHNOPHARMACOLOGICAL SIGNIFICANCE: Diabetic chronic foot ulcers pose a significant therapeutic challenge as a result of the oxidative stress caused by hyperglycemia. Which impairs angiogenesis and delays wound healing, potentially leading to amputation. Gynura divaricata (L.) DC. (GD), a traditional Chinese herbal medicine with hypoglycemic effects, has been proposed as a potential therapeutic agent for diabetic wound healing. However, the underlying mechanisms of its effects remain unclear.
    AIM OF THE STUDY: In this study, we aimed to reveal the effect and potential mechanisms of GD on accelerating diabetic wound healing in vitro and in vivo.
    MATERIALS AND METHODS: The effects of GD on cell proliferation, apoptosis, reactive oxygen species (ROS) production, migration, mitochondrial membrane potential (MMP), and potential molecular mechanisms were investigated in high glucose (HG) stimulated human umbilical vein endothelial cells (HUVECs) using CCK-8, flow cytometry assay, wound healing assay, immunofluorescence, DCFH-DA staining, JC-1 staining, and Western blot. Full-thickness skin defects were created in STZ-induced diabetic rats, and wound healing rate was tracked by photographing them every day. HE staining, immunohistochemistry, and Western blot were employed to investigate the effect and molecular mechanism of GD on wound healing in diabetic rats.
    RESULTS: GD significantly improved HUVEC survival, decreased apoptosis, lowered ROS production, restored MMP, improved migration ability, and raised VEGF expression. The use of Nrf2-siRNA completely abrogated these effects. Topical application of GD promoted angiogenesis and granulation tissue growth, resulting in faster healing of diabetic wounds. The expression of VEGF, CD31, and VEGFR was elevated in the skin tissue of diabetic rats after GD treatment, which upregulated HO-1, NQO-1, and Bcl-2 expression while downregulating Bax expression via activation of the Nrf2 signaling pathway.
    CONCLUSION: The findings of this study indicate that GD has the potential to serve as a viable alternative treatment for diabetic wounds. This potential arises from its ability to mitigate the negative effects of oxidative stress on angiogenesis, which is regulated by the Nrf2 signaling pathway. The results of our study offer valuable insights into the therapeutic efficacy of GD in the treatment of diabetic wounds, emphasizing the significance of directing interventions towards the Nrf2 signaling pathway to mitigate oxidative stress and facilitate the process of angiogenesis.
    Keywords:  Angiogenesis; Diabetic wound healing; Gynura divaricata (L.) DC.; Nrf2; Oxidative stress
    DOI:  https://doi.org/10.1016/j.jep.2023.117638
  54. Ecotoxicol Environ Saf. 2023 Dec 18. pii: S0147-6513(23)01345-3. [Epub ahead of print]270 115841
    Modulatory mechanisms of copperII-albumin complex toward N-nitrosodiethylamine-induced neurotoxicity in mice via regulating oxidative damage, inflammatory, and apoptotic signaling pathways.
    Obeid Shanab, Laila Mostafa, Ahmed Abdeen, Rania Atia, Ahmed Y Nassar, Mohammed Youssef, Samah F Ibrahim, Zainab M Maher, Florin Imbrea, Liana Fericean, Khaled Ghareeb, Tabinda Hasan, Heba I Ghamry, Reem T Atawia, Omar Sadeq, Afaf Abdelkader.
      N-nitrosodiethylamine (ND) is an extremely toxic unavoidable environmental contaminant. CopperII-albumin (CuAB) complex, a newly developed Cu complex, showed antioxidant and anti-inflammatory potential. Hereby, we explored the plausible neuroprotective role of CuAB complex toward ND-evoked neurotoxicity in mice. Twenty-four male mice were sorted into 4 groups (6 mice each). Control group, mice were administered oral distilled water; and CuAB group, mice received CuAB complex at a dose of 817 µg/kg orally, three times weekly. In ND group, ND was given intraperitoneally (50 mg/kg body weight, once weekly for 6 w). CuAB+ND group, mice were administered a combination of CuAB and ND. The brain was quickly extracted upon completion of the experimental protocol for the evaluation of the oxidative/antioxidative markers, inflammatory cytokines, and histopathological examination. Oxidative stress was induced after ND exposure indicated by a reduction in GSH and SOD1 level, with increased MDA level. In addition, decreased expression of SOD1 proteins, Nrf2, and 5-HT mRNA expression levels were noticed. An apoptotic cascade has also been elicited, evidenced by overexpression of Cyt c, Cl. Casp 3. In addition, increased regulation of proinflammatory genes (TNF-α, IL-6, iNOS, Casp1, and NF-κB (p65/p50); besides, increment of protein expression of P-IKBα and reduced expression of IKBα. Pretreatment with CuAB complex significantly ameliorated ND neuronal damage. Our results recommend CuAB complex supplementation because it exerts neuroprotective effects against ND-induced toxicity.
    Keywords:  Apoptosis; Inflammation; N-nitrosodiethylamine; Neurodegenerative diseases; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.115841
  55. ACS Med Chem Lett. 2023 Dec 14. 14(12): 1700-1706
    Tuning the Reactivity of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Optimal in Vivo Efficacy.
    Vadim Markovtsov, Matthew A J Duncton, Art Bagos, Sothy Yi, Sylvia Braselmann, Somasekhar Bhamidipati, Ihab S Darwish, Jiaxin Yu, Alexander M Owyang, Beth Fernandez, Bhushan Samant, Gary Park, Esteban S Masuda, Simon J Shaw.
      Dimethyl fumarate 1 is approved for the treatment of multiple sclerosis but is also associated with off-target activation of the niacin receptor. By using a tetrazolone or triazolone bioisostere approach to the fumarate and vinyl sulfone series of Nrf2 activators, we have optimized the electrophilicity of the double bond to tune the on-target Nrf2 activation with PK properties to achieve efficacy in animal models of multiple sclerosis. The study linked highly potent, highly electrophilic molecules to low plasma stability and, subsequently, limited efficacy. By contrast, a sulfonylvinyltriazolone 17 retains on-target potency but shows much weaker electrophilic potential. As a consequence, in vivo high exposures of 17 are obtained, resulting in efficacy in the EAE model similar to that observed for DMF. 17 (R079) is Ames negative, is not cytotoxic to cells, and shows little inhibition of either the niacin receptor or a panel of off-target receptors.
    DOI:  https://doi.org/10.1021/acsmedchemlett.3c00336
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