bims-nurfan Biomed News
on NRF2 and Neurological Diseases
Issue of 2023‒12‒03
39 papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

  1. Heliyon. 2023 Nov;9(11): e21800
      Alzheimer's disease (AD) is a progressive neurodegenerative disease that has still not been effectively treated. Paeoniflorin is a traditional Chinese medicine with potential neuroprotective effects against brain injury; however, the beneficial effects and mechanisms of action in AD have not been clarified. We aimed to explore the mechanisms of action of paeoniflorin in AD using network pharmacology and experimental validation. Network pharmacology analysis revealed 30 candidate targets through the intersection of the targets of paeoniflorin and related genes in AD, which were mainly enriched in oxidative stress and inflammation. Moreover, key targets of paeoniflorin against AD, namely Nrf2 (encoded by NFE2L2) and TLR4, were screened and found to be closely related to oxidative stress and inflammation. Subsequent in vivo experiments revealed that paeoniflorin treatment improved the cognition of APP/PS1 mice by ameliorating oxidative stress and neuroinflammation, which were associated with the upregulation of Nrf2 and HO1, and the downregulation of TLR4. Collectively, the present study demonstrates that paeoniflorin alleviates cognitive impairment in AD by regulating oxidative stress and neuroinflammation, and that Nrf2, HO1, and TLR4 could be key targets.
    Keywords:  Alzheimer's disease; Network pharmacology; Neuroinflammation; Oxidative stress; Paeoniflorin
  2. Neuroscience. 2023 Nov 29. pii: S0306-4522(23)00532-8. [Epub ahead of print]
      Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by abnormal α-synuclein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, as well as progressive death of dopaminergic neurons in the substantia nigra. Molecular chaperones play a role in stabilizing proteins and helping them achieve their proper structure. Previous studies have shown that overexpression of heat shock protein 90 (HSP90) can lead to the death of dopaminergic neurons associated with PD. Inhibiting HSP90 is considered a potential treatment approach for neurodegenerative disorders, as it may reduce protein aggregation and related toxicity, as well as suppress various forms of regulated cell death (RCD). This review provides an overview of HSP90 and its role in PD, focusing on its modulation of proteostasis and quality control of LRRK2. The review also explores the effects of HSP90 on different types of RCD, such as apoptosis, chaperone-mediated autophagy (CMA), necroptosis, and ferroptosis. Additionally, it discusses HSP90 inhibitors that have been tested in PD models. We will highlight the under-investigated neuroprotective effects of HSP90 inhibition, including modulation of oxidative stress, mitochondrial dysfunction, PINK/PARKIN, heat shock factor 1 (HSF1), histone deacetylase 6 (HDAC6), and the PHD2-HSP90 complex-mediated mitochondrial stress pathway. By examining previous literature, this review uncovers overlooked neuroprotective mechanisms and emphasizes the need for further research on HSP90 inhibitors as potential therapeutic strategies for PD. Finally, the review discusses the potential limitations and possibilities of using HSP90 inhibitors in PD therapy.
    Keywords:  Chaperones; Heat shock protein 90; Parkinson's disease; Regulated cell death; chaperone-mediated autophagy
  3. Heliyon. 2023 Nov;9(11): e21695
      Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, which is distinguished by the loss of dopaminergic (DA) neurons in the substantia nigra and the formation of intraneuronal. Numerous studies showed that the damage and dysfunction of mitochondria may play key roles in DA neuronal loss. Thus, it is necessary to seek therapeutic measures for PD targeting mitochondrial function and biogenesis. In this study, through screening the purchased compound library, we found that marine derived vidarabine had significant neuroprotective effects against rotenone (ROT) induced SH-SY5Y cell injury. Further studies indicated that vidarabine pretreatment significantly protected ROT-treated SH-SY5Y cells from toxicity by preserving mitochondrial morphology, improving mitochondrial function, and reducing cell apoptosis. Vidarabine also reduced the oxidative stress and increased the expression levels of PGC-1α, NRF1, and TFAM proteins, which was accompanied by the increased mitochondrial biogenesis. However, the neuroprotective effects of vidarabine were counteracted in the presence of SIRT1-specific inhibitor Ex-527. Besides, vidarabine treatment attenuated the weight loss, alleviated the motor deficits and inhibited the neuronal injury in the MPTP induced mouse model. Thus, vidarabine may exert neuroprotective effects via a mechanism involving specific connections between the SIRT1-dependent mitochondrial biogenesis and its antioxidant capacity, suggesting that vidarabine has potential to be developed into a novel therapeutic agent for PD.
    Keywords:  Parkinson's disease; SH-SY5Y cells; SIRT1; mitochondrial biogenesis; oxidative stress
  4. Cond Med. 2022 Dec;5(6): 192-195
      In the context of central nervous system (CNS) disease, oxidative stress may cause progression of cell death and neuroinflammation. Therefore, restoring mitochondrial antioxidant ability within cells is a major therapeutic strategy in many CNS disorders. A recent study uncovers a novel mechanism of astrocytic mitochondria being neuroprotective after intracerebral hemorrhage in mice. In their work, systemic administration of mitochondria obtained from astrocytes restores neuronal antioxidant defense, prevents neuronal death while promoting neurite outgrowth, indicating that extracellular mitochondria may play key roles in mediating beneficial non-cell autonomous effects. Given that mitochondria are also responsible for tolerance to stress and injury, is it possible that exogenous mitochondria signals may regulate cellular conditioning by boosting antioxidant ability? Further studies are warranted to build on these emerging findings in the pursuit of conditioning therapies mediated by mitochondrial transplantation in CNS injury and disease.
    Keywords:  Antioxidant defense; Astrocytic mitochondria; CNS disorders; Mitochondrial transplantation
  5. Front Pharmacol. 2023 ;14 1265571
      Numerous studies have shown that neuroinflammation is involved in the process of neuronal damage in neurodegenerative diseases such as Parkinson's disease (PD), for example, and that inhibiting neuroinflammation help improve PD. Shikimic acid (SA) has anti-inflammatory, analgesic and antioxidant activities in numerous diseases. However, its effect and mechanism in PD remain unclear. In this experiment, we found that SA inhibits production of pro-inflammatory mediators and ROS in LPS-induced BV2 cells. Mechanistic studies demonstrated that SA suppresses neuro-inflammation by activating the AKT/Nrf2 pathway and inhibiting the NF-κB pathway. Further in vivo study, we confirmed that SA ameliorated the neurological damage and behavioral deficits caused by LPS injection in mice. In summary, these study highlighted the beneficial role of SA as a novel therapy with potential PD drug by targeting neuro-inflammation.
    Keywords:  microglia; neuro-inflammation; neuroprotection; parkinson’s disease; shikimic acid
  6. Cell Biochem Funct. 2023 Nov 27.
      Polystyrene microplastics (PS-MPs) are environmental contaminants due to their potential to induce damages in multiple organs specifically liver. Tamarixetin (TMT) is a naturally occurring flavonoid present in Tamarix ramosissima plant that exhibits multiple pharmacological properties. Therefore, the present research was designed to evaluate the palliative role of TMT against PS-MPs instigated liver dysfunction in rats. The exposure to PS-MPs reduced the expressions of nuclear factor erythroid 2-related factor 2 and antioxidant genes, while increasing the expression of Kelch-like ECH-associated protein 1. PS-MPs exposed rats exhibited considerably (p < .05) higher alkaline phosphatase (ALP), aspartate aminotransferase (AST) as well as alanine aminotransferase (ALT) contents. Additionally, PS-MPs treatment resulted in a notable decrease in anti-oxidants activity, that is, glutathione S-transferase (GST), superoxide dismutase (SOD), heme oxygenase-1 (HO-1), glutathione reductase (GSR), glutathione peroxidase (GPx), catalase (CAT) and glutathione (GSH) content, whereas upregulating reactive oxygen species (ROS) and malondialdehyde (MDA) contents. Moreover, PS-MPs intoxication noticeably increased (p < .05) the inflammatory indices (interleukin-1ß [IL-1ß], nuclear factor kappa B [NF-κB], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α] levels, and cyclooxygenase-2 [COX-2] activity). Besides, Caspase-3 and Bax expressions were upregulated and Bcl-2 expression was decreased after PS-MPs exposure. Additionally, the histomorphological examination revealed notable hepatic damage in PS-MPs treated group. However, TMT treatment substantially (p < .05) recovered all the PS-MPs-induced damages and histopathological changes. Taken together, it can be deduced that TMT might be used as a pharmacological agent to ameliorate hepatic damage.
    Keywords:  apoptosis; histopathology; inflammation; liver; oxidation; polystyrene microplastics; tamarixetin
  7. J Immunol Res. 2023 ;2023 9439536
      Pulmonary fibrosis (PF) can lead to chronic inflammation, the destruction of alveoli and irreversible lung damage. Sestrin2 is a highly protective stress-inducible protein that is involved in the cell response to various stress factors and the regulation of homeostasis and has a certain protective effect against PF. In this study, TGF-β1 was used to establish a PF cell model. Bleomycin was used to induce PF in mice, and the expression levels of related proteins were detected by western blotting. The levels of the inflammatory cytokine, TNF-α, IL-6, and IL-1β were detected by enzyme-linked immunosorbent assays. Immunoprecipitation was used to verify the interaction between ATF4 and NRF2 and between Sestrin2 and NRF2 to explore the specific mechanism by which Sestrin2 affects PF. The results showed that Sestrin2 inhibited fibroblast-to-myofibroblast transition (FMT), improved inflammation, promoted cell proliferation, and alleviated PF. Activating transcription factor 4/nuclear factor erythroid 2-related factor 2 (NRF2/ATF4) signaling pathway activation could alleviate endoplasmic reticulum stress, inhibit ferroptosis and FMT, and reduce reactive oxygen species levels, thereby alleviating PF. Overexpression of ATF4 and the addition of a ferroptosis inducer reversed Sestrin2-mediated alleviation of PF. In conclusion, Sestrin2 alleviates PF and endoplasmic reticulum stress-dependent ferroptosis through the NRF2/ATF4 pathway.
  8. Br J Nutr. 2023 Jan 14. 129(1): 104-114
      Ergothioneine is a naturally occurring amino acid and thiol antioxidant found in high amounts in mushrooms and fermented foods. Humans and animals acquire ergothioneine from the diet through the pH-dependent activity of a membrane transporter, the large solute carrier 22A member 4 (SLC22A4), expressed on the apical membrane of the small intestine. The SLC22A4 transporter also functions in the renal reabsorption of ergothioneine in the kidney, with avid absorption and retention of ergothioneine from the diet observed in both animals and humans. Ergothioneine is capable of scavenging a diverse range of reactive oxygen and nitrogen species, has metal chelation properties, and is predicted to directly regulate nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Although not lethal, the genetic knockout of the SLC22A4 gene in multiple organisms increases susceptibility to oxidative stress, damage and inflammation; in agreement with a large body of preclinical data suggesting the physiological function of ergothioneine is as a cellular antioxidant and cytoprotectant agent. In humans, blood levels of ergothioneine decline after the age of 60 years, and lower levels of ergothioneine are associated with more rapid cognitive decline. Conversely, high plasma ergothioneine levels have been associated with significantly reduced cardiovascular mortality and overall mortality risks. In this horizon’s manuscript, we review evidence suggesting critical roles for dietary ergothioneine in healthy ageing and the prevention of cardiometabolic disease. We comment on some of the outstanding research questions in the field and consider the question of whether or not ergothioneine should be considered a conditionally essential micronutrient.
    Keywords:  CVD; Cardiometabolic disease; Ergothioneine; Non-alcoholic fatty liver disease; Type 2 diabetes
  9. Cell Death Dis. 2023 Nov 25. 14(11): 772
      Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.
  10. Chem Biol Interact. 2023 Nov 26. pii: S0009-2797(23)00487-8. [Epub ahead of print] 110820
      Baicalin, a potent anti-oxidative and anti-inflammatory flavonoid compound derived from Scutellaria baicalensis, has emerged as a neuroprotective agent. However, the mechanisms by which baicalin is neuroprotective in Parkinson's disease (PD) remain unclear. In this research, α-syn/MPP+ and MPTP were used to establish PD models in BV2 cells and C57BL/6 mice, respectively. The effect and mechanism of action of baicalin in PD were investigated by Western blotting, RT-qPCR, ELISA, immunohistochemistry (IHC) staining, immunofluorescence (IF) staining, HPLC and methods. Results demonstrate that baicalin mitigates oxidative stress, microglia activation and inflammatory response caused by α-syn/MPP+ and MPTP. It protects against dopaminergic neuron loss and relieves motor deficits. Meanwhile, baicalin not only significantly up-regulates the expression of Nrf2 and its downstream antioxidant enzyme, but also suppresses the activation of NLRP3 inflammasome simultaneously. Notably, the beneficial effects of baicalin in PD treatment are blocked by Nrf2 knockdown. This research reveals that baicalin may exert neuroprotective effects in PD treatment by suppressing the activation of NLRP3 inflammasome and it is dependent on the Nrf2-mediated antioxidative response.
    Keywords:  Baicalin; Inflammation; NLRP3 inflammasome; Oxidative stress; Parkinson's disease
  11. Food Funct. 2023 Nov 30.
      In this study, a polysaccharide known as PAPS2 was eluted from Pleurotus abieticola fruiting bodies using 0.1 M NaCl solutions. PAPS2 has a Mw of 19.64 kDa and its backbone is mainly composed of →6)-α-D-Galp-(1→, →6)-β-D-Glcp-(1→ and →2,6)-α-D-Galp-(1→ residues, and its branches mainly end with β-D-Manp-(1→, which is attached at C2 of →2,6)-α-D-Galp-(1→. PAPS2 elicited several effects in high-fat diet (HFD)-fed ApoE-/- mice. It significantly reduced the body weight, liver index, and serum levels of total cholesterol (TC) and triglycerides (TGs), and it alleviated lipid accumulation in the aorta. Intestinal microflora analysis showed that PAPS2 suppressed the abundances of Adlercreutzia, Turicibacter, and Helicobacter and enriched that of Roseburia. It also influenced lipid metabolism, suggesting that it reduced the levels of TGs, lysophosphatidylcholine (LPC), phosphatidylcholine (PC), and ceramide (Cer). Moreover, it suppressed oxidative response by increasing nuclear factor erythroid 2 (Nrf2)-related factor expression and activating the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) to reduce the level of reactive oxygen species (ROS). Meanwhile, it showed anti-inflammatory effects partially related to the inhibition of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling induced by lipopolysaccharide (LPS) in RAW 264.7 cells, as well as in the aorta of HFD-fed ApoE-/- mice. This study provides experimental evidence of the auxiliary applicability of PAPS2 in atherosclerosis treatment.
  12. Exp Neurol. 2023 Nov 27. pii: S0014-4886(23)00306-0. [Epub ahead of print]372 114621
      Traumatic brain injury (TBI) is an outside force causing a modification in brain function and/or structural brain pathology that upregulates brain inducible nitric oxide synthase (iNOS), instigating increased levels of nitric oxide activity which is implicated in secondary pathology leading to behavioral deficits (Hall et al., 2012; Garry et al., 2015; Kozlov et al., 2017). In mammals, TBI-induced NO production activates an immune response and potentiates metabolic crisis through mitochondrial dysfunction coupled with vascular dysregulation; however, the direct influence on pathology is complicated by the activation of numerous secondary cascades and activation of other reactive oxygen species. Drosophila TBI models have demonstrated key features of mammalian TBI, including temporary incapacitation, disorientation, motor deficits, activation of innate immunity (inflammation), and autophagy responses observed immediately after injury (Katzenberger et al., 2013; Barekat et al., 2016; Simon et al., 2017; Anderson et al., 2018; Buhlman et al., 2021b). We hypothesized that acute behavioral phenotypes would be associated with deficits in climbing behavior and increased oxidative stress. Because flies lack mammalian-like cardiovascular and adaptive immune systems, we were able to make our observations in the absence of vascular disruption and adaptive immune system interference in a system where highly targeted interventions can be rapidly evaluated. To demonstrate the induction of injury, ten-day-old transgenic flies received an injury of increasing angles from a modified high impact trauma (HIT) device where angle-dependent increases occurred for acute neurological behavior assessments and twenty-four-hour mortality, and survival was significantly decreased. Injury caused sex-dependent effects on climbing activity and measures of oxidative stress. Specifically, after a single 60-degree HIT, female flies exhibited significant impairments in climbing activity beyond that observed in male flies. We also found that several measures of oxidative stress, including Drosophila NOS (dNOS) expression, protein nitration, and hydrogen peroxide production were significantly decreased in female flies. Interestingly, protein nitration was also decreased in males, but surpassed sham levels with a more severe injury. We also observed decreased autophagy demand in vulnerable dopaminergic neurons in female, but not male flies. In addition, mitophagy initiation was decreased in females. Collectively, our data suggest that TBI in flies induces acute behavioral phenotypes and climbing deficits that are analogous to mammalian TBI. We also observed that various indices of oxidative stress, including dNOS expression, protein tyrosine nitration, and hydrogen peroxide levels, as well as basal levels of autophagy, are altered in response to injury, an effect that is more pronounced in female flies.
    Keywords:  Apoptosis; Drosophila; Inflammation; Innate immunity; Mitochondria; Neurodegeneration; Oxidative stress; Secondary injury; Traumatic brain injury; dNOS
  13. Naunyn Schmiedebergs Arch Pharmacol. 2023 Nov 27.
      Thymoquinone (THQ) and its nanoformulation (NFs) have emerged as promising candidates for the treatment of neurological diseases due to their diverse pharmacological properties, which include anti-inflammatory, antioxidant, and neuroprotective effects. In this study, we conducted an extensive search across reputable scientific websites such as PubMed, ScienceDirect, Scopus, and Google Scholar to gather relevant information. The antioxidant and anti-inflammatory properties of THQ have been observed to enhance the survival of neurons in affected areas of the brain, leading to significant improvements in behavioral and motor dysfunctions. Moreover, THQ and its NFs have demonstrated the capacity to restore antioxidant enzymes and mitigate oxidative stress. The primary mechanism underlying THQ's antioxidant effects involves the regulation of the Nrf2/HO-1 signaling pathway. Furthermore, THQ has been found to modulate key components of inflammatory signaling pathways, including toll-like receptors (TLRs), nuclear factor-κB (NF-κB), interleukin 6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNFα), thereby exerting anti-inflammatory effects. This comprehensive review explores the various beneficial effects of THQ and its NFs on neurological disorders and provides insights into the underlying mechanisms involved.
    Keywords:  Anti-inflammation; Antioxidant; Central nervous system; Molecular mechanisms; Nanoformulations; Neurological disorders; Thymoquinone
  14. J Intensive Med. 2023 Oct 31. 3(4): 313-319
      Stroke is the third most common cause of death globally and a leading cause of disability. The cellular and molecular changes following stroke and causes of neuronal death are not fully understood, and there are few effective treatments currently available. A rapid increase in the levels of reactive oxygen species (ROS) post stroke can overwhelm antioxidant defenses and trigger a series of pathophysiologic events including the inflammatory response, blood-brain barrier (BBB) disruption, apoptosis, and autophagy, ultimately leading to neuron degeneration and apoptosis. It is thought that beyond a certain age, the ROS accumulation resulting from stroke increases the risk of morbidity and mortality. In the present review, we summarize the role of oxidative stress (OS) as a link between aging and stroke pathogenesis. We also discuss how antioxidants can play a beneficial role in the prevention and treatment of stroke by eliminating harmful ROS, delaying aging, and alleviating damage to neurons.
    Keywords:  Age; Oxidative stress; Review; Stroke
  15. Curr Diabetes Rev. 2023 Nov 24.
      BACKGROUND: Type 2 diabetes mellitus (T2DM) is a worldwide socioeconomic burden, and is accompanied by a variety of metabolic disorders, as well as nerve dysfunction referred to as diabetic neuropathy (DN). Despite a tremendous body of research, the pathogenesis of DN remains largely elusive. Currently, two schools of thought exist regarding the pathogenesis of diabetic neuropathy: a) mitochondrial-induced toxicity, and b) microvascular damage. Both mechanisms signify DN as an intractable disease and, as a consequence, therapeutic approaches treat symptoms with limited efficacy and risk of side effects.OBJECTIVE: Here, we propose that the human body exclusively employs mechanisms of adaptation to protect itself during an adverse event. For this purpose, two control systems are defined, namely the autonomic and the neural control systems. The autonomic control system responds via inflammatory and immune responses, while the neural control system regulates neural signaling, via plastic adaptation. Both systems are proposed to regulate a network of temporal and causative connections which unravel the complex nature of diabetic complications.
    RESULTS: A significant result of this approach infers that both systems make DN reversible, thus opening the door to novel therapeutic applications.
    Keywords:  Diabetes; adaptive control systems; autonomic control system; diabetic neuropathy; neural control system.
  16. Toxicology. 2023 Nov 23. pii: S0300-483X(23)00265-2. [Epub ahead of print]500 153678
      Bisphenol A (BPA) was traditionally used in epoxy resins and polycarbonate plastics, but it was found to be harmful to human health due to its endocrine-disrupting effects. It can affect various biological functions of human beings and interfere with brain development. However, the neurotoxic mechanisms of BPA on brain development and associated neurodegeneration remain poorly understood. Here, we reported that BPA (100, 250, 500 μM) inhibited cell viability of neural cells PC12, SH-SY5Y and caused dose-dependent cell death. In addition, BPA exposure increased intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS) levels, decreased mitochondrial membrane potential, reduced the expression of cytochrome c oxidase IV (COX4), downregulated Bcl-2, and initiated apoptosis. Moreover, BPA treatment resulted in the accumulation of intracellular acidic vacuoles and increased the autophagy marker LC3 II to LC3 I ratio. Furthermore, BPA exposure inhibited Nrf2/ HO-1 and AKT/mTOR pathways and mediated cellular oxidative stress, apoptosis, and excessive autophagy, leading to neuronal degeneration. The interactions between oxidative stress, autophagy, and apoptosis during BPA-induced neurotoxicity remain unclear and require further in vivo confirmation.
    Keywords:  Akt/mTOR; Apoptosis; Autophagy; Bisphenol A; Neurotoxicity; Nrf2/HO-1
  17. Front Endocrinol (Lausanne). 2023 ;14 1207142
      Introduction: Research has shown that pyroptosis contributes greatly to the progression of diabetes and its complications. However, the exact relationship between this particular cell death process and the pathology of type 2 diabetes mellitus (T2DM) remains unclear. In this study, we used bioinformatic tools to identify the pyroptosis-related genes (PRGs) associated with T2DM and to analyze their roles in the disease pathology.Methods: Two microarray datasets, GSE7014 and GSE25724, were obtained from the GEO database and assessed for differentially expressed genes (DEGs). The T2DM-associated DEGs that overlapped with differentially expressed PRGs were noted as T2DM-PRGs. Subsequently, 25 T2DM-PRGs were validated and subjected to functional enrichment analysis through Gene Ontology annotation analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and gene set enrichment analysis (GSEA). The diagnostic and predictive value of the T2DM-PRGs was evaluated using receiver operating characteristic curves (ROC). Additionally, a single-sample GSEA algorithm was applied to study immune infiltration in T2DM and assess immune infiltration levels.
    Results: We identified 25 T2DM-PRGs that were significantly enriched in the nuclear factor-kappa B signaling and prostate cancer pathways. The top five differentially expressed prognostic T2DM-PRGs targeted by miRNAs were PTEN, BRD4, HSP90AB1, VIM, and PKN2. The top five differentially expressed T2DM-PRGs associated with transcription factors were HSP90AB1, VIM, PLCG1, SCAF11, and PTEN. The genes PLCG1, PTEN, TP63, CHI3L1, SDHB, DPP8, BCL2, SERPINB1, ACE2, DRD2, DDX58, and BTK showed excellent diagnostic performance. The immune infiltration analysis revealed notable differences in immune cells between T2DM and normal tissues in both datasets. These findings suggest that T2DM-PRGs play a crucial role in the development and progression of T2DM and could be used as potential diagnostic biomarkers and therapeutic targets.
    Discussion: Investigating the mechanisms and biomarkers associated with pyroptosis may offer valuable insights into the pathophysiology of T2DM and lead to novel therapeutic approaches to treat the disease.
    Keywords:  biomarkers; diabetes mellitus; immune infiltration; mechanisms; pyroptosis; risk prediction
  18. Behav Brain Res. 2023 Nov 29. pii: S0166-4328(23)00508-9. [Epub ahead of print] 114790
      Complex regional pain syndrome type I (CRPS-I) is a disabling pain condition without adequate treatment. Chronic post-ischemia pain injury (CPIP) is a model of CRPS-I that causes allodynia, spontaneous pain, inflammation, vascular injury, and oxidative stress formation. Antioxidants, such as alpha lipoic acid (ALA), have shown a therapeutic potential for CRPS-I pain control. Thus, we aim to evaluate if ALA repeated treatment modulates neuroinflammation in a model of CRPS-I in mice. We used male C57BL/6 mice to induce the CPIP model (O-ring torniquet for 2h in the hindlimb). For the treatment with ALA or vehicle (Veh) mice were randomly separated in four groups and received 100mg/kg orally once daily for 15 days (CPIP-ALA, CPIP-Veh, Control-ALA, and Control-Veh). We evaluated different behavioral tests including von Frey (mechanical stimulus), acetone (cold thermal stimulus), rotarod, open field, hind paw edema determination, and nest-building (spontaneous pain behavior). Also, hydrogen peroxide (H2O2) levels, NADPH oxidase and superoxide dismutase (SOD) activity in the sciatic nerve and spinal cord, and Iba1, Nrf2, and Gfap in spinal cord were evaluated at 16 days after CPIP or sham induction. Repeated ALA treatment reduced CPIP-induced mechanical and cold allodynia and restored nest-building capacity without causing locomotor or body weight alteration. ALA treatment reduced SOD and NADPH oxidase activity, and H2O2 production in the spinal cord and sciatic nerve. CPIP-induced neuroinflammation in the spinal cord was associated with astrocyte activation and elevated Nfr2, which were reduced by ALA. ALA repeated treatment prevents nociception by reducing oxidative stress and neuroinflammation in a model of CRPS-I in mice.
    Keywords:  ALA; CPIP; NADPH oxidase; Thioctic acid; chronic pain; oxidative stress
  19. Neurotoxicology. 2023 Nov 29. pii: S0161-813X(23)00149-3. [Epub ahead of print]
      α-Pyrrolidinononanophenone (α-PNP) derivatives are known to be one of the hazardous new psychoactive substances due to the most extended hydrocarbon chains of any pyrrolidinophenones on the illicit drug market. Our previous report showed that 4'-iodo-α-PNP (I-α-PNP) is the most potent cytotoxic compound among α-PNP derivatives and induces apoptosis due to mitochondrial dysfunction and suppression of nitric oxide (NO) production in differentiated human neuronal SH-SY5Y cells. In this study, to clarify the detailed action mechanisms by I-α-PNP, we investigated the mechanism of reactive oxygen species (ROS) -dependent apoptosis by I-α-PNP in differentiated SH-SY5Y with a focus on the antioxidant activities. Treatment with I-α-PNP elicits overproduction of ROS such as H2O2, hydroxyl radical, and 4-hydroxy-2-nonenal, and pretreatment with antioxidant N-acetyl-L-cysteine is attenuated the SH-SY5Y cells apoptosis by I-α-PNP. These results suggested that the overproduction of ROS is related to SH-SY5Y cell apoptosis by I-α-PNP. In addition, I-α-PNP markedly decreased antioxidant capacity in differentiated cells than in undifferentiated cells and inhibited the upregulation of hemeoxygenase 1 (HO1) and glutathione peroxidase 4 (GPX4) expression caused by induction of differentiation. Furthermore, the treatment with I-α-PNP increased the nuclear expression level of BTB Domain And CNC Homolog 1 (Bach1), a transcriptional repressor of Nrf2, only in differentiated cells, suggesting that the marked decrease in antioxidant capacity in differentiated cells was due to suppression of Nrf2/HO1 signaling by Bach1. Additionally, pretreatment with an NO donor suppresses the I-α-PNP-evoked ROS overproduction, HO1 down-regulation, increased nuclear Bach1 expression and reduced antioxidant activity in the differentiated cells. These findings suggest that the ROS-dependent apoptosis by I-α-PNP in differentiated cells is attributed to the inactivation of the Nrf2/HO1 signaling pathway triggered by NO depletion.
    Keywords:  4'-iodo-α-pyrrolidinononanophenone; Heme oxygenase 1; Pyrrolidinophenones; antioxidant activity; human neuronal SH-SY5Y cell; nuclear factor-erythroid 2-related factor 2
  20. Brain Res. 2023 Nov 27. pii: S0006-8993(23)00460-2. [Epub ahead of print] 148689
      Recently, human umbilical cord mesenchymal stem cell (HucMSC) is a new focus of research in neurological diseases, and the beneficial effect of HucMSC is mediated by paracrine factors which are transported by exosome. Our previous study has shown that HucMSC-derived exosome could provide neuroprotection after traumatic brain injury (TBI). However, the underlying mechanisms were not fully understood. In the present study, we found that administration of exosome suppressed TBI-induced inflammation and ferroptosis. In addition, exosome activated the long non-coding ribonucleic acid (lncRNA) TUBB6/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway after TBI. However, exosome partly failed to provide neuroprotection following TBI when TUBB6 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed inflammation, inhibited ferroptosis and activated the lncRNA TUBB6/Nrf2 pathway after TBI in vitro. Taken together, our results provided the first evidence that HucMSC-derived exosome played a key role in neuroprotection after TBI through the lncRNA TUBB6/Nrf2 pathway.
    Keywords:  Exosome; Human umbilical cord mesenchymal stem cell; Neuroprotection; Nrf2; Traumatic brain injury; lncRNA
  21. J Chem Neuroanat. 2023 Nov 26. pii: S0891-0618(23)00134-5. [Epub ahead of print]134 102364
      Gallic acid (GA) is known to be a natural phenolic compound with antioxidant and neuroprotective effects. This study aims to investigate the impact of GA against restraint stress-induced oxidative damage, anxiety-like behavior, neuronal loss, and spatial learning and memory impairment in male Wistar rats. The animals were divided into four groups (n = 8) and subjected to restraint stress for 4 h per day for 14 consecutive days or left undisturbed (control without inducing stress). In the treatment group, the animals were treated with 2 mL normal saline plus 100 mg/kg GA per day for 14 consecutive days (STR + GA group). The animals received the drug or normal saline by gavage 2 h before inducing restraint stress. ELISA assay measured oxidative stress factors. Elevated-plus maze and Morris water maze tests assessed anxiety-like behavior and spatial learning and memory, respectively. Also, neuronal density was determined using Nissl staining. Restraint stress significantly increased MDA and reduced the activities of GPX and SOD in the stressed rats, which were reserved by treatment with 100 mg/kg GA. Restraint stress markedly enhanced the anxiety-like behavior and spatial learning and memory impairment that were reserved by GA. In addition, treatment with GA reduced the neuronal loss in the stressed rats in the hippocampus and prefrontal cortex (PFC) regions. Taken together, our findings suggest that GA has the potential to be used as a good candidate to attenuate neurobehavioral disorders as well as neuronal loss in the hippocampus and PFC induced by restraint stress via reducing oxidative damage.
    Keywords:  Anxiety; Gallic acid; Oxidative damage; Restraint stress; Spatial learning and memory
  22. Brain Res. 2023 Nov 27. pii: S0006-8993(23)00462-6. [Epub ahead of print]1824 148691
      INTRODUCTION: Parkinson's disease (PD) is the most prevalent disorder of the basal ganglia, propagated by the degeneration of axon terminals within the striatum and subsequent loss of dopaminergic neurons in the substantia nigra (SN). Exposure of environmental neurotoxins and mutations of several mitochondrial and proteasomal genes are primarily responsible.METHODS: To determine whether signal transducer and activator of transcription 3 (STAT3) could protect dopaminergic neurons against degeneration, we first screened it in the in vitro capacity using immortalized rat dopaminergic N27 cells under 6-OHDA neurotoxicity. We then evaluated the effectiveness of constitutively active (ca) STAT3 as a neuroprotective agent on N27 cells in a 6-hydroxydopamine (6-OHDA) induced rat model of PD and compared it to control animals or animals where AAV/caRheb was expressed in SN. Behavioral outcomes were assessed using rotational and cylinder assays and mitochondrial function using reactive oxygen species (ROS) levels.
    RESULTS: Using flow cytometry, the in vitro analysis determined caSTAT3 significantly decreased dopaminergic neuronal death under 6-OHDA treatment conditions. Importantly, in vivo overexpression of caSTAT3 in SN dopaminergic neurons using AAV-mediated expression demonstrated significant neuroprotection of dopaminergic neurons following 6-OHDA. Both caSTAT3 and caRheb + caSTAT3 co-injection into substantia nigra reduced D-amphetamine-induced rotational behavior and increased ipsilateral forelimb function when compared to control animals. In addition, caSTAT3 decreased mitochondrial ROS production following 6-OHDA induced neurotoxicity.
    CONCLUSION: caSTAT3 confers resistance against ROS production in mitochondria of susceptible SN dopaminergic neurons potentially offering a new avenue for treatment against PD.
    Keywords:  Neurodegeneration; Neuroprotection; Parkinson’s disease; Regeneration; STAT3
  23. Front Neurosci. 2023 ;17 1244022
      Parkinson's disease (PD) is a predominantly idiopathic pathological condition characterized by protein aggregation phenomena, whose main component is alpha-synuclein. Although the main risk factor is ageing, numerous evidence points to the role of type 2 diabetes mellitus (T2DM) as an etiological factor. Systemic alterations classically associated with T2DM like insulin resistance and hyperglycemia modify biological processes such as autophagy and mitochondrial homeostasis. High glucose levels also compromise protein stability through the formation of advanced glycation end products, promoting protein aggregation processes. The ability of antidiabetic drugs to act on pathways impaired in both T2DM and PD suggests that they may represent a useful tool to counteract the neurodegeneration process. Several clinical studies now in advanced stages are looking for confirmation in this regard.
    Keywords:  Parkinson’s disease; alpha-synuclein; autophagy; hyperglycemia; insulin-resistance; islet amyloid peptide protein; type 2 diabetes mellitus
  24. Environ Sci Pollut Res Int. 2023 Nov 30.
      Gas explosions (GE) are a prevalent and widespread cause of traumatic brain injury (TBI) in coal miners. However, the impact and mechanism of curcumin on GE-induced TBI in rats remain unclear. In this study, we simulated GE-induced TBI in rats and administered curcumin orally at a dose of 100 mg/kg every other day for 7 days to modulate the gut microbiota in TBI rats. We employed 16S rRNA sequencing and LC-MS/MS metabolomic analysis to investigate changes in the intestinal flora and its metabolic profile. Additionally, we utilized ELISA, protein assays, and immunohistochemistry to assess neuroinflammatory signaling molecules for validation. In a rat TBI model, GE resulted in weight loss, pathological abnormalities, and cortical hemorrhage. Treatment with curcumin significantly mitigated histological abnormalities and microscopic mitochondrial structural changes in brain tissue. Furthermore, curcumin treatment markedly ameliorated GE-induced brain dysfunction by reducing the levels of several neuroinflammatory signaling molecules, including neuron-specific enolase, interleukin (IL)-1β, IL-6, and cryptothermic protein 3. Notably, curcumin reshaped the gut microbiome by enhancing evenness, richness, and composition. Prevotella_9, Alloprevotella, Bacilli, Lactobacillales, Proteobacteria, and Gammaproteobacteria were identified as prominent members of the gut microbiota, increasing the linear discriminant analysis scores and specifically enhancing the abundance of bacteria involved in the nuclear factor (NF)-κB signaling pathway, such as Lachnospiraceae and Roseburia. Additionally, there were substantial alterations in serum metabolites associated with metabolic NF-κB signaling pathways in the model group. Curcumin administration reduced serum lipopolysaccharide levels and downregulated downstream Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/NF-κB signaling. Furthermore, curcumin alleviated GE-induced TBI in rats by modulating the gut microbiota and its metabolites. Based on these protective effects, curcumin may exert its influence on the gut microbiota and the TLR4/MyD88/NF-κB signaling pathways to ameliorate GE-induced TBI.
    Keywords:  Brain; Curcumin; Gas explosion; Lipopolysaccharide; NF-κB; Traumatic brain injury
  25. Front Immunol. 2023 ;14 1273570
      Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.
    Keywords:  AMPK; APOE-ε4; SIRT1; WISP1; autophagy; diabetes mellitus; ferroptosis; pyroptosis
  26. Int J Nanomedicine. 2023 ;18 6797-6812
      Background: Oxidative stress induced reactive oxygen species (ROS) and aggregation of amyloid β (Aβ) in the nervous system are significant contributors to Alzheimer's disease (AD). Cerium dioxide and manganese oxide are known as to be effective and recyclable ROS scavengers with high efficiency in neuroprotection.Methods: A hollow-structured manganese-doped cerium dioxide nanoparticle (LMC) was synthesized for loading Resveratrol (LMC-RES). The LMC-RES were characterized by TEM, DLS, Zeta potential, and X-ray energy spectrum analysis. We also tested the biocompatibility of LMC-RES and the ability of LMC-RES to cross the blood-brain barrier (BBB). The antioxidant effects of LMC-RES were detected by SH-SY5Y cells. Small animal live imaging was used to detect the distribution of LMC-RES in the brain tissue of AD mice. The cognitive abilities of mice were tested by water maze and nesting experiments. The effects of LMC-RES in reducing oxidative stress and protecting neurons was also explored by histological analysis.
    Results: The results showed that LMC-RES had good sustained release effect and biocompatibility. The drug release rate of LMC-RES at 24 hours was 80.9 ± 2.25%. Meanwhile, LMC-RES could cross the BBB and enrich in neurons to exert antioxidant effects. In Aβ-induced SH-SY5Y cells, LMC-RES could inhibits oxidative stress through the Nrf-2/HO-1 signaling pathway. In AD model mice, LMC-RES was able to reduce ROS levels, inhibit Aβ-induced neurotoxicity, and protect neurons and significantly improve cognitive deficits of AD mice after drug administration.
    Conclusion: LMC-RES can effectively across the BBB, reduce oxidative stress, inhibit Aβ aggregation, and promote the recovery of neurological function.
    Keywords:  Alzheimer’s disease; cerium dioxide nanoparticles; manganese; oxidative stress; resveratrol
  27. Medicine (Baltimore). 2023 Nov 24. 102(47): e35961
      BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is a complex pathophysiological process that typically occurs during the treatment of ischemia, with limited therapeutic options. Autophagy plays a vital role during the reperfusion phase and is a potential therapeutic target for preventing and treating cerebral ischemia-reperfusion injury.METHODS: We conducted a comprehensive search of the Web of Science Core Collection for publications related to cerebral ischemia-reperfusion injury with autophagy, published between January 1, 2008, and January 1, 2023. We analyzed the selected publications using VOSviewer, CiteSpace, and other bibliometric tools.
    RESULTS: Our search yielded 877 relevant publications. The field of autophagy in cerebral ischemia-reperfusion injury has grown rapidly since 2016. China has been the leading contributor to publications, followed by the USA and Iran. Chen Zhong and Qin Zhenghong have been influential in this field but have yet to reach all groups. In addition, there has been a shortage of collaboration among authors from different institutions. Our literature and keyword analysis identified Neurovascular protection (#11 Neuroprotective, #13 Neurovascular units, etc) and Inflammation (NLRP3 inflammasome) as popular research directions. Furthermore, the terms "Blood-Brain Barrier," "Mitophagy," and "Endoplasmic reticulum stress" have been frequently used and may be hot research topics in the future.
    CONCLUSIONS: The role of autophagy in cerebral ischemia-reperfusion injury remains unclear, and the specific mechanisms of drugs used to treat ischemia-reperfusion injury still need to be explored. This work outlines the changing trends in investigating cerebral ischemia-reperfusion injury involving autophagy and suggests future lines of inquiry.
  28. Environ Toxicol. 2023 Nov 27.
      BACKGROUND: Bortezomib (BTZ) is a commonly used antitumor drug, but its peripheral neuropathy side effect poses a limitation on its dosage. Evodiamine (EVO) exhibits various biological activities, including antioxidant, anti-inflammatory, and anticancer effects. The purpose of this investigation is to confirm the impact of EVO on BTZ-induced peripheral neurotoxicity.METHODS: GeneCards and HERB were applied to analyze the targets of peripheral neurotoxicity and EVO. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of the hub genes were identified by DAVID. Rat dorsal root ganglion neurons (DRGs) and rat RSC96 Schwann cells (SCs) were treated with BTZ to simulate peripheral neurotoxicity. BTZ-induced peripheral neurotoxicity was assessed by detecting cell viability, proliferation, oxidative stress, and ferroptosis in DRGs and SCs. The mitogen-activated protein kinase (MAPK) signaling was scrutinized by Western blot assay.
    RESULTS: The Venn diagram for the overlapping targets of EVO and peripheral neurotoxicity showed that EVO might regulate peripheral neurotoxicity by influencing cell oxidative stress, ferroptosis, and MAPK signaling pathway. EVO attenuated BTZ-induced toxicity in DRGs and SCs. EVO attenuated BTZ-induced oxidative stress damage in DRGs and SCs by reducing reactive oxygen species and malondialdehyde levels and enhancing glutathione level. EVO attenuated BTZ-induced ferroptosis in DRGs and SCs. EVO inhibited BTZ-induced activation of the MAPK signaling in DRGs and SCs. Activation of the MAPK signaling reversed the neuroprotective effect of EVO on BTZ-induced oxidative stress injury and ferroptosis.
    CONCLUSION: EVO attenuated oxidative stress and ferroptosis by inhibiting the MAPK signaling to improve BTZ-induced peripheral neurotoxicity.
    Keywords:  bortezomib; evodiamine; ferroptosis; oxidative stress; peripheral neurotoxicity
  29. Analyst. 2023 Nov 28.
      Oxidative stress, a condition involving an imbalance between reactive oxygen species (ROS) and antioxidants, is closely linked to epilepsy, contributing to abnormal neuronal excitability. This study introduces a novel fluorescent probe, the MDP probe, designed for the efficient detection of malondialdehyde (MDA), a critical biomarker associated with oxidative stress. The MDP probe offers several key advantages, including high sensitivity with a low detection limit of 0.08 μM for MDA, excellent selectivity for MDA even in the presence of interfering substances, and biocompatibility, making it suitable for cell-based experiments. The probe allows for real-time monitoring of MDA levels, enabling dynamic studies of oxidative stress. In vivo experiments in mice demonstrate its potential for monitoring MDA levels, particularly in epilepsy models, which could have implications for disease research and diagnosis. Overall, the MDP probe represents a promising tool for studying oxidative stress, offering sensitivity and specificity in cellular and in vivo settings. Its development opens new avenues for exploring the role of oxidative stress in various biological processes and diseases, contributing to advancements in healthcare and biomedical research.
  30. J Ethnopharmacol. 2023 Nov 25. pii: S0378-8741(23)01354-5. [Epub ahead of print] 117484
      ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes is a common chronic disease. Chinese herbal medicine (CHM) has a history of several thousand years in the treatment of diabetes, and active components with hypoglycemic effects extracted from various CHM, such as polysaccharides, flavonoids, terpenes, and steroidal saponins, have been widely used in the treatment of diabetes.AIM OF THE STUDY: Research exploring the potential of various CHM compounds to regulate the mitochondrial respiratory chain complex to improve type 2 diabetes mellitus (T2DM).
    MATERIALS AND METHODS: The literature data were primarily obtained from authoritative databases such as PubMed, CNKI, Wanfang, and others within the last decade. The main keywords used include "type 2 diabetes mellitus", "Chinese medicine", "Chinese herbal medicine", "mitochondrial respiratory chain complex", and "mitochondrial dysfunction".
    RESULTS: Chinese herbal medicine primarily regulates the activity of mitochondrial respiratory chain complexes in various tissues such as liver, adipose tissue, skeletal muscle, pancreatic islets, and small intestine. It improves cellular energy metabolism through hypoglycemic, antioxidant, anti-inflammatory and lipid-modulating effects. Different components of CHM can regulate the same mitochondrial respiratory chain complexes, while the same components of a particular CHM can regulate different complex activities. The active components of CHM target different mitochondrial respiratory chain complexes, regulate their aberrant changes and effectively improve T2DM and its complications.
    CONCLUSION: Chinese herbal medicine can modulate the function of mitochondrial respiratory chain complexes in various cell types and exert their hypoglycemic effects through various mechanisms. CHM has significant therapeutic potential in regulating mitochondrial respiratory chain complexes to improve T2DM, but further research is needed to explore the underlying mechanisms and conduct clinical trials to assess the safety and efficacy of these medications. This provides new perspectives and opportunities for personalized improvement and innovative developments in diabetes management.
    Keywords:  Chinese herbal medicine; Mitochondrial dysfunction; Mitochondrial respiratory chain complexes; Traditional Chinese medicine; Type 2 diabetes mellitus
  31. Heliyon. 2023 Nov;9(11): e22443
      Ferroptosis has been observed during retinal photoreceptor cell death, suggesting that it plays a role in retinitis pigmentosa (RP) pathogenesis. Qi-Shen-Tang (QST) is a combination of two traditional Chinese medicines used for the treatment of ophthalmic diseases; however, its mechanism of action in RP and ferroptosis remains unclear. Therefore, this study aimed to explore the effect and potential molecular mechanisms of QST on RP. QST significantly improved tissue morphology and function of the retina in the RP model mice. A significant increase in retinal blood flow and normalization of the fundus structure were observed in mice in the treatment group. After QST treatment, the level of iron and the production of malondialdehyde decreased significantly; the levels of superoxide dismutase and glutathione increased significantly; and the protein expression of glutathione peroxidase 4 (GPX4), glutathione synthetase, solute carrier family 7 member 11, and nuclear factor erythroid 2-related factor 2 (NRF2) increased significantly. The molecular docking results demonstrated potential interactions between the small molecules of QST and the key proteins of NRF2/GPX4 signaling pathway. Our results indicate that QST may inhibit ferroptosis by inhibiting the NRF2/GPX4 signaling pathway, thereby reducing RP-induced damage to retinal tissue.
    Keywords:  GPX4; NRF2; Qi-Shen-Tang; Retinitis pigmentosa; ferroptosis
  32. Transl Neurodegener. 2023 Nov 30. 12(1): 55
      Deep brain stimulation (DBS) is a well-established and effective treatment for patients with advanced Parkinson's disease (PD), yet its underlying mechanisms remain enigmatic. Optogenetics, primarily conducted in animal models, provides a unique approach that allows cell type- and projection-specific modulation that mirrors the frequency-dependent stimulus effects of DBS. Opto-DBS research in animal models plays a pivotal role in unraveling the neuronal and synaptic adaptations that contribute to the efficacy of DBS in PD treatment. DBS-induced neuronal responses rely on a complex interplay between the distributions of presynaptic inputs, frequency-dependent synaptic depression, and the intrinsic excitability of postsynaptic neurons. This orchestration leads to conversion of firing patterns, enabling both antidromic and orthodromic modulation of neural circuits. Understanding these mechanisms is vital for decoding position- and programming-dependent effects of DBS. Furthermore, patterned stimulation is emerging as a promising strategy yielding long-lasting therapeutic benefits. Research on the neuronal and synaptic adaptations to DBS may pave the way for the development of more enduring and precise modulation patterns. Advanced technologies, such as adaptive DBS or directional electrodes, can also be integrated for circuit-specific neuromodulation. These insights hold the potential to greatly improve the effectiveness of DBS and advance PD treatment to new levels.
    Keywords:  Antidromic effects; Deep brain stimulation; Long-lasting therapeutic effects; Opto-DBS; Optogenetics; Orthodromic effects; Parkinson’s disease; Synaptic adaptation
  33. Biochem Biophys Res Commun. 2023 Nov 18. pii: S0006-291X(23)01340-2. [Epub ahead of print]691 149246
      Huntington's disease (HD) is a progressive genetic neurodegenerative disease caused by an abnormal expansion of a cytosine-adenine-guanine trinucleotide repeat in the huntingtin gene. One pathological feature of HD is neuronal loss in the striatum. Despite many efforts, mechanisms underlying neuronal loss in HD striatum remain elusive. It was suggested that the mutant huntingtin protein interacts mitochondrial proteins and causes mitochondrial dysfunction in striatal neurons. However, whether axonal transport of mitochondria is altered in HD striatal neurons remains controversial. Here, we examined axonal transport of single mitochondria labelled with Mito-DsRed2 in cultured striatal neurons of zQ175 knock-in mice (a knock-in mouse model of HD). We observed decreased anterograde axonal transport of proximal mitochondria in HD striatal neurons compared with wild-type (WT) striatal neurons. Decreased anterograde transport in HD striatal neurons was prevented by overexpressing mitochondrial Rho GTPase 1 (Miro1). Our results offer a new insight into mechanisms underlying neuronal loss in the striatum in HD.
    Keywords:  Axonal transport; Huntington's disease; Miro1; Mitochondria; Neurodegenerative disease; Real-time imaging
  34. Mol Neurobiol. 2023 Nov 27.
      Clinical trials have demonstrated the potential neuroprotective effects of uric acid (UA) in Alzheimer's disease (AD). However, the specific mechanism underlying the neuroprotective effect of UA remains unclear. In the present study, we investigated the neuroprotective effect and underlying mechanism of UA in AD mouse models. Various behavioral tests including an elevated plus maze, Barnes maze, and Morris water maze were conducted to evaluate the impact of UA on cognitive function in β-amyloid (Aβ) microinjection and APP23/PS45 double transgenic mice models of AD. Immunohistochemical staining was employed to visualize pathological changes in the brains of AD model mice. Western blotting and immunofluorescence techniques were used to assess levels of autophagy-related proteins and transcription factor EB (TFEB)-related signaling pathways. BV2 cells were used to investigate the association between UA and microglial autophagy. We reported that UA treatment significantly alleviated memory decline in Aβ-induced AD model mice and APP23/PS45 double transgenic AD model mice. Furthermore, UA activated microglia and upregulated the autophagy-related proteins such as LC3II/I ratio, Beclin-1, and LAMP1 in the hippocampus of AD model mice. Similarly, UA protected BV2 cells from Aβ toxicity by upregulating the expressions of Beclin-1, LAMP1, and the LC3II/I ratio, whereas genetic inhibition of TFEB completely abolished these protective effects. Our results indicate that UA may serve as a novel activator of TFEB to induce microglia autophagy and facilitate Aβ degradation, thereby improving cognitive function in AD model mice. Therefore, these findings suggest that UA may be a novel therapeutic agent for AD treatment.
    Keywords:  Alzheimer’s disease; Autophagy; Neuroprotection; Transcription factor EB; Uric acid
  35. Front Neurosci. 2023 ;17 1297984
      Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.
    Keywords:  Alzheimer’s disease; brain energy fuel; circulating biomarkers; disease-modifying therapy; ketogenesis; ketogenic intervention; metabolic interaction
  36. Cell Signal. 2023 Nov 23. pii: S0898-6568(23)00401-1. [Epub ahead of print]114 110986
      Low back pain (LBP) is a pervasive global health issue. Roughly 40% of LBP cases are attributed to intervertebral disc degeneration (IVDD). While the underlying mechanisms of IVDD remain incompletely understood, it has been confirmed that apoptosis and extracellular matrix (ECM) degradation caused by many factors such as inflammation, oxidative stress, calcium (Ca2+) homeostasis imbalance leads to IVDD. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are involved in these processes. The initiation of ER stress precipitates cell apoptosis, and is also related to inflammation, levels of oxidative stress, and Ca2+ homeostasis. Additionally, mitochondrial dynamics, antioxidative systems, disruption of Ca2+ homeostasis are closely associated with Reactive Oxygen Species (ROS) and inflammation, promoting cell apoptosis. However, numerous crosstalk exists between the ER and mitochondria, where they interact through inflammatory cytokines, signaling pathways, ROS, or key molecules such as CHOP, forming positive and negative feedback loops. Furthermore, the contact sites between the ER and mitochondria, known as mitochondria-associated membranes (MAM), facilitate direct signal transduction such as Ca2+ transfer. However, the current attention towards this issue is insufficient. Therefore, this review summarizes the impacts of ER stress and mitochondrial dysfunction on IVDD, along with the possibly potential crosstalk between them, aiming to unveil novel avenues for IVDD intervention.
    Keywords:  Endoplasmic reticulum stress; Inflammation; Intervertebral disc degeneration; Mitochondria-associated membrane; Mitochondrial dysfunction; Oxidative stress
  37. Eur Rev Med Pharmacol Sci. 2023 Nov;pii: 34473. [Epub ahead of print]27(22): 11039-11056
      OBJECTIVE: Diabetes mellitus (DM) has been considered a major problem because of its related complications and growing incidence worldwide. Testicular dysfunction has become a predominant diabetic complication characterized by impaired reproductive function and testicular damage. Stevia rebaudiana Bertoni has been known for its antioxidant effect on diabetes, inflammation, and obesity. The current study investigates the protective effect of Stevia on diabetic-induced testicular injury.MATERIALS AND METHODS: Sprague Dawley adult male rats were divided into three groups: the control group, the diabetic group, and the diabetic + Stevia group, type 2 diabetes is induced by a high-fat diet (HFD) and a single dose of 35 mg/kg streptozotocin injection. The effects of Stevia were evaluated regarding biochemical, oxidative stress, histopathological and ultrastructural changes, and immunohistochemical expression of vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), receptor-interacting serine/threonine-protein kinase 1 (RIPK 1), and caspase 3.
    RESULTS: Stevia extract attenuated the diabetic-induced oxidative stress, restored the testicular architecture, and decreased testicular damage, inflammation, necroptosis, and apoptosis by upregulating VEGF and downregulating VCAM 1, RIPK 1, and caspase 3.
    CONCLUSIONS: The current study highlights the importance of Stevia as an antioxidant anti-inflammatory that ameliorates diabetic-induced testicular injury by modulating oxidative stress, inflammation, necroptosis, and apoptosis.
  38. Neuroscience. 2023 Nov 29. pii: S0306-4522(23)00506-7. [Epub ahead of print]
      BACKGROUND AND PURPOSE: Apoptosis is involved in the occurrence and development of acute ischemic stroke (AIS). This study aimed to assess whether Chuanzhitongluo (CZTL), a multi-target and multi-pathway compound preparation, plays a neuroprotective role in AIS by modulating neuronal apoptosis via the PI3K/AKT signaling pathway.METHODS: A mouse model of AIS was established by photochemical processes. Cerebral infarction volume was measured by 2% staining with 2, 3, and 5-triphenyl tetrazole chloride (TTC). Neuron apoptosis was assessed by TUNEL staining. Apoptosis RNA arrays were used to detect changes in apoptosis-related gene expression profiles. Western blotting was used to detect proteins involved in the PI3K/AKT signaling pathway.
    RESULTS: The study demonstrated that CZTL could potentially mitigate neuronal apoptosis in AIS mice. This appears to be achieved via the up-regulation of certain genes such as BCL-2, Birc6, and others, coupled with the down-regulation of genes like BAX, Bid, and Casp3. Further validation revealed that CZTL could enhance the expression of BCL-2 and reduce the expression of Cleaved Caspase-3 and BAX at both the gene and protein levels. The study also found that CZTL can enhance the phosphorylation level of the PI3K/AKT signaling pathway. In contrast to these findings, the PI3K inhibitor LY294002 notably amplified neuronal apoptosis in AIS mice.
    CONCLUSIONS: These findings imply that CZTL's ability to inhibit neuronal apoptosis may be linked to the activation of AIS's PI3K/AKT signaling pathway.
    Keywords:  Acute ischemic stroke; Apoptosis; BAX; BCL-2; Chuanzhitongluo; PI3K/AKT
  39. J Biochem. 2023 Nov 28. pii: mvad100. [Epub ahead of print]
      With population aging, cognitive impairments and movement disorders due to neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), are increasingly considered as key social issues. Clinically, it has remained challenging to diagnose them before the onset of symptoms because of difficulty to observe the progressive loss of neurons in the brain. Therefore, with exploratory research into biomarkers, a number of candidates have previously been proposed, such as activities of mitochondrial respiratory chain complexes in blood in AD and PD. In this study, we focused on the formation of mitochondrial respiratory chain supercomplexes (SCs) because the formation of SC itself modulates the activity of each complex. Here we investigated the SC formation in leukocytes from patients with AD, PD, and DLB. Our results showed that SCs were well formed in AD and PD compared with controls, while poorly formed in DLB. We highlighted that the disruption of the SC formation correlated with the progression of PD and DLB. Taking our findings together, we propose that pronounced SC formation would already have occurred before the onset of AD, PD, and DLB and, with the progression of neurodegeneration, the SC formation would gradually be disrupted.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; dementia with Lewy bodies; high-resolution clear native polyacrylamide gel electrophoresis; in-gel activity assay; mitochondrial respiratory chain complexes