bims-nurfan 2023-12-10 papers

bims-nurfan

Biomed News

on NRF2 and Neurological Diseases

Issue of 2023–12–10
35 papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

Ethanol extract of Andrographis paniculata alleviates aluminum-induced neurotoxicity and cognitive impairment through regulating the p62-keap1-Nrf2 pathway.
Aureusidin ameliorates 6-OHDA-induced neurotoxicity via activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway in SH-SY5Y cells and Caenorhabditis elegans.
Artemisinin protects dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in a mouse model of Parkinson's disease.
Inhibition of NADPH oxidase 2 improves cognitive abilities by modulating aquaporin-4 after traumatic brain injury in mice.
Recent progress and applications of small molecule inhibitors of Keap1-Nrf2 axis for neurodegenerative diseases.
Sestrin2 can alleviate endoplasmic reticulum stress to improve traumatic brain injury by activating AMPK/mTORC1 signaling pathway.
TMT-based quantitative proteomics analysis of neuroprotective effects of Forsythoside A on the MPTP-induced Parkinson's disease mouse model.
Induced oxidative stress and apoptosis by 1-bromopropane in SH-SY5Y cells correlates with inhibition of Nrf2 function.
Eriocitrin Alleviates Inflammation and Oxidative Stress in Subarachnoid Hemorrhage by Regulating DUSP14.
Brazilin-7-acetate, a novel potential drug of Parkinson's disease, hinders the formation of α-synuclein fibril, mitigates cytotoxicity, and decreases oxidative stress.
Protective potential of naringenin and its nanoformulations in redox mechanisms of injury and disease.
Echinometra lucunter molecules reduce Aβ42-induced neurotoxicity in SH-SY5Y neuron-like cells: effects on disaggregation and oxidative stress.
Crosstalk between inflammasomes, inflammation, and Nrf2: Implications for gestational diabetes mellitus pathogenesis and therapeutics.
miR-221 and Parkinson's disease: A biomarker with therapeutic potential.
Insufficient autophagy enables the nuclear factor erythroid 2-related factor 2 (NRF2) to promote ferroptosis in morphine-treated SH-SY5Y cells.
Ang-(1-7)/Mas axis ameliorates bleomycin-induced pulmonary fibrosis in mice via restoration of Nox4-Nrf2 redox homeostasis.
HSP90 Inhibition Attenuated Isoflurane-Induced Neurotoxicity in Mice and Human Neuroglioma Cells.
Aerobic exercise combined with chlorogenic acid exerts neuroprotective effects and reverses cognitive decline in Alzheimer's disease model mice (APP/PS1) via the SIRT1/ /PGC-1α/PPARγ signaling pathway.
Tangzhiqing decoction attenuates cognitive dysfunction of mice with type 2 diabetes by regulating AMPK/mTOR autophagy signaling pathway.
Biotin rescues manganese-induced Parkinson's disease phenotypes and neurotoxicity.
Menaquinone-4 attenuates ferroptosis by upregulating DHODH through activation of SIRT1 after subarachnoid hemorrhage.
PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway.
Fasudil mediates neuroprotection in ischemia/reperfusion by modulating the ROCK-PPARα-NOX axis.
Mitochondrial-targeted and ROS-responsive nanocarrier via nose-to-brain pathway for ischemic stroke treatment.
Ferulago angulata Methanolic Extract Protects PC12 Cells Against Beta-amyloid-induced Toxicity.
Nanoparticle-Mediated Delivery of Non-viral Gene Editing Technology to the Brain.
High-fat diet exacerbated motor dysfunction via necroptosis and neuroinflammation in acrylamide-induced neurotoxicity in mice.
Rethinking neurodegenerative diseases: neurometabolic concept linking lipid oxidation to diseases in the central nervous system.
The Effect of PGAM5 on Regulating Mitochondrial Dysfunction in Ischemic Stroke.
Metformin protects retinal pigment epithelium cells against H2O2-induced oxidative stress and inflammation via the Nrf2 signaling cascade.
White matter injury across neurodegenerative disease.
Melamine Exacerbates Neurotoxicity in D-Galactose-Induced Neuronal SH-SY5Y Cells.
Can small molecule GLP-1 agonists be the next first-line drugs in type-2 diabetes mellitus?
Microglial TLR4/NLRP3 Inflammasome Signaling in Alzheimer's Disease.
Activation of Nrf2 antioxidant signaling alleviates gout arthritis pain and inflammation.

BMC Complement Med Ther. 2023 Dec 06. 23(1): 441

Ethanol extract of Andrographis paniculata alleviates aluminum-induced neurotoxicity and cognitive impairment through regulating the p62-keap1-Nrf2 pathway.

Jianping Ma, Miao Zheng, Xinyue Zhang, Jiaqi Lu, Lili Gu.

   BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative and remains incurable. Aluminum is a potent neurotoxin associated with AD. The main pathological features of AD are extracellular amyloid-β protein deposition and intracellular hyperphosphorylated Tau protein. A body of evidence suggest that oxidative stress and autophagy are involved in the pathogenesis of AD. Andrographis paniculata (AP) is a native plant with anti-inflammatory, anti-oxidative stress, and regulation of autophagy properties. AP significantly alleviated cognitive impairments, reduced Aβ deposition and has neuroprotective effect. However, its effects on aluminum-induced AD model have not been studied much. In this study, we investigated whether AP protect against aluminum-induced neurotoxicity through regulation of p62-Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathway and activation autophagy in vivo and in vitro.
METHODS: UPLC-ESI-qTOF-MS/MS was used to identify the chemical constituents of AP ethanol extract. The mice with cognitive deficit were established by injecting aluminum chloride and D-galactose, and treated with either AP extract (200, 400, or 600 mg/kg/d) or andrographolide (2 mg/kg/2d).The spatial memory ability was detected by Morris water maze, HE staining were used to detect in brain tissue,Oxidative stress indexs and SOD activity in both serum and brain tissue were detected by kit.The expression of p62-Nrf2 pathway proteins were measured via western blotting. Furthermore, the neurotoxicity model was induced by aluminum maltolate (700 µM) in PC12 cells. Following AP and andrographolide treatment, the cell viability was detected. The relevant mRNA and protein expressions were detected in cells transfected with the p62 siRNA.
RESULTS: The main active components of AP included andrographolide, neoandrographolide and deoxyandrographolide as identified. AP and andrographolide significantly improved the spatial memory ability of mice, attenuated pathological changes of hippocampal cells, reduced the level of malondialdehyde, and increased superoxide dismutase activity in serum or brain tissue as compared to model control. In addition, the Nrf2, p62 and LC3B-II proteins expression were increased, and p-Tau and Keap1 proteins were decreased in the hippocampus after AP and andrographolide treatment.Furthermore, AP increased aluminum maltolate-induced cell viability in PC12 cells. Silencing p62 could reverse the upregulation expression of Nrf2 and downregulation of Keap1 and Tau proteins induced by AP in aluminum maltolate-treated cells.
CONCLUSIONS: AP had neuroprotective effects against aluminum -induced cognitive dysfunction or cytotoxicity, which was involved in the activation of the p62-keap1-Nrf2 pathway and may develop as therapeutic drugs for the treatment of AD. However, this study has certain limitations, further optimize the protocol or model and study the molecular mechanism of AP improving AD.

Keywords:  Aluminum; Andrographis paniculata; Andrographolide; Autophagy; Cognitive dysfunction; Neuroprotective

DOI:  https://doi.org/10.1186/s12906-023-04290-4
Chem Biol Interact. 2023 Dec 04. pii: S0009-2797(23)00491-X. [Epub ahead of print] 110824

Aureusidin ameliorates 6-OHDA-induced neurotoxicity via activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway in SH-SY5Y cells and Caenorhabditis elegans.

Kun Hu, Susu Zhu, Fanyu Wu, Yongzhen Zhang, Minyue Li, Ling Yuan, Wenjing Huang, Yichi Zhang, Jie Wang, Jie Ren, Hao Yang.

  Movement disorder Parkinson's disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer's disease, which severely affects the quality of patients' lives and imposes an increasingly heavy socioeconomic burden. Aureusidin is a kind of natural flavonoid compound with anti-inflammatory and anti-oxidant activities, while its pharmacological action and mechanism are rarely reported in PD. This study aimed to explore the neuroprotective effects and potential mechanisms of Aureusidin in PD. The present study demonstrated that Aureusidin protected SH-SY5Y cells from cell damage induced by 6-hydroxydopamine (6-OHDA) via inhibiting the mitochondria-dependent apoptosis and activating the Nrf2/HO-1 antioxidant signaling pathway. Additionally, Aureusidin diminished dopaminergic (DA) neuron degeneration induced by 6-OHDA and reduced the aggregation toxicity of α-synuclein (α-Syn) in Caenorhabditis elegans (C. elegans.) In conclusion, Aureusidin showed a neuroprotective effect in the 6-OHDA-induced PD model via activating Nrf2/HO-1 signaling pathway and prevented mitochondria-dependent apoptosis pathway, and these findings suggested that Aureusidin may be an effective drug for the treatment of PD.

Keywords:  Antioxidant; Apoptosis; Aureusidin; Nrf2/HO-1 signaling pathway; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.cbi.2023.110824
Biomed Pharmacother. 2023 Dec 05. pii: S0753-3322(23)01770-5. [Epub ahead of print]170 115972

Artemisinin protects dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in a mouse model of Parkinson's disease.

Hye-Sun Lim, Gunhyuk Park.

  Artemisinin is an antimalarial drug that has been used for almost half a century. However, the anti-Parkinson's disease (PD) effects of artemisinin with respect to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress have not yet been investigated while focusing on NF-E2-related factor 2 (Nrf2) signaling. Thus, we sought to assess the behavioral and oxidative mechanistic effects of artemisinin on MPTP-induced toxicity via the Nrf2 signaling pathway. We explored this through immunohistochemical assays, ELISA, in differentiated PC12 cells treated with siRNA, and with a PD mouse model. Artemisinin increased Nrf2 DNA-binding activity and HO-1 and NQO1 expression. Artemisinin treatment protected cells against MPP+ -induced neuronal death signaling, including NADH dehydrogenase activity, reactive oxygen species, mitochondrial membrane potential, and cleaved caspase-3. Moreover, it protected cells against MPTP-induced behavioral impairments and significantly reduced dopaminergic neuronal loss. Additionally, Nrf2 pre-inhibition using ML385 neutralized the inhibitory effects of artemisinin on dopaminergic neuronal damage and behavioral impairments induced by MPTP. Our results suggest that artemisinin inhibits MPTP-induced behavioral and neurotoxic effects in mice. This provides a foundation for further research to evaluate artemisinin as a potential therapeutic agent for PD.

Keywords:  Artemisinin; Dopamine; ML385; Nrf2

DOI:  https://doi.org/10.1016/j.biopha.2023.115972
Heliyon. 2023 Nov;9(11): e22035

Inhibition of NADPH oxidase 2 improves cognitive abilities by modulating aquaporin-4 after traumatic brain injury in mice.

Ruixing He, Xiaotian Zhang, Cong Pang, Lihui Lin, Shaoxun Li, Luhao Jin, Lianshu Ding, Weijie Wang.

  Traumatic brain injury (TBI) is caused by acquired damage that includes cerebral edema after a mechanical injury and may cause cognitive impairment. We explored the role of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2; NOX2) and aquaporin-4 (AQP4) in the process of edema and cognitive abilities after TBI in NOX2-/- and AQP4-/- mice by using the Morris water maze test (MWM), step-down test (STD), novel object recognition test (NOR) and western blotting. Knockout of NOX2 in mice decreased the AQP4 and reduce edema in the hippocampus and cortex after TBI in mice. Moreover, inhibiting AQP4 by 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) or genetic deletion of AQP4 could attenuate neurological deficits without changing reactive oxygen species (ROS) levels after TBI in mice. Taken together, we suspected that inhibiting NOX2 could improve cognitive abilities by modulating ROS levels, then affecting AQP4 levels and brain edema after in TBI mice. Our study demonstrated that NOX2 play a key role in decreasing edema in brain and improving cognitive abilities by modulating AQP4 after TBI.

Keywords:  AQP4; Brain edema; Cognitive abilities; NOX2; TBI

DOI:  https://doi.org/10.1016/j.heliyon.2023.e22035
Eur J Med Chem. 2023 Nov 29. pii: S0223-5234(23)00965-0. [Epub ahead of print]264 115998

Recent progress and applications of small molecule inhibitors of Keap1-Nrf2 axis for neurodegenerative diseases.

Jing Wang, Yu Cao, Yang Lu, Huajian Zhu, Jiankang Zhang, Jinxin Che, Rangxiao Zhuang, Jiaan Shao.

  The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS) damage in various cells and organs. It has garnered significant attention as a potential therapeutic target for neurodegenerative diseases (NDD). Although progress has been achieved in strategies to regulate the Keap1-Nrf2 pathway, the availability of Nrf2 activators applicable to NDD is currently limited. Currently, the FDA has approved the Nrf2 activators dimethyl fumarate (DMF) and Omaveloxolone (Omav) as novel first-line oral drugs for the treatment of patients with relapsing forms of multiple sclerosis and Friedreich's ataxia. A promising alternative approach involves the direct inhibition of Keap1-Nrf2 protein-protein interactions (PPI), which offers numerous advantages over the use of electrophilic Nrf2 activators, primarily in avoiding off-target effects. This review examines the compelling evidence supporting the beneficial role of Nrf2 in NDD and explores the potential of Keap1 inhibitors and Keap1-Nrf2 PPI inhibitors as therapeutic agents, with the aim to provide further insights into the development of inhibitors targeting this pathway for the treatment of NDD.

Keywords:  Keap1–Nrf2 pathway; Neurodegenerative diseases; Nrf2 activator; PPI

DOI:  https://doi.org/10.1016/j.ejmech.2023.115998
Metab Brain Dis. 2023 Dec 04.

Sestrin2 can alleviate endoplasmic reticulum stress to improve traumatic brain injury by activating AMPK/mTORC1 signaling pathway.

Yu Zhou, Yong Zhang, Benson O A Botchway, Min Huang, Xuehong Liu.

  Traumatic brain injury (TBI), as a serious central nervous system disease, can result in severe neurological dysfunction or even disability and death of patients. The early and effective intervention of secondary brain injury can improve the prognosis of TBI. Endoplasmic reticulum (ER) stress is one of the main reasons to recover TBI. ER stress inhibition may be beneficial in treating TBI. Sestrin2 is a crucial regulator of ER stress, and its activation can significantly improve TBI. In this paper, we analyze the biological function of sestrin2, the latest findings on ER stress, and the relationship between ER stress and TBI. We elucidate the relationship of sestrin2 inhibiting ER stress via activating the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (MTORC1) signaling. Finally, we elaborate on the possible role of sestrin2 in TBI and explain how its activation potentially improves TBI.

Keywords:  Apoptosis; Inflammatory response; Injury; Mitochondrial dysfunction; Neurological dysfunction

DOI:  https://doi.org/10.1007/s11011-023-01323-2
Exp Neurol. 2023 Dec 04. pii: S0014-4886(23)00327-8. [Epub ahead of print] 114642

TMT-based quantitative proteomics analysis of neuroprotective effects of Forsythoside A on the MPTP-induced Parkinson's disease mouse model.

Bo Niu, Minhong Zhao, Xiu''an Gao, Jiangping Xu, Linzhong Yu.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder characteristized by the presence of dyskinesia and the progressive loss of dopaminergic neurons. Although certain drugs can mitigate the symptoms of PD, they are unable to delay the disease progression, and their prolonged use may result in complications. Therefore, there exists an urgent necessity to identify potential agents that can effectively delay PD progression with fewer side effects. Recent research has unveiled that several traditional Chinese medicines (TCM) exhibit neuroprotective properties in various models pertinent to PD. Forsythoside A (FSA), the primary bioactive compound derived from TCM Lianqiao, has undergone extensive research in animal models of Alzheimer's disease and cerebral ischemia. However, the investigation into the impact of FSA on PD is limited in existing research. In this study, we aimed to evaluate the neuroprotective effects of FSA on MPTP-induced PD mouse model. FSA demonstrated significant improvements in the behavioral and neuropathological changes triggered by MPTP in mice. Furthermore, it exerted a suppressive effect on the activation of astrocytes and microglia. Meanwhile, Tandem mass tag (TMT)-based quantitative proteomics of striatal tissue and bioinformatics analysis were performed to elucidate the underlying mechanisms of FSA on PD mouse model. Proteomics demonstrated a total of 68 differentially expressed proteins (DEPs) were identified between MPTP and HFSA groups including 26 upregulated and 42 downregulated. Systematic bioinformatics analysis of the 68 DEPs illustrated that they were predominantly related to estrogen signaling pathway and calcium signaling pathway. The related DEPs (PLCβ4, Grm2, HPAC and Cox4i1) expression levels were verified by Western blot. FSA effectively restored the altered expression of the four DEPs induced by MPTP. Summarily, FSA exerted remarkable neuroprotective effects in MPTP-induced mice. Further, our research may provide proteomics insights that contribute to the further exploration of FSA as a potential treatment for PD.

Keywords:  Forsythoside A; MPTP-induced Parkinson's disease mouse model; Tandem mass tag(TMT)-based quantitative proteomics

DOI:  https://doi.org/10.1016/j.expneurol.2023.114642
Drug Chem Toxicol. 2023 Dec 04. 1-11

Induced oxidative stress and apoptosis by 1-bromopropane in SH-SY5Y cells correlates with inhibition of Nrf2 function.

Guangtao Yang, Wei Zhou, Minhong Zhang, Xiaohuan Zhong, Haili Qiu, Yingping Xiang, Zhimin Zhang, Peimao Li, Dianpeng Wang.

  In this study, we established SH-SY5Y human neuroblastoma cells as an in vitro model to investigate whether oxidative stress and the nuclear erythroid-2 related factor 2 (Nrf2) signaling pathway are associated with 1-bromopropane (1-BP) -induced nerve cell injury. We identified that 1-BP exhibited neurotoxicity mainly through oxidant-based processes in SH-SY5Y cells, as reactive oxygen species, malondialdehyde levels, and 8-hydroxy-2' -deoxyguanosine significantly increased, while superoxide dismutase activity decreased. Furthermore, Nrf2 translocation from the cytosol to the nucleus was inhibited, as was downstream protein expression of the Nrf2-regulated genes HO-1 and Bcl-2. Activation of caspase-9 and -3 increased, and apoptosis was observed. Vitamin C alleviated 1-BP-induced apoptosis by decreasing oxidative stress and activating the Nrf2 signaling pathway. Knockdown of Nrf2 in SH-SY5Y cells increased 1-BP-induced reactive oxygen species production and cell apoptosis, and inhibited HO-1 and Bcl-2 protein expression, while overexpression of Nrf2 alleviated these processes. These findings suggest that 1-BP-induced oxidative stress and apoptosis in SH-SY5Y cells are associated with Nrf2 function inhibition.

Keywords:  1-bromopropane; CRISP R/Cas9; Nrf2; SH-SY5Y; oxidative stress

DOI:  https://doi.org/10.1080/01480545.2023.2288795
Discov Med. 2023 Dec;35(179): 1134-1146

Eriocitrin Alleviates Inflammation and Oxidative Stress in Subarachnoid Hemorrhage by Regulating DUSP14.

Liuqing Sheng, Xiaolong Yao, Jianfeng Ye, Zhizhong Wang, Yinchun Chen, Jun Li, Mingchang Li.

   BACKGROUND: Inflammation and oxidative stress (OS) are major causes of aneurysmal subarachnoid hemorrhage (aSAH)-induced early brain injury (EBI). Eriocitrin (EC), a flavonoid compound, has anti-inflammatory and antioxidant actions. However, there is still no relevant studies on the role of EC in SAH. Accordingly, this research aims to clarify the anti-OS and anti-inflammatory efficacy of EC in SAH.
METHOD: Rat SAH model was established in vivo and administered with Eriocitrin (25 mg/kg). In vitro, BV2 cells were exposed to oxyhemoglobin (OxyHb) for 24 hours and pretreated with Eriocitrin (1 uM/mL, 2 uM/mL, 4 uM/mL) for 30 minutes. Water maze experiments and neurological function scores were conducted to assess cognitive and motor function. TdT-mediated dUTP Nick-End Labeling (TUNEL) staining was used to detect cortical cell apoptosis. Enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) were used to detect the inflammatory factors and malondialdehyde (MDA), as well as the expression of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). Western blots were used to semi quantify nuclear factor erythroid-2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), dual specificity phosphatase 14 (DUSP14) expression.
RESULTS: The findings suggest that EC (25 mg/kg) reduced SAH-induced central nervous system (CNS) damage, neuronal apoptosis, inflammatory reactions and OS. Regarding a mechanistic study, EC enhanced Nrf2 and NF-κB by increasing DUSP14 activation, thereby reducing the inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6. In addition, EC decreased MDA while markedly elevating SOD and enhancing GSH-px. Furthermore, specifically inhibiting DUSP14 expression via using protein-tyrosine-phosphatase (PTP) inhibitor IV, neutralized the protective action of EC and aggravated inflammation and OS. In vitro experiments of OxyHb-induced BV2 cells revealed that EC promoted Nrf2 while markedly suppressing NF-κB by increasing DUSP14 activation, thereby reducing the concentrations of the above inflammatory cytokines. Moreover, EC decreased MDA while evidently increasing SOD and GSH-px.
CONCLUSION: In summary, this paper lays a theoretical grounding for EC treatment of SAH-induced inflammatory reactions and OS by regulating DUSP14.

Keywords:  DUSP14; NF-κB; SAH; eriodocitrin; inflammatory; oxidative stress

DOI:  https://doi.org/10.24976/Discov.Med.202335179.110
Eur J Med Chem. 2023 Nov 23. pii: S0223-5234(23)00932-7. [Epub ahead of print]264 115965

Brazilin-7-acetate, a novel potential drug of Parkinson's disease, hinders the formation of α-synuclein fibril, mitigates cytotoxicity, and decreases oxidative stress.

Zhan Cui, Fang-Yan Guo, Li Li, Fuping Lu, Cheng-Hua Jin, Xiangming Wang, Fufeng Liu.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the accumulation of α-synuclein (α-Syn) aggregates. However, there are currently no effective therapies for PD. Brazilin, an inhibitor of α-Syn aggregation, is unstable and toxic. Therefore, we have developed and synthesized derivatives of brazilin. One of these derivatives, called brazilin-7-acetate (B-7-A), has shown reduced toxicity and a stronger effect on inhibiting α-Syn aggregation. It showed that B-7-A prevented the formation of α-Syn fibers and disrupted existing fibers in a dosage-dependent manner. Additionally, B-7-A significantly reduced the cytotoxicity of α-Syn aggregates and alleviated oxidative stress in PC12 cells. The beneficial effects of B-7-A were also confirmed using the Caenorhabditis elegans model. These effects included preventing the accumulation of α-Syn clumps, improving behavior disorder, increasing lifespan, reducing oxidative stress, and protecting against lipid oxidation and loss. Finally, B-7-A showed good ADMET properties in silico. Based on these findings, B-7-A exhibits potential as a prospective treatment for PD.

Keywords:  Aggregation; Brazilin-7-acetate; Caenorhabditis elegans; Inhibitor; Oxidative stress; Parkinson's disease; α-synuclein

DOI:  https://doi.org/10.1016/j.ejmech.2023.115965
Heliyon. 2023 Dec;9(12): e22820

Protective potential of naringenin and its nanoformulations in redox mechanisms of injury and disease.

Nasrin Mehranfard, Maedeh Ghasemi, Arezoo Rajabian, Legha Ansari.

  Increasing evidence suggests that elevated intracellular levels of reactive oxygen species (ROS) play a significant role in the pathogenesis of many diseases. Increased intracellular levels of ROS can lead to the oxidation of lipids, DNA, and proteins, contributing to cellular damage. Hence, the maintenance of redox hemostasis is essential. Naringenin (NAR) is a flavonoid included in the flavanones subcategory. Various pharmacological actions have been ascribable to this phytochemical composition, including antioxidant, anti-inflammatory, antibacterial, antiviral, antitumor, antiadipogenic, neuro-, and cardio-protective activities. This review focused on the underlying mechanism responsible for the antioxidative stress properties of NAR and its' nanoformulations. Several lines of in vitro and in vivo investigations suggest the effects of NAR and its nanoformulation on their target cells via modulating signaling pathways. These nanoformulations include nanoemulsion, nanocarriers, solid lipid nanoparticles (SLN), and nanomicelle. This review also highlights several beneficial health effects of NAR nanoformulations on human diseases including brain disorders, cancer, rheumatoid arthritis, and small intestine injuries. Employing nanoformulation can improve the pharmacokinetic properties of NAR and consequently efficiency by reducing its limitations, such as low bioavailability. The protective effects of NAR and its' nanoformulations against oxidative stress may be linked to the modulation of Nrf2-heme oxygenase-1, NO/cGMP/potassium channel, COX-2, NF-κB, AMPK/SIRT3, PI3K/Akt/mTOR, BDNF, NOX, and LOX-1 pathways. Understanding the mechanism behind the protective effects of NAR can facilitate drug development for the treatment of oxidative stress-related disorders.

Keywords:  Antioxidant; Nanoformulation; Nanotechnology; Naringenin; Oxidative stress; Redox mechanisms

DOI:  https://doi.org/10.1016/j.heliyon.2023.e22820
J Venom Anim Toxins Incl Trop Dis. 2023 ;29 e20230031

Echinometra lucunter molecules reduce Aβ42-induced neurotoxicity in SH-SY5Y neuron-like cells: effects on disaggregation and oxidative stress.

Amanda Gomes da Silva, Mariana da Mata Alves, Admilson Aparecido da Cunha, Giovanna Arruda Caires, Irina Kerkis, Hugo Vigerelli, Juliana Mozer Sciani.

   Background: Echinometra lucunter is a sea urchin commonly found on America's rocky shores. Its coelomic fluid contains molecules used for defense and biological processes, which may have therapeutic potential for the treatment of amyloid-based neurodegenerative diseases, such as Alzheimer's, that currently have few drug options available.
Methods: In this study, we incubated E. lucunter coelomic fluid (ELCF) and fractions obtained by solid phase extraction in SH-SY5Y neuron-like cells to evaluate their effect on cell viability caused by the oligomerized amyloid peptide 42 (Aβ42o). Moreover, the Aβ42o was quantified after the incubation with ELCF fractions in the presence or not of cells, to evaluate if samples could cause amyloid peptide disaggregation. Antioxidant activity was determined in ELCF fractions, and cells were evaluated to check the oxidative stress after incubation with samples. The most relevant fraction was analyzed by mass spectrometry for identification of molecules.
Results: ELCF and certain fractions could prevent and treat the reduction of cell viability caused by Aβ42o in SH-SY5Y neuron-like cells. We found that one fraction (El50) reduced the oligomerized Aβ42 and the oxidative stress caused by the amyloid peptide through its antioxidant molecules, which in turn reduced cell death. Mass spectrometry analysis revealed that El50 comprises small molecules containing flavonoid antioxidants, such as phenylpyridazine and dihydroquercetin, and two peptides.
Conclusion: Our results suggest that sea urchin molecules may interact with Aβ42o and oxidative stress, preventing or treating neurotoxicity, which may be useful in treating dementia.

Keywords:  Alzheimer’s disease; amyloid peptide 42; oxidative stress; protein clearance; sea urchin

DOI:  https://doi.org/10.1590/1678-9199-JVATITD-2023-0031
Eur J Pharmacol. 2023 Dec 01. pii: S0014-2999(23)00755-0. [Epub ahead of print] 176241

Crosstalk between inflammasomes, inflammation, and Nrf2: Implications for gestational diabetes mellitus pathogenesis and therapeutics.

Vijaya Gayatri, Murali Krishna Prasad, Sundhar Mohandas, Sanjushree Nagarajan, Kriya Kumaran, Kunka Mohanram Ramkumar.

  The role of inflammasomes in gestational diabetes mellitus (GDM) has emerged as a critical area of research in recent years. Inflammasomes, key components of the innate immune system, are now recognized for their involvement in the pathogenesis of GDM. Activation of inflammasomes in response to various triggers during pregnancy can produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), contributing to systemic inflammation and insulin resistance. This dysregulation not only impacts maternal health but also poses significant risks to fetal development and long-term health outcomes. Understanding the intricate interplay between inflammasomes and GDM holds promise for developing novel therapeutic strategies and interventions to mitigate the adverse effects of this condition on both mothers and their offspring. Researchers have elucidated that targeting inflammasomes using anti-inflammatory drugs and compounds can effectively reduce inflammation in GDM. Furthermore, the addition of nuclear factor erythroid 2-related factor 2 (Nrf2) to this complex mechanism opens novel avenues for therapeutics. The antioxidant properties of Nrf2 may potentially suppress inflammasome activation in GDM. This comprehensive review investigates the intricate relationship between inflammasomes and GDM, emphasizing the pivotal role of inflammation in its pathogenesis. It also sheds light on potential therapeutic strategies targeting inflammasome activation and explores the role of Nrf2 in mitigating inflammation in GDM.

Keywords:  Diabetes mellitus; GDM; Inflammasomes; NLRP3; Nrf2

DOI:  https://doi.org/10.1016/j.ejphar.2023.176241
Eur J Neurosci. 2023 Dec 03.

miR-221 and Parkinson's disease: A biomarker with therapeutic potential.

Mohammad Yasin Zamanian, Mehraveh Sadeghi Ivraghi, Reena Gupta, K D V Prasad, Hashem O Alsaab, Beneen M Hussien, Hazem Ahmed, Montather F Ramadan, Maryam Golmohammadi, Nikta Nikbakht, Tuba Oz, Małgorzata Kujawska.

  Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non-motor symptoms. Several cellular and molecular mechanisms such as alpha-synuclein (α-syn) accumulation, mitochondrial dysfunction, oxidative stress and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post-transcriptional gene regulation. They are typically about 21-25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. miRNAs like miR-221 play important roles in various biological processes, including development, cell proliferation, differentiation and apoptosis. miR-221 promotes neuronal survival against oxidative stress and neurite outgrowth and neuronal differentiation. Additionally, the role of miR-221 in PD has been investigated in several studies. According to the results of these studies, (1) miR-221 protects PC12 cells against oxidative stress induced by 6-hydroxydopamine; (2) miR-221 prevents Bax/caspase-3 signalling activation by stopping Bim; (3) miR-221 has moderate predictive power for PD; (4) miR-221 directly targets PTEN, and PTEN over-expression eliminates the protective action of miR-221 on p-AKT expression in PC12 cells; and (5) miRNA-221 controls cell viability and apoptosis by manipulating the Akt signalling pathway in PD. This review study suggested that miR-221 has the potential to be used as a clinical biomarker for PD diagnosis and stage assignment.

Keywords:  Parkinson's disease; biomarkers; miR-221; neuroprotection

DOI:  https://doi.org/10.1111/ejn.16207
Psychopharmacology (Berl). 2023 Dec 05.

Insufficient autophagy enables the nuclear factor erythroid 2-related factor 2 (NRF2) to promote ferroptosis in morphine-treated SH-SY5Y cells.

Xin Huang, Xinyue Yan, Gang Chen, Yue Feng, Yuying Bai, Peng Yan, Jianghua Lai, Shuguang Wei.

   RATIONALE: While morphine has important therapeutic value it is also one of the most widely abused drugs in the world. As a newly discovered style of cell death, ferroptosis is involved in the occurrence and development of many diseases, however, the current understanding of the relationship between ferroptosis and morphine is still limited.
OBJECTIVE: To clarify the role of opioid receptors in morphine-induced ferroptosis and to investigate the role of NRF2 in morphine-induced ferroptosis.
METHODS: We first used different doses of morphine (0, 0.5, 1, and 1.5 mM) to investigate morphine-induced ferroptosis in SH-SY5Y cells, and we choose 1.5 mM morphine for subsequent experiments. We next inhibited opioid receptors and NRF2 separately and examined their influence on morphine-induced ferroptosis. Finally, we tested morphine-induced insufficient autophagy.
RESULTS: Morphine triggered ferroptosis in a dose-dependent manner, which could be significantly rescued by the ferroptosis-specific inhibitor DFO. Moreover, GPX4 rather than xCT antiporter might be involved in morphine-induced ferroptosis. We also found naloxone could inhibit morphine-induced ferroptosis. Interestingly, our results demonstrated that NRF2 could promote rather than defend morphine-induced ferroptosis; this may be due to the increased p62-related insufficient autophagy.
CONCLUSION: Morphine-induced ferroptosis is regulated by the opioid receptor and GPX4 rather than the xCT antiporter. NRF2-mediated ferroptosis in morphine-exposed cells may stem from increased p62-related insufficient autophagy.

Keywords:  Ferroptosis; Insufficient autophagy; Morphine

DOI:  https://doi.org/10.1007/s00213-023-06485-6
Eur J Pharmacol. 2023 Dec 01. pii: S0014-2999(23)00747-1. [Epub ahead of print] 176233

Ang-(1-7)/Mas axis ameliorates bleomycin-induced pulmonary fibrosis in mice via restoration of Nox4-Nrf2 redox homeostasis.

Min Sheng, Qinke Li, Wenhan Huang, Dan Yu, Hang Pan, Kechen Qian, Feifeng Ren, Lei Luo, Lin Tang.

  Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by diffuse alveolar inflammation, fibroblast differentiation, and the excessive deposition of extracellular matrix. During the progression of PF, redox imbalance caused by excessive reactive oxygen species (ROS) production can result in further destruction of lung tissue. At present, data on the role of NADPH oxidase-4 (Nox4)-nuclear factor erythroid 2-related factor 2 (Nrf2) redox imbalance in PF are limited. The angiotensin (1-7) [Ang-(1-7)]/Mas axis is a protective axis in the renin-angiotensin system (RAS) that exerts antifibrotic effects. Therefore, this study aimed to investigate the role of the Ang-(1-7)/Mas axis in PF and to explore its mechanism in depth. The results revealed that the Ang-(1-7)/Mas axis inhibited TGF-β1-induced lung fibroblast differentiation, inflammation and fibrosis in bleomycin (BLM)-treated lung tissue. A mechanistic study suggested that the Ang-(1-7)/Mas axis may restore Nox4-Nrf2 redox homeostasis by upregulating the level of p62, reducing oxidative stress and the inflammatory response and thus delaying the progression of lung fibrosis. This study provides a theoretical basis for exploring the mechanisms of PF and therapeutic targets for PF.

Keywords:  Ang-(1–7)/Mas axis; Fibroblast; Nox4-Nrf2 redox homeostasis; Pulmonary fibrosis

DOI:  https://doi.org/10.1016/j.ejphar.2023.176233
Neurochem Res. 2023 Dec 06.

HSP90 Inhibition Attenuated Isoflurane-Induced Neurotoxicity in Mice and Human Neuroglioma Cells.

Chunlu Zhang, Xi Chen, Ruizhu Liu, Guoqing Zhao.

  Isoflurane, a widely used inhalation anesthetic in clinical practice, is associated with an increased risk of neuronal injury. Heat shock protein 90 (HSP90) plays a crucial role in maintaining neuronal homeostasis under stress conditions; however, its role during isoflurane exposure remains poorly understood. In this study, we aimed to investigate the protective effects of HSP90 inhibition and explore the regulatory mechanisms underlying these effects during isoflurane exposure. We found that the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17 AAG) has great protective effects in mitigating isoflurane-induced ferroptosis of mouse hippocampus and cultured neuronal cells. We focused on the activity of the crucial protein GPX4 in ferroptosis and found that 17 AAG exerted protective effects, preserving the physiological GPX4 activity under isoflurane exposure; further, 17 AAG restored the protein level of GPX4. Further, we observed that the chaperone-mediated autophagy (CMA) pathway was activated; 17 AAG also mediated GPX4 degradation under isoflurane exposure. Additionally, it interfered with the formation of complexes between HSP90 and Lamp-2a, inhibiting CMA activity, followed by the blockade of GPX4 degradation, further affecting the isoflurane-induced ferroptosis. Based on these findings, we proposed HSP90 inhibition as a protective mechanism against isoflurane-induced ferroptosis in neurons.

Keywords:  Anesthetic neurotoxicity; Chaperone-mediated autophagy (CMA); Ferroptosis; Heat shock protein 90 (HSP90)

DOI:  https://doi.org/10.1007/s11064-023-04060-1
Front Aging Neurosci. 2023 ;15 1269952

Aerobic exercise combined with chlorogenic acid exerts neuroprotective effects and reverses cognitive decline in Alzheimer's disease model mice (APP/PS1) via the SIRT1/ /PGC-1α/PPARγ signaling pathway.

Dan Shi, Zikang Hao, Wenxiao Qi, Fengyi Jiang, Kerui Liu, Xiao Shi.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disease account for 60-80% of the total number of people with dementia, but its treatment and prevention strategies are still in a long process of exploration. It has been reported that a healthy lifestyle may be an effective non-pharmacological intervention for the prevention and treatment of AD, including increased physical activity and the consumption of polyphenol-rich foods. This study, therefore, investigated the effects of 8 weeks of moderate-intensity aerobic exercise (EX), administration of chlorogenic acid administration (GCA), and a combination of both (EX+GCA) on β-amyloid (Aβ) deposition, inflammatory factors, oxidative stress markers, neuronal damage, and cognitive performance in the brains of AD model mice (APP/PS1) and which signaling pathways may be responsible for these effects. The study used Western blot to detect the expression of signaling pathway-related proteins, enzyme-linked immunosorbent assay to detect the expression of inflammatory factors, hematoxylin-eosin staining to detect hippocampal neuronal morphology, immunohistochemistry to detect changes in Aβ deposition in the hippocampus, an oxidative stress marker kit to detect oxidative stress status and the Morris water maze to detect changes in cognitive performance. This study showed that an 8-week intervention (EX/GCA/EX+GCA) activating the SIRT1/PGC-1α signaling pathway improved oxidative stress, neuroinflammation, Aβ deposition, and cognitive performance in mice. However, there was no obvious difference between the EX and GCA groups. In contrast, the combined EX+GCA intervention was significantly better than phase EX or GCA. Our study suggests that although relief of Aβ deposition, neuroinflammation, oxidative stress, neuronal damage, and cognitive decline could also be achieved with EX or GCA, the combined EX+GCA intervention showed better results. These relief effects on AD-related conditions may be obtained by mediating the activation of the SIRT1/PGC-1α signaling pathway. This study is the first to explore the improvement of AD-related conditions with a combined lifestyle of EX+GCA. This healthy lifestyle could be a candidate option for the treatment of AD.

Keywords:  Alzheimer’s disease; chlorogenic acid; cognitive deficit; neuroinflammation; oxidative stress; physical activity

DOI:  https://doi.org/10.3389/fnagi.2023.1269952
J Ethnopharmacol. 2023 Dec 04. pii: S0378-8741(23)01406-X. [Epub ahead of print] 117536

Tangzhiqing decoction attenuates cognitive dysfunction of mice with type 2 diabetes by regulating AMPK/mTOR autophagy signaling pathway.

Wenqiang Yao, Qing Zhang, Yun Zhao, Xiru Xu, Shu Zhang, Xu Wang.

   ETHNOPHARMACOLOGICAL RELEVANCE: Tangzhiqing decoction (TZQD) is an effective prescription developed by Jiangsu Province Hospital of Chinese Medicine for the treatment of diabetes mellitus (DM) and its complications, which has a clear cerebral protective effect on mice with diabetic cognitive dysfunction, but its specific mechanism has not been well elucidated.
AIMS OF THE STUDY: This study aims to verify the protection of TZQD on cognitive function in mice with type 2 diabetes mellitus (T2DM) and explore the possible underlying mechanisms.
MATERIALS AND METHODS: Six active ingredients in TZQD were detected using high-performance liquid chromatography analysis. In vivo experiments, the protection of TZQD on cognitive function and hippocampal neurons in type 2 diabetes mice was verified to obtain the optimal intervention dose of TZQD. TZQD and 3-methyladenine (3MA) respectively or jointly intervened in mice with T2DM for 12 weeks, followed by detecting the cognitive difference, hippocampus cornu ammonis 1 (CA1) region injury, and hippocampal neuronal apoptosis in each group. Simultaneously, the investigation of autophagosome formation and organelle impairment in hippocampal neurons, along with the examination of AMPK/mTOR pathway proteins and autophagy-related proteins, was conducted to elucidate the potential mechanisms, through which TZQD modulates autophagy and enhances cognitive function. In vitro experiments, TZQD-containing serum and AMPK inhibitor Compound C (CC) were used to intervene in mouse hippocampal neuron HT22 cells under high glucose environment, further clarifying the regulatory role of TZQD on the AMPK/mTOR pathway and its impact on HT22 cell apoptosis and autophagy.
RESULTS: In vivo experiment results showed that TZQD had an obvious hypoglycemic effect. Different doses of TZQD could improve cognitive function and hippocampus damage in diabetes mice, with the middle dose of TZQD showing the best effect. TZQD increased the swimming speed of diabetes mice, improved their spatial recognition and memory ability, and reduced hippocampal neuronal apoptosis, Nissl body injury, and p-tau217 protein deposition. In addition, through transmission electron microscopy (TEM), immunofluorescence, and western blot (WB) detection, TZQD significantly improved the organelle damage of hippocampal neurons in diabetes mice, promoted the formation of autophagy lysosomes, increased the expression of autophagy-related proteins like Beclin 1, LC3II/LC3I, LAMP1, and LAMP2, reduced the level of P62 and promoted autophagy flow, which, however, were all significantly weakened by 3MA. Meanwhile, TZQD regulated the expressions of AMPK/mTOR pathway proteins. In vitro experimental study results showed that TZQD can regulate the expression ratio of p-AMPK/AMPK alpha 1 and p-mTOR/mTOR in HT22 cells under high glucose conditions and improved the morphology and vitality of HT22 cells. By employing techniques such as monodansylcadaverine (MDC) staining, Lysosomal red fluorescent probe staining, and Annexin V-FITC/PI double staining, the investigation revealed that TZQD administration resulted in enhanced autophagosome formation, preservation of a lysosomal acidic milieu, and consequent mitigation of HT22 cell apoptosis under high glucose conditions.
CONCLUSIONS: TZQD can regulate the AMPK/mTOR pathway to activate autophagy to attenuate hippocampal neuronal apoptosis, thereby protecting cognitive function in diabetic mice.

Keywords:  AMPK/mTOR signaling pathway; Autophagy; Cognitive function; TZQD

DOI:  https://doi.org/10.1016/j.jep.2023.117536
bioRxiv. 2023 Nov 21. pii: 2023.11.21.568033. [Epub ahead of print]

Biotin rescues manganese-induced Parkinson's disease phenotypes and neurotoxicity.

Yunjia Lai, Pablo Reina-Gonzalez, Gali Maor, Gary W Miller, Souvarish Sarkar.

Occupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson's disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying such link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adult Drosophila model of Mn toxicity to recapitulate key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosome and mitochondria. We performed global metabolomics on flies at an early stage of toxicity and identified metabolism of the B vitamin, biotin (vitamin B 7 ), as a master pathway underpinning Mn toxicity with systemic, body-brain increases in Mn-treated groups compared to the controls. Using Btnd RNAi mutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction; while in Mn-exposed wild-type flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)- differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated circulating levels of biotin transporters but not of metabolic enzymes compared to healthy controls, suggesting humoral biotin transport as a key event involved in PD. Taken together, our findings identified compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and parkinsonian pathology, providing new basis for devising effective countermeasures against manganism and PD.
Significance Statement: Environmental exposure to manganese (Mn) may increase the risk for Parkinson's disease (PD); however, the mechanistic basis linking the two remains unclear. Our adult fruit fly ( Drosophila ) model of Mn toxicity recapitulated key Parkinson's hallmarks in vivo spanning behavioral deficits, neuronal loss, and mitochondrial dysfunction. Metabolomics identified the biotin (vitamin B 7 ) pathway as a key mediator, featuring systemic biotin increases in the flies. Rescue trials leveraging biotin-deficient flies, wild-type flies, and human iPSC-derived dopaminergic neurons determined biotin as a driver of manganism, with the parkinsonian phenotypes dramatically reversed through biotin supplementation. Our findings, in line with overexpressed circulating biotin transporters observed in PD patients, suggest compensatory biotin pathway as a key to untangle the Mn-PD link for combating neurodegenerative disease.

DOI: https://doi.org/10.1101/2023.11.21.568033
Free Radic Biol Med. 2023 Nov 30. pii: S0891-5849(23)01132-2. [Epub ahead of print]

Menaquinone-4 attenuates ferroptosis by upregulating DHODH through activation of SIRT1 after subarachnoid hemorrhage.

Jiatong Zhang, Qi Zhu, Zheng Peng, Xiao-Jian Li, Peng-Fei Ding, Sen Gao, Bin Sheng, Yang Liu, Yue Lu, Zong Zhuang, Chun-Hua Hang, Wei Li.

   BACKGROUND: Menaquinone-4(MK-4), the isoform of vitamin K2 in the brain, exerts neuroprotective effects against a variety of central nervous system disorders. This study aimed to demonstrate the anti-ferroptosis effects of MK-4 in neurons after SAH.
METHODS: A subarachnoid hemorrhage (SAH) model was prepared by endovascular perforation in mice. In vitro hemoglobin stimulation of primary cortical neurons mimicked SAH. MK-4, Brequinar (BQR, DHODH inhibitor), and Selisistat (SEL, SIRT1 inhibitor) were administered, respectively. Subsequently, WB, immunofluorescence was used to determine protein expression and localization, and transmission electron microscopy was used to observe neuronal mitochondrial structure while other indicators of ferroptosis were measured.
RESULTS: MK-4 treatment significantly upregulated the protein levels of DHODH; decreased GSH, PTGS2, NOX1, ROS, and restored mitochondrial membrane potential. Meanwhile, MK-4 upregulated the expression of SIRT1 and promoted its entry into the nucleus. BQR or SEL partially abolished the protective effect of MK-4 on, neurologic function, and ferroptosis.
CONCLUSIONS: Taken together, our results suggest that MK-4 attenuates ferroptosis after SAH by upregulating DHODH through the activation of SIRT1.

Keywords:  Dihydroorotate dehydrogenase; Early brain injury; Ferroptosis; Sirtuin 1; Subarachnoid hemorrhage; Vitamin K2

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.031
Int Immunopharmacol. 2023 Dec 03. pii: S1567-5769(23)01522-9. [Epub ahead of print]126 111195

PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway.

Yaling Zheng, Tianrui Zhu, Gang Li, Luran Xu, Yue Zhang.

   BACKGROUND: Ischemic stroke is the second leading cause of death worldwide, and neuroinflammation has been recognized as a critical player in its progression. Meanwhile, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) has been demonstrated to inhibit inflammatory response. However, the effects of PCSK9i on ischemic stroke remain unclear and require further investigation.
METHODS: Temporary middle cerebral artery occlusion (tMCAO) was performed to establish animal models of ischemic stroke in C57BL/6 mice. The PCSK9i were administered subcutaneously after 2 h tMCAO. Neurological function and cerebral infarct volume were measured by mNSS and TTC staining, respectively. RNA-seq was performed to investigate the changes in mechanistic pathways. Western blotting and immunofluorescence were applied to detect expression of GPNMB, CD44, IL-6, and iNOS.
RESULTS: Treatment with PCSK9i significantly improved neurological deficits and reduced the volume of cerebral infarction. PCSK9i suppressed neuroinflammation by activating the GPNMB/CD44 signaling pathway, further exerting their protective effects.
CONCLUSION: Taken together, treatment with PCSK9i is an effective way to prevent ischemic stroke-induced brain injury.

Keywords:  GPNMB; Ischemic stroke; Neuroinflammation; PCSK9i

DOI:  https://doi.org/10.1016/j.intimp.2023.111195
Acta Cir Bras. 2023 ;pii: S0102-86502023000100252. [Epub ahead of print]38 e387023

Fasudil mediates neuroprotection in ischemia/reperfusion by modulating the ROCK-PPARα-NOX axis.

Xitong Yang, Guangming Wang.

PURPOSE: Cerebral ischemia-reperfusion (I/R) is a neurovascular disorder that leads to brain injury. In mice, Fasudil improves nerve injury induced by I/R. However, it is unclear if this is mediated by increased peroxisome proliferator-activated receptor-α (PPARα) expression and reduced oxidative damage. This study aimed to investigate the neuroprotective mechanism of action of Fasudil.
METHODS: MCAO (Middle cerebral artery occlusion) was performed in male C57BL/6J wild-type and PPARα KO mice between September 2021 to April 2023. Mice were treated with Fasudil and saline; 2,3,5-Triphenyltetrazolium chloride (TTC) staining was performed to analyze cerebral infarction. PPARα and Rho-associated protein kinase (ROCK) expression were detected using Western blot, and the expression of NADPH subunit Nox2 mRNA was detected using real-time polymerase chain reaction. The NADPH oxidase activity level and reactive oxygen species (ROS) content were also investigated.
RESULTS: After cerebral ischemia, the volume of cerebral necrosis was reduced in wild-type mice treated with Fasudil. The expression of PPARα was increased, while ROCK was decreased. Nox2 mRNA expression, NADPH oxidase activity, and ROS content decreased. There were no significant changes in cerebral necrosis volumes, NADPH oxidase activity, and ROS content in the PPARα KO mice treated with Fasudil.
CONCLUSIONS: In mice, the neuroprotective effect of Fasudil depends on the expression of PPARα induced by ROCK-PPARα-NOX axis-mediated reduction in ROS and associated oxidative damage.

DOI: https://doi.org/10.1590/acb387023
Acta Pharm Sin B. 2023 Dec;13(12): 5107-5120

Mitochondrial-targeted and ROS-responsive nanocarrier via nose-to-brain pathway for ischemic stroke treatment.

Yan Zhang, Haiyun Zhang, Faquan Zhao, Zhengping Jiang, Yuanlu Cui, Meitong Ou, Lin Mei, Qiangsong Wang.

  Oxidative stress injury and mitochondrial dysfunction are major obstacles to neurological functional recovery after ischemic stroke. The development of new approaches to simultaneously diminish oxidative stress and resist mitochondrial dysfunction is urgently needed. Inspired by the overproduced reactive oxygen species (ROS) at ischemic neuron mitochondria, multifunctional nanoparticles with ROS-responsiveness and mitochondrial-targeted (SPNPs) were engineered, achieving specific targeting delivery and controllable drug release at ischemic penumbra. Due to the nose-to-brain pathway, SPNPs which were encapsulated in a thermo-sensitive gel by intranasal administration were directly delivered to the ischemic penumbra bypassing the blood‒brain barrier (BBB) and enhancing delivery efficiency. The potential of SPNPs for ischemic stroke treatment was systematically evaluated in vitro and in rat models of middle cerebral artery occlusion (MCAO). Results demonstrated the mitochondrial-targeted and protective effects of SPNPs on H2O2-induced oxidative damage in SH-SY5Y cells. In vivo distribution analyzed by fluorescence imaging proved the rapid and enhanced active targeting of SPNPs to the ischemic area in MCAO rats. SPNPs by intranasal administration exhibited superior therapeutic efficacy by alleviating oxidative stress, diminishing inflammation, repairing mitochondrial function, and decreasing apoptosis. This strategy provided a multifunctional delivery system for the effective treatment of ischemic injury, which also implies a potential application prospect for other central nervous diseases.

Keywords:  Inflammation; Ischemic stroke; Mitochondrial targeted; Multifunctional nanocarriers; Nose-to-brain pathway; Oxidative stress; Puerarin; ROS-Responsiveness

DOI:  https://doi.org/10.1016/j.apsb.2023.06.011
Basic Clin Neurosci. 2023 Jul-Aug;14(4):14(4): 453-462

Ferulago angulata Methanolic Extract Protects PC12 Cells Against Beta-amyloid-induced Toxicity.

Leila Hashemi, Maliheh Soodi, Homa Hajimehdipoor, Abolfazl Dashti.

   Introduction: Alzheimer's disease (AD) is an age-dependent neurodegenerative disease. Beta-amyloid (Aβ)-induced neurotoxicity has a pivotal role in AD pathogenesis; therefore, the modulation of Aβ toxicity is the promising therapeutic approach to control the disease progression. Medicinal plants because of their multiple active ingredients are effective in complex diseases, such as AD. Therefore, several studies have studied medicinal plants to find an effective treatment for AD. Ferulago angulata is a medicinal plant with antioxidant and neuroprotective activity. The present study was done to assess the protective effect of the methanolic extract of Ferulago angulate on Aβ-induced toxicity and oxidative stress in PC12 cells.
Methods: The methanolic extract of aerial parts of the plant was prepared by the maceration method. PC12 cells were cultured according to a standard protocol. PC12 cells were incubated for 24 hours with Aβ alone, and Aβ in combination with various concentrations of the F. angulata extract. Cell viability was determined by the methyl thiazole tetrazolium (MTT) assay. Also, reactive oxygen species (ROS) production and the activity of acetylcholine esterase (AChE), glutathione peroxidase (GPx), and caspase-3 enzymes were measured.
Results: The extract dose-dependently protected PC12 cells against Aβ-induced cell death. Also, Aβ increased ROS production, AChE, and caspase-3 activity, and decreased the GPx activity, which all were ameliorated by F. angulata extract.
Conclusion: F. angulata extract protects against Aβ-induced oxidative stress and apoptosis. These effects may be due to the antioxidant and anticholinesterase activity of the extract. It is recommended to assess F. angulata extract as an anti-AD agent.
Highlights: Ferulago angulata extract dose-dependently ameliorates Aβ-induced cytotoxicity in PC12 cells.Aβ induced oxidative stress in PC12 cells, which was attenuated by the F. angulata extract.Aβ increased acetylcholinesterase activity in PC12 cells, which was prevented by the F. angulata extract.
Plain Language Summary: Alzheimer's disease (AD) is a common form of dementia in the elderly with a complex pathophysiology. Beta-amyloid (Aβ)- induced neurotoxicity plays a pivotal role in AD progression. So far, there is no cure for AD. Medicinal plants contain various pharmacologically active compounds that make them suitable for the treatment of complex diseases. In this study, the anti-AD effect of F. angulata extract was investigated by assessing its protective effect against Aβ-induced toxicity in PC12 cells F. angulata extract improved Aβ-induced toxicity by diminishing oxidative stress and apoptosis. Therefore, F. angulata extract merits further studies for use in the treatment of AD.

Keywords:  Alzheimer’s disease; Beta-amyloid; Ferulago angulate; Oxidative stress

DOI:  https://doi.org/10.32598/bcn.2022.919.2
Prog Neurobiol. 2023 Nov 30. pii: S0301-0082(23)00148-X. [Epub ahead of print] 102547

Nanoparticle-Mediated Delivery of Non-viral Gene Editing Technology to the Brain.

Lucian Williams, Jessica Larsen.

  Neurological disorders pose a significant burden on individuals and society, affecting millions worldwide. These disorders, including but not limited to Alzheimer's disease, Parkinson's disease, and Huntington's disease, often have limited treatment options and can lead to progressive degeneration and disability. Gene editing technologies offer a promising avenue for potential cures by targeting and correcting the underlying genetic mutations responsible for neurologic disorders. However, efficient delivery methods are crucial for the successful application of gene editing technologies in the context of neurological disorders. The central nervous system presents unique challenges to treatment development due to the blood-brain barrier, which restricts the entry of large molecules. While viral vectors are traditionally used for gene delivery, nonviral delivery methods, such as nanoparticle-mediated delivery, offer safer alternatives that can efficiently transport gene editing components. Herein we aim to introduce the three main gene editing nucleases as nonviral treatments for neurologic disorders, the delivery barriers associated with brain targeting, and the current nonviral techniques used for brain-specific delivery. We highlight the challenges and opportunities for future research in this exciting and growing field that could lead to blood-brain barrier bypassing therapeutic gene editing. Neurological disorders pose a significant burden on individuals and society, affecting millions worldwide. These disorders, including but not limited to Alzheimer's disease, Parkinson's disease, and Huntington's disease, often have limited treatment options and can lead to progressive degeneration and disability. Gene editing technologies, including Zinc Finger Nucleases (ZFN), Transcription Activator-Like Effector Nucleases (TALEN), and Clustered Regularly Interspaced Short Palindromic Repeats-associated Protein 9 (CRISPR-Cas9), offer a promising avenue for potential cures by targeting and correcting the underlying genetic mutations responsible for neurologic disorders. However, efficient delivery methods are crucial for the successful application of gene editing technologies in the context of neurological disorders. The central nervous system presents unique challenges to treatment development due to the blood-brain barrier, which restricts the entry of large molecules. While viral vectors are traditionally used for gene delivery, nonviral delivery methods, such as nanoparticle-mediated delivery, offer safer alternatives that can efficiently transport gene editing components. Herein we aim to introduce the three main gene editing nucleases as nonviral treatments for neurologic disorders, the delivery barriers associated with brain targeting, and the current nonviral techniques used for brain-specific delivery. We highlight the challenges and opportunities for future research in this exciting and growing field that could lead to blood-brain barrier bypassing therapeutic gene editing.

Keywords:  Gene Editing Technologies; Genome Editing; Non-viral vectors; blood-brain barrier

DOI:  https://doi.org/10.1016/j.pneurobio.2023.102547
Ecotoxicol Environ Saf. 2023 Dec 05. pii: S0147-6513(23)01281-2. [Epub ahead of print]269 115777

High-fat diet exacerbated motor dysfunction via necroptosis and neuroinflammation in acrylamide-induced neurotoxicity in mice.

Yalong Qiang, Mingxue Song, Shuai Wang, Zhidan Liu, Shulin Shan, Yanan Sun, Wenting Ni, Shihua Chao, Zhaoxiong Liu, Xiulan Zhao, Yao Bai, Fuyong Song.

  Health risks associated with acrylamide (ACR) or high-fat diet (HFD) exposure alone have been widely concerned in recent years. In a realistic situation, ACR and HFD are generally co-existence, and both are risk factors for the development of neurological diseases. The purpose of the present study was to investigate the combined effects of ACR and HFD on the motor nerve function. As a result, neurobehavioral tests and Nissl staining disclosed that long-term HFD exacerbated motor dysfunction and the damage of spinal cord motor neurons in ACR-exposed mice. Co-exposure of ACR and HFD resulted in morphological changes in neuronal mitochondria of the spinal cord, a significantly reduced mitochondrial subunits NDUFS1, UQCRC2, and MTCO1, released the mitochondrial DNA (mtDNA) into the cytoplasm, and promoted the production of reactive oxygen species (ROS). Combined exposure of HFD and ACR activated the calpain/CDK5/Drp1 axis and caused the mitochondrial excessive division, ultimately increasing MLKL-mediated necroptosis in spinal cord motor neurons. Meanwhile, HFD significantly exacerbated ACR-induced activation of NFkB, NLRP3 inflammasome, and cGAS-STING pathway. Taken together, our findings demonstrated that combined exposure of ACR and HFD aggravated the damage of spinal cord motor neurons via neuroinflammation and necroptosis signaling pathway, pointing to additive effects in mice than the individual stress effects.

Keywords:  Acrylamide; High-fat diet; Mitochondrial dysfunction; Necroptosis; Neuroinflammation; Neurotoxicity

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115777
Neural Regen Res. 2024 Jul 01. 19(7): 1437-1445

Rethinking neurodegenerative diseases: neurometabolic concept linking lipid oxidation to diseases in the central nervous system.

Steinunn Sara Helgudóttir, Anne Skøttrup Mørkholt, Jacek Lichota, Preben Bruun-Nyzell, Mads Christian Andersen, Nanna Marie Juhl Kristensen, Amanda Krøger Johansen, Mikela Reinholdt Zinn, Hulda Maria Jensdóttir, John Dirk Vestergaard Nieland.

ABSTRACT: Currently, there is a lack of effective medicines capable of halting or reversing the progression of neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, or Alzheimer's disease. Given the unmet medical need, it is necessary to reevaluate the existing paradigms of how to target these diseases. When considering neurodegenerative diseases from a systemic neurometabolic perspective, it becomes possible to explain the shared pathological features. This innovative approach presented in this paper draws upon extensive research conducted by the authors and researchers worldwide. In this review, we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases. We provide an overview of the risk factors associated with developing neurodegenerative disorders, including genetic, epigenetic, and environmental factors. Additionally, we examine pathological mechanisms implicated in these diseases such as oxidative stress, accumulation of misfolded proteins, inflammation, demyelination, death of neurons, insulin resistance, dysbiosis, and neurotransmitter disturbances. Finally, we outline a proposal for the restoration of mitochondrial metabolism, a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

DOI: https://doi.org/10.4103/1673-5374.387965
Discov Med. 2023 Dec;35(179): 1123-1133

The Effect of PGAM5 on Regulating Mitochondrial Dysfunction in Ischemic Stroke.

Chunli Ma, Qing Gao, Li Zhang, Chao Li, Geng Wu, Lei Yang.

   BACKGROUND: Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to patients and society, making the exploration of new therapeutic targets for preventing and treating ischemic stroke urgent. This study aimed to explore the effect of phosphoglycerate mutase family member 5 (PGAM5) on oxidative stress and mitochondrial dysfunction in ischemic stroke.
METHODS: The model of ischemic neuronal brain injury was established through culturing purchased human neuroblastoma cells (SH-SY5Y) by oxygen-glucose deprivation/reoxygenation (OGD/R). There were six experimental groups, including the OGD/R model group (SH-cells of OGD/R model), OE-NC group (cells of OGD/R model transfected with scramble cDNA), OE-PGAM5 group (cells of OGD/R model transfected with full-length sequence of PGAM5), si-NC group (cells of OGD/R model transfected with negative control small interference (si)RNA), si-PGAM5 group (cells of OGD/R model transfected with siRNA for PGAM5 knockdown), and a control group (cells cultured normally). Cell counting kit-8 (CCK-8) and flow cytometry were used to determine the activity and apoptosis of cells. Subsequently, the effects of PGAM5 expression on oxidative stress and mitochondrial dysfunction were analyzed. Mitochondrial morphology was observed by transmission electron microscopy (TEM), and mitochondrial membrane potential (MMP) was determined by JC-1 fluorescent probe. The levels of reactive oxygen species (ROS) were measured by flow cytometry, and levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay (ELISA) assay. The expression of light chain (LC)3-II/I and autophagy-related gene 5 (ATG5) proteins were measured, and the regulation of PGAM5 expression on PTEN-induced putative protein kinase 1 (PINK1)/Parkin pathway was also explored.
RESULTS: PGAM5 overexpression in OGD/R cells decreased the cell viability (p < 0.001) while increasing cell apoptosis (p < 0.01) compared to the OGD/R group. Inhibition of PGAM5 expression reversed the decreased cell viability (p < 0.001) and the increased cell apoptosis (p < 0.01). The JC-1 fluorescence showed that OGD/R treatment reduced mitochondrial membrane potential (p < 0.001) and TEM showed an obvious increase in phagosomes. In addition, OGD/R treatment enhanced oxidative stress (increased ROS, p < 0.01; increased MDA, p < 0.001; decreased SOD, p < 0.001), which could be further enhanced by overexpression of PGAM5 (ROS, p < 0.001; MDA, p < 0.001; SOD, p < 0.001) while reversed by the inhibition of PGAM5 (ROS, p < 0.01; MDA, p < 0.001; SOD, p < 0.001). The OGD/R-activated PINK1/Parkin pathway was inhibited by the knockdown of PGAM5 (p < 0.01) but promoted by the overexpression of PGAM5 (p < 0.05).
CONCLUSIONS: PGAM5 stimulates oxidative stress and impairs mitochondrial function in ischemic stroke, and regulates the PINK1/Parkin signaling pathway. Therefore, PGAM5 is likely to be a target for the therapy of ischemic stroke.

Keywords:  PGAM5; PINK1/Parkin pathway; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.24976/Discov.Med.202335179.109
Graefes Arch Clin Exp Ophthalmol. 2023 Dec 07.

Metformin protects retinal pigment epithelium cells against H2O2-induced oxidative stress and inflammation via the Nrf2 signaling cascade.

Qiting Feng, Xiangcai Ruan, Min Lu, Shimiao Bu, Yuehong Zhang.

   PURPOSE: Dysfunctions of retinal pigment epithelium (RPE) attributed to oxidative stress and inflammation are implicated with age-related macular degeneration (AMD). A debate on the curative role of metformin in AMD has been raised, though several recent clinical studies support the lower odds by using metformin. This study aimed to determine whether metformin could exert cytoprotection against RPE oxidative damages and the potential mechanisms.
METHODS: A cellular AMD model was established by treating ARPE-19 cells with hydrogen peroxide (H2O2) for 24 h. The reactive oxygen species (ROS) generation, expression of antioxidant enzymes, and levels of pro-inflammatory cytokines were monitored under administrations with H2O2 with/without metformin. The expression and DNA-binding activity of transcription factor erythroid-related factor 2 (Nrf2) were determined by western blot, immunofluorescence, and electrophoretic mobility shift assay. Knockout of Nrf2 was conducted by CRISPR/Cas9 gene deletion system.
RESULTS: Metformin pretreatment significantly improved the H2O2-induced low viability of ARPE-19 cells, reduced ROS production, and increased contents of antioxidative molecules. Concurrently, metformin also suppressed levels of pro-inflammatory cytokines caused by H2O2. The metformin-augmented nuclear translocation and DNA-binding activity of Nrf2 were further verified by the increased expression of its downstream targets. Genetic deletion of Nrf2 blocked the cytoprotective role of metformin.
CONCLUSION: Metformin possesses antioxidative and anti-inflammatory properties in ARPE-19 cells by activating the Nrf2 signaling. It supports the potential use for the control and prevention of AMD.

Keywords:  Age-related macular degeneration; Inflammation; Metformin; Nrf2; Oxidative stress; Retinal pigment epithelial cells

DOI:  https://doi.org/10.1007/s00417-023-06321-9
Trends Neurosci. 2023 Dec 04. pii: S0166-2236(23)00263-1. [Epub ahead of print]

White matter injury across neurodegenerative disease.

Lindsay K Festa, Judith B Grinspan, Kelly L Jordan-Sciutto.

  Oligodendrocytes (OLs), the myelin-generating cells of the central nervous system (CNS), are active players in shaping neuronal circuitry and function. It has become increasingly apparent that injury to cells within the OL lineage plays a central role in neurodegeneration. In this review, we focus primarily on three degenerative disorders in which white matter loss is well documented: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We discuss clinical data implicating white matter injury as a key feature of these disorders, as well as shared and divergent phenotypes between them. We examine the cellular and molecular mechanisms underlying the alterations to OLs, including chronic neuroinflammation, aggregation of proteins, lipid dysregulation, and organellar stress. Last, we highlight prospects for therapeutic intervention targeting the OL lineage to restore function.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; lipid dysregulation; neuroinflammation; organellar stress

DOI:  https://doi.org/10.1016/j.tins.2023.11.003
J Aging Res. 2023 ;2023 6635370

Melamine Exacerbates Neurotoxicity in D-Galactose-Induced Neuronal SH-SY5Y Cells.

Juhi Goyal, Preet Jain, Vivek Jain, Dibyajyoti Banerjee, Rajasri Bhattacharyya, Sharmistha Dey, Rambabu Sharma, Nitish Rai.

Numerous studies have depicted the role of diet and environmental toxins in aging. Melamine (Mel) is a globally known notorious food adulterant, and its toxicity has been shown in several organs including the brain. However, till now, there are no reports regarding Mel neurotoxicity in aging neurons. So, this study examined the in vitro neurotoxicity caused by Mel in the D-galactose (DG)-induced aging model of neuronal SH-SY5Y cells. In the present study, the neuronal SH-SY5Y cells were treated with DG and Mel separately and in combination to assess the neurotoxicity potential using MTT assay and neurite length measurement. Further, the superoxide dismutase (SOD), catalase (CAT), and total antioxidant activities were evaluated followed by the determination of the intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase3 (Casp3) activity. The cotreatment of Mel and DG in neuronal SH-SY5Y cells showed maximum cell death than the cells treated with DG or Mel individually and untreated control cells. The neurite length shrinkage and ROS production were maximum in the DG and Mel cotreated cells showing exacerbated toxicity of Mel. The activity of SOD, CAT, and total antioxidants was also found to be lowered in the cotreatment group (Mel + DG) than in Mel- or DG-treated and untreated cells. Further, the combined toxicity of Mel and DG also elevated the Casp3 activity more than any other group. This is the first study showing the increased neurotoxic potential of Mel in an aging model of neuronal SH-SY5Y cells which implicates that Mel consumption by the elderly may lead to increased incidences of neurodegeneration like Alzheimer's disease and Parkinson's disease.

DOI: https://doi.org/10.1155/2023/6635370
J Basic Clin Physiol Pharmacol. 2023 Dec 05.

Can small molecule GLP-1 agonists be the next first-line drugs in type-2 diabetes mellitus?

Rajmohan Seetharaman, Swarnima Pandit.



Keywords:  affordability; enhanced efficacy; incretins; orforglipron; retatrutide

DOI:  https://doi.org/10.1515/jbcpp-2023-0234
J Alzheimers Dis. 2023 Nov 30.

Microglial TLR4/NLRP3 Inflammasome Signaling in Alzheimer's Disease.

Yunfeng Li, Xiongjin Chen, Mulan Zhou, Sifan Feng, Xiaoping Peng, Yan Wang.

  Alzheimer's disease is a pervasive neurodegenerative disease that is estimated to represent approximately 70% of dementia cases worldwide, and the molecular complexity that has been highlighted remains poorly understood. The accumulation of extracellular amyloid-β (Aβ), intracellular neurofibrillary tangles formed by tau hyperphosphorylation, and neuroinflammation are the major pathological features of Alzheimer's disease (AD). Over the years, there has been no apparent breakthrough in drug discovery based on the Aβ and tau hypotheses. Neuroinflammation has gradually become a hot spot in AD treatment research. As the primary cells of innate immunity in the central nervous system, microglia play a key role in neuroinflammation. Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes are vital molecules in neuroinflammation. In the pathological context of AD, the complex interplay between TLR4 and the NLRP3 inflammasomes in microglia influences AD pathology via neuroinflammation. In this review, the effect of the activation and inhibition of TLR4 and NLRP3 in microglia on AD pathology, as well as the cross-talk between TLR4 and the NLRP3 inflammasome, and the influence of essential molecules in the relevant signaling pathway on AD pathology, were expounded. In addition, the feasibility of these factors in representing a potential treatment option for AD has been clarified.

Keywords:  Alzheimer’s disease; NLRP3 inflammasomes; TLR4; microglia

DOI:  https://doi.org/10.3233/JAD-230273
Biomed Pharmacother. 2023 Dec 01. pii: S0753-3322(23)01755-9. [Epub ahead of print]170 115957

Activation of Nrf2 antioxidant signaling alleviates gout arthritis pain and inflammation.

Danyi Zeng, Chengyu Yin, Huina Wei, Yuanyuan Li, Yunqin Yang, Huimin Nie, Yushuang Pan, Ruoyao Xu, Yan Tai, Junying Du, Jinggen Liu, Ping Wang, Boyu Liu, Boyi Liu.

  Excessive deposition of monosodium urate (MSU) crystal in the joint results in gout arthritis, which triggers severe pain and affects life quality. Oxidative stress is a pivotal mechanism that contributes to etiology of gout pain and inflammation. Here we investigated whether activating Nrf2, which plays important roles in regulating endogenous antioxidant response, would attenuate gout arthritis via promoting antioxidant signaling in joint tissues. Gout arthritis model was established by intra-articular injection of MSU (500 μg/ankle) into the right ankle joint of mouse. Pharmacologically activating Nrf2 by activator oltipraz (50, 100 or 150 mg/kg, intraperitoneal) at 1 h before and 5, 23, 47 h after model establishment dose-dependently inhibited joint inflammation, mechanical and heat hypersensitivities in model mice. Oltipraz (100 mg/kg) reversed gait impairments without altering locomotor activity and reduced neutrophil infiltrations in ankle joints. In vitro studies revealed oltipraz (25 μM) inhibited MSU-induced ROS production in mouse macrophages and improved mitochondrial bioenergetics impairments caused by MSU. In vivo ROS imaging combined with biochemical assays confirmed the antioxidant effects of oltipraz on model mice. Nrf2 activation inhibited pro-inflammatory cytokine overproduction in ankle joint and attenuated the overexpression and enhancement in TRPV1 channel in DRG neurons innervating hind limb. Therapeutic effects of oltipraz were abolished by inhibiting Nrf2 or in Nrf2 knockout mice. These results suggest pharmacologically activating Nrf2 alleviates gout pain, gait impairments, inflammation and peripheral sensitization via Nrf2-dependent antioxidant mechanism. Targeting Nrf2 may represent a novel treatment option for gout arthritis.

Keywords:  Gout; Inflammation; Nrf2; Pain; ROS; TRPV1

DOI:  https://doi.org/10.1016/j.biopha.2023.115957