Parkinson's disease (PD) is a complex neurodegenerative disease, which is often treated with obvious side effects such as dopamine replacement therapy. Our team has validated the unique advantages of the traditional Chinese medicine formula, YiQiWenYangSanHan formula (YQWYSHF), through in vitro experiments, confirming its therapeutic potential for PD. Nevertheless, further research and validation are required to fully understand its protective effects and underlying mechanisms against PD.

This study employed an in vivo model to investigate the effects of YQWYSHF on motor impairments, neuroinflammation, and mitochondrial dysfunction in C57BL/6 J mice caused by MPTP.

Sixty C57BL/6 J mice were randomly divided into 5 groups, all groups except the control group were intraperitoneally administered MPTP for 7 days (30 mg/kg). After 4 weeks of drug intragastric treatment, we assessed the dyskinesia of mice treated with different doses of YQWYSHF by behavioral examination. Additionally, immunofluorescence was used to examine the expression of ionized calcium binding adaptor protein 1 (IBA1) and glial fibrillary acidic protein-positive (GFAP) cells. Western blotting was used to assess the expression level of tyrosine hydroxylase (TH), pyrin domain-containing 3 protein (NLRP3), apoptosis-associated speck-like proteins (ASC), cysteine-containing aspartate protease-1 (Caspase-1), interleukin-1β (IL-1β), α-synuclein (α-syn), poly (ADP-ribose) polymerase 1 (PARP1), and poly ADP ribose (PAR). Furthermore, transmission electron microscopy revealed mitochondrial impairment in the neuronal cells of the substantia nigra (SN).

YQWYSHF treatment alleviated dyskinesia in a mouse model of PD. Moreover, it increased the TH expression, and could reverse the increase of IBA1, GFAP, NLRP3, ASC, caspase-1,IL-1β, α-syn, PARP1 and PAR proteins induced by MPTP.

YQWYSHF protects dopaminergic neurons in PD by attenuating neuroinflammation and mitochondrial dysfunction. This study provides new evidence for the clinical application of traditional Chinese medicine in the treatment of PD.

Perioperative neurocognitive disorders (PND), common complications that occur after anesthetized surgery in elderly patients, are major challenges to our rapidly growing aging population. The transcription factor known as nuclear factor erythroid-2-related factor 2 (Nrf2) is an essential component of the cellular antioxidant response, purportedly contributing to the preservation of cognitive functions such as learning and memory. Nevertheless, the function and intracellular processes involving Nrf2 in PND remain largely unknown. Therefore, we evaluate the influence and fundamental mechanism of Nrf2 on PND in aged mice. To establish the postoperative neurocognitive dysfunction (PND) model, aged mice were subjected to anesthesia via inhalation of 3% sevoflurane for a duration of 2 h. The role of Nrf2 in PND was investigated by administering microinjections of either the adeno-associated virus (AAV)-Nrf2 vector or a null virus vector into the hippocampal CA1 region of aged mice 28 days before exposure to sevoflurane. Various assays including enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blotting were employed to assess levels of pro-inflammatory cytokines, microglial activation, and the oxidative stress response. Furthermore, synaptic plasticity was evaluated through long-term potentiation (LTP) recording and Golgi staining techniques. Elevated expression of Nrf2 within the hippocampal CA1 region ameliorated sevoflurane-induced cognitive deficits, synaptic plasticity anomalies, and the oxidative stress reaction in aged mice. Furthermore, the activation of microglia and the release of pro-inflammatory cytokines (including IL-6, TNF-α, and IL-1β) within the hippocampus post-sevoflurane exposure were modulated in an Nrf2-dependent fashion. Based on the findings from present research, we conclude that Nrf2 ameliorates sevoflurane-induced cognitive dysfunction by inhibiting hippocampal neuroinflammation, thereby proposing a potential therapeutic target for PND.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by classical symptoms including bradykinesia, rest tremor and rigidity. Oxidative stress and mitochondrial dysfunction are recognized as pivotal factors in PD progression. Gentiopicroside (GPS), a secoiridoid derived from Gentiana manshurica Kitagawa, exhibits antioxidant and mitophagy induction properties. Nonetheless, the effects and mechanisms by which GPS mitigates neurodegeneration in PD remain to be thoroughly elucidated.

The goal of this study was to investigate the neuroprotective effects and mechanisms of GPS in PD models.

We established the MPTP/MPP+-induced PD models to measure the neuroprotection of GPS. Transcriptomic analysis, oxidative biochemical kits, western blot and cell immunofluorescence were conducted to elucidate the fundamental mechanisms at play. Subsequently, the targeting and activation of the transmembrane G protein-coupled receptor-5 (TGR5) by GPS were measured by molecular docking, cellular thermal shift assay, microscale thermophoresis (MST) and cyclic adenosine monophosphate (cAMP) quantitation. Finally, we verified whether the neuroprotective and antioxidant effects of GPS were dependent on TGR5 by using specific small interfering RNA (siRNA), pharmacological antagonist and knockout mice.

GPS significantly attenuated dopaminergic (DAergic) neuron loss and restored motor function in the MPTP-induced PD mouse model. Whole-genome RNA sequencing and subsequent mechanistic investigations revealed that GPS enhanced the expression and facilitated nuclear entry of factor erythroid-related 2-factor 2 (Nrf2), and reduced oxidative stress and mitochondrial dysfunction stimulated by neurotoxin. Additionally, GPS could target TGR5 and prevent its downregulation in PD model. TGR5's silencing or inhibition weakened the neuroprotective effect of GPS and blocked GPS-mediated activation of Nrf2 antioxidant signaling in PD model. Moreover, the therapeutic effect of GPS in mitigating motor deficits and neurodegeneration was also abolished in Tgr5 knockout mice.

These findings collectively indicated that GPS targeted TGR5 to activate Nrf2 antioxidant signaling and ultimately ameliorated the pathological progression of PD.

Neurological disorders arising from structural and functional disruptions in the nervous system present major global health challenges. This review examines the intricacies of various cellular signaling pathways, including Nrf2/Keap1/HO-1, SIRT-1, JAK/STAT3/mTOR, and BACE-1/gamma-secretase/MAPT, which play pivotal roles in neuronal health and pathology. The Nrf2-Keap1 pathway, a key antioxidant response mechanism, mitigates oxidative stress, while SIRT-1 contributes to mitochondrial integrity and inflammation control. Dysregulation of these pathways has been identified in neurodegenerative and neuropsychiatric disorders, including Alzheimer's and Parkinson's diseases, characterized by inflammation, protein aggregation, and mitochondrial dysfunction. Additionally, the JAK/STAT3 signaling pathway emphasizes the connection between cytokine responses and neuroinflammation, further compounding disease progression. This review explores the crosstalk among these signaling networks, elucidating how their disruption leads to neuronal decline. It also addresses the dual roles of these pathways, presenting challenges in targeting them for therapeutic purposes. Despite the potential benefits of activating neuroprotective pathways, excessive stimulation may cause deleterious effects, including tumorigenesis. Future research should focus on designing multi-targeted therapies that enhance the effectiveness and safety of treatments, considering individual variabilities and the obstacles posed by the blood-brain barrier to drug delivery. Understanding these complex signaling interactions is crucial for developing innovative and effective neuroprotective strategies that could significantly improve the management of neurological disorders.

Parkinson's disease (PD)-a progressive neurodegenerative disorder-is characterized by motor and gastrointestinal dysfunction. The exploration of novel therapeutic strategies for PD is vital.

To investigate the potential mechanism of action of rhapontin-a natural compound with known antioxidant and anti-inflammatory properties-in the context of PD.

Network pharmacology was used to predict the targets and mechanisms of action of rhapontin in PD. Behavioral tests and tyrosine hydroxylase immunofluorescence analysis were used to assess the effect of rhapontin on symptoms and pathology in MPTP-induced mice. Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and IL-10 levels in tissues were measured using an enzyme-linked immunosorbent assay (ELISA). Additionally, nuclear factor erythroid 2-related factor 2 (NRF2) activation was confirmed using western blotting.

NRF2 was predicted to be the key transcription factor underlying the therapeutic effects of rhapontin in PD, and its anti-PD action may be associated with its anti-inflammatory and antioxidant properties. Rhapontin ameliorated the loss of dopaminergic neurons and gastrointestinal dysfunction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice by activating NRF2. Additionally, rhapontin treatment significantly decreased pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) in the substantia nigra, striatum, and colon, whereas it increased anti-inflammatory cytokine (IL-10) levels only in the colon, indicating the involvement of gut-brain axis in its neuroprotective potential. Finally, NRF2 was identified as a key transcription factor activated by rhapontin, particularly in the colon.

We elucidated the effects of rhapontin in MPTP-induced PD mouse models using a combination of network pharmacology analysis, behavioral assessments, immunofluorescence, ELISA, and Western blotting. Our findings revealed the multifaceted role of rhapontin in ameliorating PD through its anti-inflammatory and antioxidant properties, particularly by activating NRF2, paving the way for future research into targeted therapies for PD.

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor symptoms such as tremors, rigidity, and bradykinesia. Although the exact etiology is unknown, the nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome-induced inflammation, plays a crucial role in the pathogenesis of Parkinson's disease. Many NLRP3 inhibitors are recognized for their role as potential therapeutic interventions for Parkinson's disease.

A systematic literature search was performed in PubMed, Embase, and Science Direct databases for papers published during the 10 years prior to May 2023. All animal interventional studies assessing the effects of NLRP3 inhibitors on Parkinson's disease animal models were included. Primary outcomes included NLRP3 inflammasome inhibition, microglial activation reduction, oxidative stress, and anti-inflammatory marker reduction. The secondary outcomes included dopaminergic neuron loss alleviation and behavioral motor function attenuation. Quality assessment and narrative synthesis of the studies were performed.

Twenty-four studies out of 796 papers initially identified met the inclusion criteria. All the included studies, except one, found a reduction in NLRP3 inflammasome activation and anti-inflammatory markers in Parkinson's disease animal models after treatment with various NLRP3 inhibitors compared to control groups without inhibitors. Additionally, eighteen out of twenty-four inhibitors decreased microglial activation and behavioral deficits. Moreover, ten inhibitors attenuated oxidative stress, and twenty-two out of twenty-four alleviated dopaminergic neuron loss. The inhibitors utilized different mechanisms and pathways to exert their effects, including the NLRP3/Caspase-1 pathway, the NF-κB/NLRP3 pathway, inhibition of ROS and/or pyroptosis, as well as autophagy and mitophagy.

NLRP3 inhibitors represent a prospective therapy for Parkinson's disease, demonstrating efficacy in lowering neuroinflammation and protecting against dopaminergic loss. However, constraints, such as a male animal focus, apparent regional bias from China-centric studies, and diversity in induction models, entail the results presented herein require cautious interpretation. Further research, including preclinical and clinical studies, is required to thoroughly examine the safety, effectiveness, and generalizability of NLRP3 inhibitors in Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet effective therapeutic options remain limited. Dendrobium huoshanense (DH), a medicinal and edible herb mainly distributed in Ta-pieh Mountains of Central China, has been used to treat disorders of consciousness and chronic nervous diseases in the local hospital for thousands of years. Erianin, a bioactive bibenzyl compound isolated from DH, has emerged as a potential neuroprotective agent due to its anti-inflammatory and antioxidant properties.

This study aimed to investigate the neuroprotective effects of Erianin in the treatment of PD and the underlying mechanisms, particularly focusing on inflammation and oxidative stress, through both in vivo and in vitro models.

A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was employed. The protective effects of Erianin were evaluated through neurobehavioral tests, immunohistochemistry, immunofluorescence, Nissl staining, serum biochemical tests, and Western blotting. The role of Erianin in modulating the NF-κB/NLRP3 pathway was investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells.

Erianin significantly alleviated MPTP-induced motor deficits, reduced neuroinflammation, and reversed abnormal secretion of inflammatory and oxidative stress factors in the serum. Additionally, Erianin suppressed the gene expression of NOD-like receptor protein 3 (NLRP3) and tyrosine hydroxylase (TH) in the striatum of PD mice. And, Erianin inhibited the activation of the NF-κB/NLRP3 pathway, decreased the production of oxidative stress factors, and reversed the secretion of inflammatory mediators in LPS-stimulated BV-2 microglia cells.

Erianin exerts neuroprotective effects in Parkinson's disease primarily by inhibiting the NF-κB/NLRP3 signaling pathway. These findings suggest that Erianin holds promise as a potential therapeutic candidate for the treatment of PD.

Gouty arthritis (GA), a prevalent and intricate form of inflammatory arthritis, affects individuals across all age groups. Existing therapeutic agents for GA are associated with substantial adverse effects. The overarching objective of this study is to identify an efficacious and biocompatible intervention strategy for GA.

In this investigation, we developed a zinc ferrite nanoparticle (ZFN) characterized by outstanding catalytic activities in anti-inflammatory and antioxidative processes, along with negligible biotoxicity. ZFN features low-content Zn2+ doping, which effectively overcomes the issue of low biocompatibility commonly encountered in Zn-based nanoparticles. Both in vitro and in vivo experimental models were utilized to comprehensively evaluate the effects of ZFN.

The experimental results demonstrate that ZFN exhibits remarkable efficacy in alleviating inflammation and oxidative stress both in vitro and in vivo. It exerts its therapeutic effect on GA by modulating the NF-κB signaling pathway, suppressing the activation of the NLRP3 inflammasome, and activating the Nrf2 pathway.

The protective effect of ZFN against GA holds great promise for the clinical translation of biocompatible inorganic nanoplatforms in the treatment of GA. This finding offers a potential alternative to the currently available medications, thereby providing new insights and possibilities for the management of GA.

Tripterygium wilfordii is a traditional Chinese medicine used to treat rheumatic diseases, with properties such as clearing heat, detoxifying, dispelling wind, and relieving pain. In recent years, its active compound, celastrol, garnered significant attention for its potential therapeutic effects on metabolic diseases. Celastrol exhibits bioactivities such as regulating metabolic functions and anti-inflammatory effects, positioning it as a promising candidate for the treatment of obesity, diabetes, atherosclerosis (AS), and non-alcoholic fatty liver disease (NAFLD).

This review aims to explore the pharmacological mechanisms of celastrol in metabolic diseases, focusing on its anti-inflammatory mechanisms and metabolic regulation effects, providing theoretical support for further investigation of its therapeutic potential in metabolic diseases.

Literature was retrieved from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar. This review primarily focuses on anti-inflammatory mechanisms of celastrol, its metabolic regulation, and toxicity studies, by systematically analyzing its effects in obesity, diabetes, AS, and NAFLD, providing scientific evidence for its potential clinical applications.

Celastrol regulates multiple signaling pathways, particularly inhibiting NF-κB and activating AMPK, reducing the production of pro-inflammatory cytokines and improving insulin sensitivity, enhancing its therapeutic potential in metabolic diseases. Additionally, celastrol regulates adipogenesis and energy metabolism by influencing key transcription factors such as PPARγ and SREBP-1c. Numerous studies highlight its role in alleviating oxidative stress and improving mitochondrial function, further enhancing its metabolic benefits.

In summary, celastrol holds great promise as a multi-target therapeutic agent for metabolic diseases, offering anti-inflammatory, metabolic regulatory, and antioxidative benefits. Despite these, challenges remain for the clinical application of celastrol due to its poor bioavailability and potential toxicity. Advanced formulation strategies and targeted delivery systems are urgently needed to overcome challenges related to bioavailability and clinical translation.

Parkinson's Disease (PD) a progressive neurodegenerative disorder is attributed to dopaminergic neuronal cell loss in the mid-brain substantia nigra pars compacta. A major risk factors associated with PD development is presence of excess oxidative stress. Previously, glycosides derived from Cistanche deserticola were reported to play a key role in counteracting PD; however, the underlying mechanisms remain to be determined. This study aimed to examine the neuroprotective effect attributed to glycosides derived from C. deserticola in PD model in mice. The model of PD was established by injecting intraperitoneally 1-methyl-4-penyl-1,2,3,6-tetrahydropyridine (MPTP). Rotarod and pole tests determined neurological behavior. The following immunohistochemistry, and metabolic biomarkers were measured mid-brain substantia nigra: (1) number of dopaminergic neuronal cell using immunohistochemistry (2) oxidative stress as evidenced by activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well levels of malondialdehyde (MDA), (3) inflammatory infiltration as measured by levels of IL-1β and TNF-α (4) by Western blot involvement of protein expression levels of Nrf2 signaling pathway. Data demonstrated that C. deserticola glycosides treatment improved behavioral performance, increased number of dopaminergic neurons, reduced cytokine levels of IL-1β and TNF-α accompanied by enhanced antioxidant activity in PD mice. These observations were associated with activation of Nrf2 signaling pathway. Data suggest that C. deserticola glycosides may thus be considered as an alternative compound for PD treatment.

This study aimed to examine the protective effect of celastrol on testicular dysfunction in diabetic rats and the potential underlying mechanisms. All rats included in the study were divided into four groups: a control group treated with sodium citrate buffer and vehicle), a celastrol-treated control group, a streptozotocin (STZ)-induced diabetic group following insulin resistance, and a celastrol-treated diabetic group. Serum glucose, triglyceride, total cholesterol, high-density lipoprotein cholesterol, interleukin (IL)-1β, tumor necrosis factor-α, and testosterone levels were measured. In addition, the levels of testicular homogenate superoxide dismutase and malondialdehyde were assessed. Furthermore, testicular tissue relative toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and myeloid differentiation factor 88 (MYD88) expressions were quantitatively measured using polymerase chain reaction. Histopathological and immunohistochemical studies were also conducted. The results revealed that treatment with celastrol significantly reduced TLR4, MyD88, and NF-κB expressions, and the levels of inflammatory mediators such as tumor necrosis factor-α and IL-1β in the testicular tissue of treated rats. These findings suggest that celastrol has the potential to be effective in the treatment of diabetes-induced testicular injury by inhibiting testicular inflammation, apoptosis, and oxidative stress.NEW & NOTEWORTHY Celastrol inhibits the production of proinflammatory cytokines in the testicular tissue by specifically targeting the TLR4/MyD88/NF-κB signaling cascade pathways. This indicates that celastrol may serve as a promising new therapeutic target for treating diabetic reproductive dysfunction.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Long non-coding RNAs (lncRNAs) are closely linked to the occurrence and development of neurodegenerative diseases, while the underlying mechanisms remain elusive. The goal of the present study was to elucidate the mechanism by which LINC02282, a significantly downregulated lncRNA in the GEO database, elicits neuroprotective effects on PD. LINC02282 was poorly expressed in SH-SY5Y and SK-N-AS cells exposed to MPP+ and mice injected with MPTP. LINC02282 overexpression plasmids inhibited apoptosis and promoted the proliferation of SH-SY5Y and SK-N-AS cells. In addition, LINC02282 overexpression using an adeno-associated virus reduced neuronal damage in PD mice. LINC02282 was mainly localized in the nucleus, and LINC02282 promoted the methylation of the tripartite motif-containing protein 6 (TRIM6) promoter to inhibit TRIM6 expression. LINC02282 bound to DNA methyltransferases (DNMTs) and LINC02282 overexpression increased the binding of DNMTs to the TRIM6 promoter. Overexpression of TRIM6 alone induced PD-like symptoms in mice and combined TRIM6 upregulation inhibited the neuroprotective effect of LINC02282 both in vitro and in vivo. In summary, LINC02282 alleviated neuronal injury in PD by recruiting DNMTs to the promoter region of TRIM6 and inhibiting TRIM6 expression.

Faced with the highly malignant challenge of lung cancer, traditional chemotherapeutic agents, although predominantly inducing apoptosis, are severely limited in their therapeutic effect by the overexpression of anti-apoptotic proteins in lung cancer. Recently discovered copper-induced non-apoptotic cell death, known as cuproptosis, represents a novel mechanism for regulating cell death. Whether Celastrol (Cel), a potential anti-tumor drug, can counter non-small cell lung cancer (NSCLC) through inducing cuproptosis remains to be thoroughly investigated. This study demonstrates that the copper chelator tetrathiomolybdate (TTM) is more effective in rescuing Cel-induced NSCLC cell death compared to other inhibitors. RNA sequencing revealed that Cel significantly upregulates the copper transporter protein SLC31A1. In addition, Cel also promotes intracellular copper accumulation, reduces GSH levels, and exhibits features of cuproptosis, including loss of iron-sulfur cluster proteins (FDX1, SDHB, POLD1), increased HSP70, and DLAT oligomerization. Experiments also found that Cel significantly increases reactive oxygen species (ROS) levels, reduces mitochondrial membrane potential, and lowers ATP levels. It was predicted through online databases that SRF may be the transcription factor for SLC31A1, and this was validated through overexpression experiments. In vivo data demonstrated that Cel significantly inhibits tumor growth without damaging the heart, liver, or kidneys of mice. This study first reveals that celastrol disrupts intracellular copper homeostasis through the SRF/SLC31A1 pathway, promoting cuproptosis in NSCLC cells, providing support for Cel as a potential safe and effective chemotherapeutic agent.

Preterm birth (PTB) is a major cause of infant morbidity and mortality. The aim of this study was to investigate the effect of vaginal microbiota and metabolites on the outcome of pregnant women. In this study, a total of 127 pregnant women provided written informed consent prior to enrollment in accordance with the approved institutional guidelines, but only 45 pregnancies met the experimental requirements, and then blood and cervical vaginal fluid (CVF) samples were collected before delivery (at the second week after cervical cerclage). Pregnant women with PTB exhibited high white blood cell and neutrophil contents, high neutrophil-to-lymphocyte ratio (NLR), and high systemic inflammation response index (SIRI) in the blood. Vaginal microbiome revealed that the proportion of beneficial bacteria (including Lactobacillus, [Ruminococcus] gnavus group, and Megamonas) significantly decreased in the PTB group, and the proportion of harmful bacteria (including Desulfovibrionaceae, Helicobacter, and Gardnerella) significantly increased, which is strongly related to the biochemical parameters of blood (white blood cells, neutrophils, NLR, and SIRI). In addition, vaginal metabolomics-based liquid chromatography-Orbitrap-tandem mass spectrometry (LC-Orbitrap-MS/MS) found that the alteration in vaginal metabolites in pregnant women with PTB is involved in starch and sucrose metabolism; arginine and praline metabolism; galactose metabolism; purine metabolism; arginine metabolism; tryptophan metabolism and N-glycan biosynthesis; cysteine and methionine metabolism; taurine and hypotaurine metabolism; amino acid metabolism; propanoate metabolism; valine, leucine, and isoleucine biosynthesis; glycine, serine, and threonine metabolism; and steroid hormone biosynthesis. These results elaborated that distinct vaginal microbiome and metabolome profiles in women with preterm delivery following cervical cerclage provide valuable information for establishing the prediction models for PTB.

Acute lung injury (ALI) is a devastating clinical syndrome without effective therapy. Celastrol, as a natural anti-inflammatory compound, has showed therapeutic potential against inflammatory diseases. In this study, we have investigated the potential effect of Celastrol on lipopolysaccharide (LPS)-induced ALI. C57BL/6J mice, Nrf1-knockout mice and A549 (human alveolar epithelial cell line) cells were used to investigate the protective role of Celastrol in LPS-induced ALI. Our data showed that administration of Celastrol significantly alleviated lung pathologic injury and increased the survival rate, which was associated with the improvement of mitochondrial function in the injured lung. Moreover, Celastrol enhanced phosphorylation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear translocation of nuclear respiratory factor 1 (Nrf1) and subsequent up-regulation of its downstream mitochondria electron transport chain complex I (NDUF) gene expression, which induced an increase in mitochondrial complex Ⅰ activity. The beneficial effects of Celastrol on regulation of Nrf1 were abolished by inhibition of AMPK and PGC-1α. Finally, in Nrf1 deficient mice, the protective effects of Celastrol on LPS-induced ALI were largely vanished. Our data indicated that Celastrol can prevent LPS-induced ALI by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism, suggesting that Celastrol may represent a novel therapeutic potential for LPS-induced ALI.

Celastrol was recently identified as a potential treatment for obesity and hepatic steatosis. However, whether Celastrol effectively suppresses the nonalcoholic fatty liver disease (NAFLD) stage remains unknown. This study aimed to evaluate the role of Celastrol in the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis.

C57BL/6 mice were fed a Western diet combined with a weekly low-dose injection of CCl4 (WD/CCl4) for 16 weeks to establish NASH models. The effects of Celastrol on NASH were further explored through histopathological assessments, immunoblotting, and in vitro analyses.

Celastrol treatment effectively attenuated hepatic steatosis and fibrosis in WD/CCl4-induced NASH models, in which Notch2 was downregulated by Celastrol in a posttranscriptional manner. In vitro experiments revealed that Notch2 suppression in Celastrol-treated hepatocytes further decreased osteopontin (OPN) levels, inhibiting hepatic stellate cells (HSCs) activation. Moreover, the protective effects of Celastrol on NASH progression were abolished in Notch2-overexpressing mice.

This study demonstrated the protective effects of Celastrol on NASH-related liver fibrosis by modulating Notch/OPN signaling, providing fresh insights into the potential application of Celastrol in NASH treatment.

Recently, a growing focus has been on identifying critical mechanisms in neurological diseases that trigger a cascade of events, making it easier to target them effectively. One such mechanism is the inflammasome, an essential component of the immune response system that plays a crucial role in disease progression. The NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome is a subcellular multiprotein complex that is widely expressed in the central nervous system (CNS) and can be activated by a variety of external and internal stimuli. When activated, the NLRP3 inflammasome triggers the production of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) and facilitates rapid cell death by assembling the inflammasome. These cytokines initiate inflammatory responses through various downstream signaling pathways, leading to damage to neurons. Therefore, the NLRP3 inflammasome is considered a significant contributor to the development of neuroinflammation. To counter the damage caused by NLRP3 inflammasome activation, researchers have investigated various interventions such as small molecules, antibodies, and cellular and gene therapy to regulate inflammasome activity. For instance, recent studies indicate that substances like micro-RNAs (e.g., miR-29c and mR-190) and drugs such as melatonin can reduce neuronal damage and suppress neuroinflammation through NLRP3. Furthermore, the transplantation of bone marrow mesenchymal stem cells resulted in a significant reduction in the levels of pyroptosis-related proteins NLRP3, caspase-1, IL-1β, and IL-18. However, it would benefit future research to have an in-depth review of the pharmacological and biological interventions targeting inflammasome activity. Therefore, our review of current evidence demonstrates that targeting NLRP3 inflammasomes could be a pivotal approach for intervention in neurological disorders.

Oxidative stress represents a pivotal mechanism in the pathogenesis of numerous chronic diseases. The Kelch-like ECH-associated protein 1-transcription factor NF-E2 p45-related factor 2 (KEAP1-NRF2) pathway plays a crucial role in maintaining redox homeostasis and regulating a multitude of biological processes such as inflammation, protein homeostasis, and metabolic homeostasis. In this paper, we present the findings of recent studies on the KEAP1-NRF2 pathway, which have revealed that it is aberrantly regulated and induces oxidative stress injury in a variety of diseases such as neurodegenerative diseases, cardiovascular diseases, metabolic diseases, respiratory diseases, digestive diseases, and cancer. Given this evidence, targeting KEAP1-NRF2 represents a highly promising avenue for developing therapeutic strategies for chronic diseases, and thus the development of appropriate therapeutic strategies based on the targeting of the NRF2 pathway has emerged as a significant area of research interest. This paper highlights an overview of current strategies to modulate KEAP1-NRF2, as well as recent advances in the use of natural compounds and traditional Chinese medicine, with a view to providing meaningful guidelines for drug discovery and development targeting KEAP1-NRF2. Additionally, it discusses the challenges associated with harnessing NRF2 as a therapeutic target.

Parkinson's disease (PD) is a progressive age-related neurodegenerative disease whose annual incidence is increasing as populations continue to age. Although its pathogenesis has not been fully elucidated, oxidative stress has been shown to play an important role in promoting the occurrence and development of the disease. Long noncoding RNAs (lncRNAs), which are more than 200 nucleotides in length, are also involved in the pathogenesis of PD at the transcriptional level via epigenetic regulation, or at the post-transcriptional level by participating in physiological processes, including aggregation of the α-synuclein, mitochondrial dysfunction, oxidative stress, calcium stabilization, and neuroinflammation. LncRNAs and oxidative stress are correlated during neurodegenerative processes: oxidative stress affects the expression of multiple lncRNAs, while lncRNAs regulate many genes involved in oxidative stress responses. Oxidative stress and lncRNAs also affect other processes associated with neurodegeneration, including mitochondrial dysfunction and increased neuroinflammation that lead to neuronal death. Therefore, modulating the levels of specific lncRNAs may alleviate pathological oxidative damage and have neuroprotective effects. This review discusses the general mechanisms of oxidative stress, pathological mechanism underlying the role of oxidative stress in the pathogenesis of PD, and teases out the mechanisms through which lncRNAs regulate oxidative stress during PD pathogenesis, as well as identifies the possible neuroprotective mechanisms of lncRNAs. Reviewing published studies will help us further understand the mechanisms underlying the role of lncRNAs in the oxidative stress process in PD and to identify potential therapeutic strategies for PD.

Celastrol is one of the main active ingredients extracted from the plant Tripterygium wilfordii Hook F. A growing number of studies have shown that celastrol has various pharmacological effects, including anti-inflammation, anti-rheumatism, treatment of neurodegenerative diseases, and anti-tumor. This article systematically summarized the mechanism and role of celastrol in lipid metabolism and obesity, rheumatoid arthritis (RA), osteoarthritis (OA), gouty arthritis, inflammatory bowel disease, neurodegenerative diseases, and cancer and other diseases (such as diabetes, respiratory-related diseases, atherosclerosis, psoriasis, hearing loss, etc.). The celastrol played roles in inflammation response, cell apoptosis, autophagy, ferroptosis, and lipid metabolism mainly by acting on chondrocytes, macrophages, mitochondria, and endoplasmic reticulum (ER) through NF-κB, STAT, MAPK, TLR, PI3K-AKT-mTOR, and other signal pathways. This review could provide a reference for the clinical application and further development and utilization of celastrol.

Inflammasomes represent a crucial component of the innate immune system, which respond to threats by recognizing different molecules. These are known as pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs). In neurodegenerative diseases and neuroinflammation, the accumulation of misfolded proteins, such as beta-amyloid and alpha-synuclein, can lead to inflammasome activation, resulting in the release of interleukin (IL)-1β and IL-18. This activation also induces pyroptosis, the release of inflammatory mediators, and exacerbates neuroinflammation. Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases. Therefore, elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance. This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases. Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed.

Despite the high sepsis-associated mortality, effective and specific treatments remain limited. Using conventional antibiotics as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging due to increasing bacterial resistance, diminishing their efficacy and leading to adverse effects. We previously found that aloe-emodin (AE) exerts therapeutic effects on sepsis by reducing systemic inflammation and regulating the gut microbiota. Here, we investigated whether administering AE and TIE post-sepsis onset, using a cecal ligation and puncture (CLP)-induced sepsis model, extends survival and improves physiological functions. Survival rates, inflammatory cytokines, tissue damage, immune cell populations, ascitic fluid microbiota, and key signaling pathways were assessed. Combining AE and TIE significantly enhanced survival rates, and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Moreover, substantial improvements in survival rates of AE + TIE-treated mice (10% to 60%) within 168 h were observed relative to the CLP group. This combination therapy also effectively modulated inflammatory marker (interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α) levels and immune cell counts by decreasing those of B, NK, and TNFR2+ Treg cells, while increasing that of CD8+ T cells; alleviated tissue damage; reduced bacterial load in the peritoneal cavity; and suppressed the NF-κB signaling pathway. We also observed a significantly altered peritoneal cavity microbiota composition post-treatment, characterized by reduced pathogenic bacteria (Bacteroides) abundance. Our findings underscore the potential of AE + TIE in treating sepsis, and encourage further research and possible clinical implementations to surmount the limitations of TIE and amplify the therapeutic potential of AE.

The novel phthalein component QBT, extracted from Ligusticum chuanxiong, shows promising biological activity against cerebrovascular diseases. This study focused on ferroptosis and pyroptosis to explore the effects of QBT on nerve injury, cognitive dysfunction, and related mechanisms in a rat model of vascular dementia (VaD).

We established a rat model of VaD and administered QBT as a treatment. Cognitive dysfunction in VaD rats was evaluated using novel object recognition and Morris water maze tests. Neuronal damage and loss in the brain tissues of VaD rats were assessed with Nissl staining and immunofluorescence. Furthermore, we investigated the neuroprotective mechanisms of QBT by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/cystine-glutamate antiporter (xCT)/glutathione peroxidase 4 (GPX4) and Nod-like receptor family pyrin domain-containing 3 (NLRP3)/cysteine-requiring aspartate protease-1 (Caspase-1)/Gasdermin D (GSDMD) pathways to inhibit ferroptosis and pyroptosis both in vivo and in vitro.

Our findings indicated that QBT significantly ameliorated neuronal damage and cognitive dysfunction in VaD rats. Additionally, QBT reversed abnormal changes associated with ferroptosis and pyroptosis in the brains of VaD rats, concurrently up-regulating the Nrf2/xCT/GPX4 pathway and down-regulating the NLRP3/Caspase-1/GSDMD pathway to inhibit ferroptosis and pyroptosis in neuronal cells, thereby exerting a neuroprotective role.

In summary, QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, demonstrating a neuroprotective effect by inhibiting ferroptosis and pyroptosis in neuronal cells. This study offers a novel perspective and theoretical foundation for the future development of drugs targeting VaD.

Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear.

Here, we established both in vitro and in vivo models of HI brain damage using CoCl2-treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models.

Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA.

We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE.

We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries. Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.

Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage.

We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH).

Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites.

Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.

Neuroinflammation is a central player in postoperative cognitive dysfunction (POCD), an intractable and highly confounding neurological complication with finite therapeutic options. Celastrol, a quinone methide triterpenoid, is a bioactive ingredient extracted from Tripterygium wilfordii with talented anti-inflammatory capacity. However, it is unclear whether celastrol can prevent anesthesia/surgery-evoked cognitive deficits in an inflammation-specific manner. The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was used to determine whether celastrol possesses neuroprotection dependent on the STING pathway in vivo and in vitro. Isoflurane and laparotomy triggered cGAS-STING activation, caspase-3/GSDME-dependent pyroptosis, and enhanced Iba-1 immunoreactivity. Celastrol improved cognitive performance and decreased the levels of cGAS, 2'3'-cGAMP, STING, NF-κB phosphorylation, Iba-1, TNF-α, IL-6, and IFN-β. Downregulation of cleaved caspase-3 and N-GSDME was observed in the hippocampus of POCD mice and HT22 cells after celastrol administration, accompanied by limited secretion of pyroptosis-pertinent pro-inflammatory cytokines IL-1β and IL-18. DMXAA neutralized the favorable influences of celastrol on cognitive function, as confirmed by the activation of the STING/caspase-3/GSDME axis. These findings implicate celastrol as a therapeutic agent for POCD through anti-inflammation and anti-pyroptosis.

Parkinson's disease (PD) is typically marked by motor dysfunction accompanied by loss of dopaminergic (DA) neurons and aggravated oxidative stress in the substantia nigra pars compacta (SNpc). Atractylenolide-I (ATR-I) is a potent antioxidant sesquiterpene with neuroprotective properties. However, whether ATR-I plays a neuroprotective role against oxidative stress in PD remains unclear. The objective of this study was to explore the mechanism of antioxidant action of ATR-I in PD models both in vivo and in vitro. Here, we show that ATR-I alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice. Moreover, ATR-I treatment effectively reduced DA neuron loss and increased tyrosine hydroxylase expression in the SNpc of MPTP-induced mice. Additionally, ATR-I inhibited oxidative stress (as manifested by elevated superoxide dismutase and glutathione peroxidase activities, and reduced malondialdehyde content) in MPTP-induced mice and attenuated reactive oxygen species levels in 1-methyl-4-phenylpyridinum (MPP+)-treated SH-SY5Y cells. Finally, ATR-I upregulated expressions of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), NF-E2-related factor-2 (Nrf2), and heme oxygenase-1 in MPTP-induced mice and MPP+-treated SH-SY5Y cells, but had little effect on these factors in the presence of the SIRT1 inhibitor EX527. Taken together, these findings indicated that the important antioxidant role of ATR-I in MPTP/MPP+-mediated oxidative stress and the pathogenesis of PD through the SIRT1/PGC-1α/Nrf2 axis, highlighting its potential as a therapeutic option for PD.

Intervertebral disc degeneration (IDD) is a common cause of low back pain, causing a huge emotional and economic burden on patients and society. Reduction of nucleus pulposus cells (NPC) and extracellular matrix (ECM) is the main feature of IDD, and NPC is the main source of ECM. Thermal apoptosis is a newly discovered form of cell death in recent years that differs significantly from apoptosis in terms of molecular mechanisms and cellular morphological changes. Diacetoxy-6-gingerdiol(D-6-G), a type of gingerol, has anti-inflammatory and antioxidant effects, but whether it has an inhibitory effect on cellular pyroptosis is not clear. Therefore, in the present study, we investigated the effect of D-6-G on the ECM of the nucleus pulposus oblongata under IL-1β treatment, as well as the mechanism of its effect on NLRP3 inflammasome and cellular focal death. In vitro cellular experiments demonstrated that D-6-G could bind to and inhibit the activity of NLRP3 inflammasome, and interestingly, D-6-G could also inhibit cellular pyroptosis and protect the nucleus pulposusry cellular microenvironment by activating the Nrf2/HO-1 axis. In conclusion, we found that D-6-G could inhibit NLRP3 inflammatory vesicle activity as well as cellular pyroptosis in NPCs and protect the ECM, suggesting the potential of D-6-G to delay IDD.

Diallyl trisulfide (DATS) has a direct antioxidant capacity and emerges as a promising neuroprotective agent. This study was designed to investigate the role of DATS in traumatic brain injury (TBI).

TBI mouse models were established using the controlled cortical impact, followed by DATS administration. The effects of DATS on neurological deficit, brain damage, inflammation and phosphoglycerate kinase 1 (PGK1) expression were detected using mNSS test, histological analysis, TUNEL assay, enzyme-linked immunosorbent assay and immunofluorescence. PC12 cells were subjected to H2O2-induced oxidative injury after pre-treatment with DATS, followed by cell counting kit-8 assay, flow cytometry and ROS production detection. Apoptosis-related proteins and the PGK1/nuclear factor erythroid-2 related factor 2 (Nrf2) pathway were examined using Western blot.

DATS ameliorated the cerebral cortex damage, neurological dysfunction and apoptosis, as well as decreased PGK1 expression and expressions of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in mice after TBI. DATS also enhanced viability, blocked apoptosis and inhibited ROS production in H2O2-induced PC12 cells. DATS downregulated Cleaved-Caspase3, Bax and PGK1 levels, and upregulated Bcl-2 and Nrf2 levels in TBI mouse models and the injured cells.

DATS regulates PGK1/Nrf2 expression and inflammation to alleviate neurological damage in mice after TBI.

Atrazine (ATR) is a broad-spectrum herbicide with dopaminergic (DAergic) neurotoxicity that can cause Parkinson's disease (PD)-like syndrome. However, research on preventing ATR neurotoxicity is unclear. Soybean isoflavones (SI) are natural plant compounds with neuroprotective effects. In this study, we found that pre-administration of SI prevented ATR-induced motor dysfunction and substantia nigra pathological damage. RNA-seq datasets revealed that the neuroprotective effect of SI was related to autophagy. Further experiments showed that ATR inhibited autophagy, and SI pre-administration before ATR exposure increased autophagy. In addition, single-cell data analysis combined with experimental verification showed that the gene VPS13A was a key target by which SI protected DAergic neurons from ATR damage, and inhibiting VPS13A-induced autophagy was a key mechanism enabling SI prevention of neuron damage. Together, these findings provide new insights for the development of preventive measures and intervention targets protecting against functional neuronal damage caused by ATR and other herbicides.

Spinal cord injury (SCI) elicits excess neuroinflammation and resident microglial pyroptosis, leading further terrible neurological collapse and locomotor dysfunction. However, the current clinical therapy is useless and a feasible treatment is urgent to be explored. Cynarin is a natural component in artichoke playing anti-inflammatory and anti-aging roles in hepatoprotection and cardioprotection, but it is unclear that the pharmacologic action and underlying mechanism of Cynarin in neuropathy.

Using the SCI mouse model and the BV2 cell line, we here investigated whether Cynarin reduces neuroinflammation and pyroptosis to promote neurological recovery after SCI.

Our results showed that treatment with Cynarin reduces the level of neuroinflammation and microglial pyroptosis. Moreover, the mice treated with Cynarin exhibited lower level of reactive oxygen species (ROS) and cell death, less damage of neurohistology and better locomotor improvement of hindlimbs than the untreated mice and the nuclear factor erythroid 2-related factor 2 (Nrf2)-inhibited mice. Mechanically, Cynarin inhibited the assembly of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome by Nrf2-dependent expression to attenuate microglial pyroptosis and neuroinflammation.

To sum up, the current study suggested that administration of Cynarin is a promising compound for anti-neuroinflammation and anti-pyroptosis after SCI. It may be an efficient Nrf2 activator and a NLRP3 inhibitor for microglia in neuropathies.

This study investigated the role of mitochondrial dynamics in postoperative cognitive dysfunction (POCD) and assessed the therapeutic potential of mitochondrial modulation, particularly through the inhibition of dynamin-related protein 1 (DRP1) with Mdivi-1. Our findings indicated that DRP1 inhibition substantially mitigated neuroinflammation mediated by microglial cells, contributing to improved cognitive function in POCD models. The administration of Mdivi-1 led to a notable decrease in mitochondrial fission, reduced reactive oxygen species (ROS) production, and stabilization of mitochondrial membrane potential, all of which correlate with diminished neuroinflammation, as evidenced by lower NOD-like receptor family pyrin domain containing 3 (NLRP3)/ interleukin-1β (IL-1β) expression in microglial cells. Importantly, Mdivi-1 treatment was also found to enhance synaptic plasticity, increasing synaptic spine density in the hippocampal region of POCD mice. This improvement in mitochondrial health and synaptic integrity was paralleled by enhanced cognitive performance, as demonstrated in Y-maze tests. These results underscored the critical role of mitochondrial dynamics in the pathophysiology of POCD and suggested that targeting mitochondrial dysfunction, specifically through DRP1 inhibition, could be an effective approach for POCD treatment.

Parkinson's disease (PD) is the second neurodegenerative disorder most prevalent in the world, characterized by the loss of dopaminergic neurons in the Substantia Nigra (SN). It is well known for its motor and non-motor symptoms including bradykinesia, resting tremor, psychiatric, cardiorespiratory, and other dysfunctions. Pathological apoptosis contributes to a wide variety of diseases including PD. Various insults and/or cellular phenotypes have been shown to trigger distinct signaling events leading to cell death in neurons affected by PD. The intrinsic or mitochondrial pathway, inflammatory or oxidative stress-induced extrinsic pathways are the main events associated with apoptosis in PD-related neuronal loss. Although SN is the main brain area studied so far, other brain nuclei are also affected by the disease leading to non-classical motor symptoms as well as non-motor symptoms. Among these, the respiratory symptoms are often overlooked, yet they can cause discomfort and may contribute to patients shortened lifespan after disease diagnosis. While animal and in vitro models are frequently used to investigate the mechanisms involved in the pathogenesis of PD in both the SN and other brain regions, these models provide only a limited understanding of the disease's actual progression. This review offers a comprehensive overview of some of the most studied forms of cell death, including recent research on potential treatment targets for these pathways. It highlights key findings and milestones in the field, shedding light on the potential role of understanding cell death in the prevention and treatment of the PD. Therefore, unraveling the connection between these pathways and the notable pathological mechanisms observed during PD progression could enhance our comprehension of the disease's origin and provide valuable insights into potential molecular targets for the developing therapeutic interventions.

Celastrol, the primary constituent of Tripterygium wilfordii, has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.

Glaucoma, as an ischemia-reperfusion (I/R) injury disease, leading irreversible blindness through the loss of retinal ganglion cells (RGCs), mediated by various pathways. Resveratrol (Res) is a polyphenolic compound that exerts protective effects against I/R injury in many tissues. This article aimed to expound the underlying mechanisms through which Res protects RGCs and reduces visual dysfunction in vivo. An experimental glaucoma model was created using 6-8-week wild-type male C57BL/6J mice. Res was injected intraperitoneally for 5 days. The mice were then grouped according to the number of days after surgery and whether Res treatment was administered. We applied the Brn3a-labeled immunofluorescence staining and flash electroretinography (ERG) to assess the survival of RGCs and visual function. The expression of components of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, the interleukin-1-beta (IL-1β), and vital indicators of kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme-oxygenase 1 (HO-1) pathway at the protein and RNA levels were detected respectively. The survival of RGCs was reduced after surgery compared to controls, whereas Res application rescued RGCs and improved visual dysfunction. In conclusion, our results discovered that Res administration showed neuroprotective effects through inhibition of the NLRP3 inflammasome pathway and activation of Keap1/Nrf2/HO-1 pathway. Thus, we further elucidated the potential of Res in glaucoma therapy.

Gout is an autoinflammatory disorder characterized by the accumulation of monosodium urate crystals in joints and other tissues, representing the predominant type of inflammatory arthritis with a notable prevalence and propensity for severe outcomes. The NLRP3 inflammasome, a member of the pyrin domain-containing NOD-like receptor family, exerts a substantial impact on both innate and adaptive immune responses and serves as a pivotal factor in the pathogenesis of gout. In recent years, there has been significant academic and industrial interest in the development of NLRP3-targeted small molecule inhibitors as a promising therapeutic approach for gout. To assess the advancements in NLRP3 inflammasome inhibitors for gout treatment, this review offers a comprehensive analysis and evaluation of current clinical candidates and other inhibitors targeting NLRP3 inflammasome from a chemical structure standpoint, with the goal of identifying more efficacious options for clinical management of gout.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that often occurs in older people. Neuroinflammation and oxidative stress are important factors in the development of PD. Gastrointestinal dysfunction is the most common non-motor symptom, and inflammation of the gut, which activates the gut-brain axis, maybe a pathogenic factor. Previous studies have attributed anti-inflammatory and antioxidant effects to Allantoin, but its function and mechanism of action in PD are unclear. This study aimed to investigate the effect and mechanism of Allantoin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice. Our results showed that Allantoin administration ameliorated motor dysfunction and neuronal damage in mice injected with MPTP by inhibiting neuroinflammation and oxidative damage. Mechanistic studies showed that Allantoin suppresses inflammatory responses by inhibiting the overactivation of the NF-κB and MAPK signaling pathways, as well as oxidative stress by regulating the AKT/Nrf2/HO-1 signaling pathway. Notably, Allantoin also restored intestinal barrier function by modulating the gut microbiota and improving antioxidant and anti-inflammatory capacities to alleviate MPTP-induced motor deficits. In conclusion, the present study shows that the administration of Allantoin attenuated neurodegeneration in mice injected with MPTP by inhibiting neuroinflammation and oxidative stress and modulating the composition of the gut microbiome.