Background:Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Huazhuo decoction (HD) has been shown to ameliorate disease progression in MS patients, but the underlying mechanisms remain poorly understood. Purpose:This study sought to assess the therapeutic efficacy of HD in an experimental autoimmune encephalomyelitis (EAE) model of MS, and to further investigate the underlying mechanisms involved. Methods:We assessed the curative effects of HD on EAE mice via neurological function scoring and histological staining and identified the chemical composition of HD by UPLC-MS. RNA sequencing identified differentially expressed genes. Flow cytometry detected the proportions of splenic Th17, Th1, and Treg cells. Expression of key molecules was evaluated by Western blotting and quantitative PCR. Immunofluorescence was used to monitor microglia, astrocytes and oligodendrocytes. Results:HD alleviated neurobehavioral impairment, inflammatory infiltration and demyelination in EAE mice. RNA sequencing revealed that HD may ameliorate EAE by modulating adaptive immunity and affecting NLRP3-related signaling pathways. Further studies demonstrated that HD suppressed the upregulation of NF-κB/NLRP3 pathway, balanced the proportions of peripheral Th17, Th1 and Treg cells and regulated inflammatory cytokines. HD influenced innate immunity by reducing microglia and astrocytes and increasing oligodendrocytes in the CNS. Notably, these protective effects of HD were attenuated by an NLRP3 agonist. Conclusion:HD effectively alleviated the clinical symptoms of EAE mice and inhibited both peripheral and central immune inflammatory responses by modulating the NF-κB/NLRP3 pathway, providing a strong basis for its clinical application.

Growing evidence suggests that the stimulator of interferon genes (STING)-dependent inflammatory pathway is crucial in the progression of non-alcoholic fatty liver disease (NAFLD). Diosgenin (DG), a natural steroidal saponin, has demonstrated multi-pharmacological potential, such as anti-inflammatory and lipid-lowering capacities. Our previous study confirmed the protective role of DG in rat models of NAFLD. Our present study sought to further explore the protective effects of DG in NAFLD and to determine whether its mechanism involves the STING-dependent inflammatory pathway. In this research, we developed experimental models for both high-fat diet (HFD)-induced NAFLD in rats and steatosis induced by free fatty acids (FFAs) in HepG2 cells. The results revealed that DG treatment significantly reduced body weight, liver index, serum lipid levels, hepatic lipid accumulation, and liver injury in HFD-fed rats. Additionally, DG markedly alleviated mitochondrial dysfunction and suppressed the protein expression of the STING-dependent inflammatory pathway in both in vivo and in vitro NAFLD models. In contrast, administration of cGAMP, a STING agonist, upregulated the STING-dependent inflammatory pathway and exacerbated lipid accumulation and mitochondrial dysfunction in FFAs-induced HepG2 cells. In conclusion, our findings suggested that DG protects against NAFLD by mitigating lipid accumulation and mitochondrial dysfunction, with its mechanism related to the inhibition of the STING-dependent inflammatory pathway.

ETHNOPHARMACOLOGICAL RELEVANCE:Polygonum cuspidatum, a traditional Chinese medicine indicated for "blood stasis" and "damp-heat" disorders (e.g., arthralgia, jaundice, amenorrhea), has modern relevance as these conditions correlate with dyslipidemia, inflammation, and microcirculatory issues. Its main constituent, polydatin (PD), exhibits multiple bioactivities, yet its role in metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. AIM OF THE STUDY:To elucidate the mechanisms by which PD alleviates MAFLD through BMAL1-mediated mitochondrial dynamics. MATERIALS AND METHODS:FFA-induced HepG2 cells and HFD-induced MAFLD rats were used to evaluate the effects of PD on hepatic lipid accumulation, mitochondrial function, and oxidative stress immune imbalance via histological staining and biochemical assays. Additionally, molecular docking, molecular dynamics simulations, and BMAL1 knockdown experiments were conducted to identify potential upstream regulators. RESULTS:PD significantly suppressed lipid accumulation, reduced levels of ROS, MDA, NLRP3, TNF-α, and IL-1β, while enhancing SOD activity, thereby alleviating oxidative stress-immune imbalance. PD increased mitochondrial membrane potential (MMP), ATP content, and mtDNA copy number, reversing mitochondrial dysfunction. Notably, PD improved expression rhythms of BMAL1 and mitochondrial dynamics-related genes (DRP1, OPA1, MFN1, MFN2, FIS1), normalizing their amplitude and phase. Concurrently, PD activated the mitochondrial autophagy pathway by upregulating PINK1 and PARKIN expression, thereby facilitating timely clearance of impaired mitochondria. Most importantly, all the aforementioned therapeutic benefits of PD were abolished upon BMAL1 knockdown, establishing BMAL1 as an essential target for PD's action. CONCLUSION:This is the first study to demonstrate that PD alleviates MAFLD by mediating BMAL1-regulated circadian rhythms of mitochondrial dynamics, positioning PD as a potential therapeutic candidate for MAFLD.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Necroptosis is a controlled, programmed form of cell death, with its core comprising a highly conserved signaling pathway that primarily involves key proteins, including Receptor-interacting protein kinase-1 (RIPK1), RIPK3, and Mixed lineage kinase domain-like protein (MLKL). Diosgenin (DG), classified as a steroidal saponin, exhibits anti-inflammatory, immune-regulating, and lipid-lowering properties, demonstrating efficacy in ameliorating dyslipidemia across multiple metabolic pathologies. However, the exact signaling pathways involved in improving NAFLD and preventing liver damage remain unclear. In our study, the data showed that the administration of diosgenin effectively mitigated hepatic damage and excessive lipid deposition in the high-fat diet (HFD)-induced rat model. Meanwhile, it also significantly downregulates Tumor necrosis factor-α (TNF-α), Tumor necrosis factor receptor-1 (TNFR1), and Tumor necrosis factor receptor-associated death domain protein (TRADD), inhibits upstream signaling of the necroptosis pathway, and suppresses necroptosis by reducing RIPK1, RIPK3, and MLKL phosphorylation. DG decreases cell damage and inhibits the expression of necroptosis-related genes in free fatty acids (FFAs)-induced HepG2 cells, which is consistent with the results of in vivo experiments. We inhibited and overexpressed RIPK1 in vitro for further research. Inhibition of RIPK1 enhances the effect of DG on NAFLD, while overexpression of RIPK1 partially reverses its beneficial effect. In addition, to test whether DG acts independently of upstream TNF-α, we introduced exogenous recombinant TNF-α to amplify upstream signals. In conclusion, DG has a favorable reduction effect on NAFLD through the RIPK1-dependent necroptosis signaling pathway. Also, this study offers further data and a theoretical basis for the use of natural medicines to improve NAFLD.

ETHNIC PHARMACOLOGICAL RELEVANCE:Epimedium, recognized within traditional Chinese medicine (TCM) as a tonic, is noted for its role in enhancing kidney Yang, fortifying muscles and bones, and alleviating wind and dampness. It also exhibits therapeutic and preventive properties against cancer. This study systematically analyzes the botany, traditional uses, principal chemical components, antitumor mechanisms, pharmacokinetics, toxicology, and drug delivery systems of Epimedium. It aims to further prospect the antitumor capabilities of Epimedium based on existing research. AIM OF THE STUDY:This review aims to explore the traditional antitumor applications of Epimedium and the contemporary pharmacological actions of its chemical components, providing robust theoretical support for further elucidating Epimedium's antitumor mechanisms. It also offers a comprehensive view for the research and development of cancer treatments involving Epimedium. MATERIALS AND METHODS:We conducted searches in classical Chinese herbal medicine resources, PubMed, Web of Science, Wanfang Database, and China National Knowledge Infrastructure (CNKI) for studies on the antitumor effects of Epimedium and its components. Existing experimental and clinical studies were systematically summarized and analyzed to understand the mechanisms by which Epimedium treats cancer. RESULTS:In the realm of Chinese medicine, Epimedium is recognized for its cancer-treating capabilities. Besides its traditional effects, flavonoids and polysaccharides from Epimedium can inhibit tumor cell proliferation, induce apoptosis, promote autophagy, reduce drug resistance, and improve the tumor immune microenvironment (TIM), addressing cancers of the digestive system, such as liver, colon, and gastric cancers, and of the reproductive system, including breast, cervical, and ovarian cancers. Although the bioavailability of Epimedium flavonoids is low due to rapid absorption and elimination, the use of nanotechnology has significantly enhanced the efficacy of targeted antitumor therapies. Nevertheless, the mechanisms and safety of Epimedium in cancer treatment merit further investigation. Despite its low acute and long-term toxicity, additional research is required to clarify its hepatotoxicity, particularly in vivo, and to further explore its metabolic pathways, distribution, and mechanisms within the body. CONCLUSION:Epimedium and its chemical constituents have been shown to inhibit tumor initiation and progression, however, further clinical studies are requiredto validate these findings. Despite its potential, significant limitations remain in the current research on Epimedium, necessitating more comprehensive studies on its potent bioactive components, potential pharmacological effects, and administration methods.

The characteristics of Alzheimer’s disease (AD) include behavioral deficits, amyloid-β (Aβ) accumulation, and mitochondrial impairment. Activating of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway significantly increases the production of inflammatory cytokines, which can exacerbate neuroinflammation and accelerate the progression of AD. Platycodin D (PD) has been reported to exhibit anti-inflammatory and neuroprotective properties and is believed to play a role in the progression of AD. Our study aimed to investigate the protective effects of PD in AD and to determine whether these protective effects are associated with the cGAS-STING pathway. In this research, APP/PS1 transgenic mice, an animal model of AD, were administered with PD via intracerebroventricular injection. SHSY5Y cells stably transfected with APPswe gene (APPswe cells) were used as a cell model of AD and treated with PD. Our findings demonstrated that PD attenuated behavioral deficits, Aβ accumulation, mitochondrial impairment, and decreased the expression level of cGAS-STING pathway proteins (cGAS and STING) as well as inflammatory cytokines (TNF-α, IL-1β and IL-18) in AD models. However, cGAMP acts as an agonist of the cGAS-STING pathway upregulated the cGAS-STING pathway and inflammatory cytokines, exacerbated Aβ accumulation and mitochondrial impairment in APPswe cells. In conclusion, our findings suggested that PD attenuated behavioral deficits, Aβ accumulation and mitochondrial impairment in AD models by inhibiting cGAS-STING pathway.

Non-alcoholic fatty liver disease (NAFLD) is becoming a global public health burden, yet effective therapeutic strategies are notably lacking. NAFLD development may be mediated by mitochondrial dysfunction, according to new research. Producing mitochondrial regulators from plant-based substances to treat mitochondrial dysfunction is an appealing approach to treating NAFLD. Hesperetin (HES) is a flavonoid that is found naturally and is a member of the flavanone family. This study aims to clarify the mechanism of HES in preventing NAFLD which is caused by a high-fat diet (HFD). Serum and liver biochemical parameters, liver histology, lipid profiles, and mitochondrial function were evaluated in HFD-induced NAFLD Sprague-Dawley (SD) rats. HES treatment significantly reduced body weight gain, liver weight, and the liver index, while also improving hepatic steatosis, lipid metabolism disorders, and mitochondrial dysfunction in rats with NAFLD. The mechanism was investigated and confirmed using western blot and real-time quantitative polymerase chain reaction (RT-qPCR). We showed that in the liver of NAFLD rats, HES decreased the expression of dynamic-related protein 1 (Drp1), phosphorylated Drp1 at serine-616 (Drp1-pS616) and induced phosphorylated Drp1 at serine-637 (Drp1-pS637), PTEN-induced kinase 1 (PINK1), and E3 Ubiquitin-Protein Ligase Parkin (Parkin) via an AMP-activated protein kinase alpha (AMPKα)-dependent mechanism. Moreover, HES increased the expression of the mitochondrial fusion proteins mitofusin-2 (Mfn2) and optic atrophy 1 (Opa1) while suppressing the expression of fission protein 1 (Fis1). In this work, we identify a unique mechanism by which HES prevents NAFLD from developing. HES may be an attractive potential therapeutic agent to cure NAFLD.

Excessive hepatic lipid accumulation and inflammatory injury are significant pathological manifestations of nonalcoholic fatty liver disease (NAFLD). Our previous research discovered that diosgenin, a natural steroidal saponin derived from Chinese herbs, can reduce hepatic lipid accumulation and steatosis; however, the exact mechanism remains unclear. This study aimed to investigate the protective mechanisms of diosgenin against NAFLD. We utilized network pharmacology and molecular docking approaches to identify the pathways through which diosgenin improves NAFLD. In high-fat diet (HFD)-fed rats, we measured biochemical markers in the serum and liver. Liver histopathology was assessed using HE and oil-red O staining. In free fatty acids (FFAs)-induced HepG2 cells, we employed the cell transfection overexpression method to verify the regulatory relationship of the identified pathways. The mechanisms in vitro and in vivo were examined using quantitative polymerase chain reaction and Western blot analyses. Bioinformatics analysis indicated that the mTOR-FASN/HIF-1α/RELA/VEGFA pathway may be the target pathway for diosgenin in alleviating NAFLD. Diosgenin inhibited hepatic lipid accumulation and pro-inflammatory cytokines in HFD-fed rats, and reduced intracellular lipid accumulation as well as TG, TC, IL-1β, and TNF-α levels in FFAs-induced HepG2 cells. Mechanistically, diosgenin downregulated the expression of p-mTOR, FASN, HIF-1α, RELA, and VEGFA, which are associated with lipid synthesis and inflammation. Overexpression of mTOR abolished the beneficial effects of diosgenin on lipid reduction and inflammation, as well as its inhibitory effects on the expression of FASN, HIF-1α, RELA, and VEGFA. In conclusion, diosgenin alleviates NAFLD through mTOR-mediated inhibition of lipid accumulation and inflammation.

Insulin resistance (IR) is a central pathogenic driver of metabolic dysfunction-associated steatotic liver disease (MASLD), yet current therapeutic strategies remain insufficient. Diosgenin (DG), a well-characterized natural compound, has been reported to modulate IR-related mechanisms and, thus, holds significant promise for MASLD treatment. In this study, rodent models fed a high-fat diet and HepG2 cells treated with free fatty acids were employed to simultaneously evaluate systemic metabolic outcomes (including hepatic indices and glucose tolerance) and cellular responses (including lipid accumulation and glucose uptake). The findings demonstrate that DG activates the ADIPOR1/APPL1 signaling pathway by elevating circulating adiponectin levels, thereby enhancing GLUT4-dependent glucose uptake, suppressing key gluconeogenic enzymes (PEPCK and G6 Pase), and inhibiting de novo lipogenesis through SREBP-1 downregulation. These mechanistic insights reveal that DG mitigates IR by augmenting adiponectin signaling, thereby providing a scientific basis for the development of phytotherapeutic strategies targeting MASLD.

The public health burden of cognitive decline escalates with population aging. While lipid species alterations are associated with cognitive function and Alzheimer’s disease (AD), causal evidence remains limited. We applied two-sample Mendelian randomization (TSMR) and Bayesian-weighted MR (BWMR) to investigate the causal effects of lipid species on cognitive function and to assess the bidirectional causal relationships between lipid species and AD. We analyzed genome-wide association study (GWAS) data from large-scale cohorts: AD (East African Development Bank [EADB], N = 487,511); cognitive function (UK Biobank, N = 20,346); and lipid species (THL Biobank, N = 7,174). Analyses were conducted using multiple MR methods, including inverse variance weighting (IVW), BWMR, MR-Egger regression, and false discovery rate (FDR) correction. Sensitivity analyses—MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), Cochran’s Q test, and leave-one-out analysis—were conducted to evaluate horizontal pleiotropy and heterogeneity. TSMR results identified 51 lipid species with causal associations for cognitive function and AD, among which 27 showed protective effects. Conversely, AD was found to influence 17 lipid species, with 14 exhibiting negative effects. These genetically supported findings highlight potential lipid-related targets for preventive and therapeutic interventions aimed at combating cognitive decline.

The most prevalent liver condition globally is non-alcoholic fatty liver disease (NAFLD), for which no approved therapies currently exist. Diosgenin, an important component in plants from the Leguminosae, Dioscoreaceae, and Solanaceae families, has demonstrated considerable anti-inflammatory and antioxidant effects. Nonetheless, the specific mechanism by which it may act in managing NAFLD remains unclear. Our research aims to explore the effects and molecular mechanisms of DG on NAFLD by utilizing both in vivo and in vitro experimental approaches. To investigate the effect of DG on hepatic steatosis, we used Sprague-Dawley rats induced by a high-fat diet (HFD) and HepG2 cells exposed to free fatty acids. Oil red O staining and hematoxylineosin (H&E) staining were used to explore lipid accumulation and hepatic degeneration. ROS staining, SOD, MDA, and Fe2 + kits were used to detect the indexes related to oxidative stress in ferroptosis in hepatic tissues and cells. IFSP1 and pcDNA3.1-ACSL4 plasmid were used to knock down Ferroptosis suppressor protein1 (FSP1) and promote the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) in HepG2 cells. DG improved lipid metabolism disorders and liver damage induced by a high-fat diet in rats with NAFLD. Furthermore, the administration of DG notably decreased oxidative stress levels and liver Fe2+concentrations in rats. Additionally, in vitro experiments demonstrated that DG treatment markedly attenuated ferroptosis and ROS accumulation in HepG2 cells induced by FFAs. Moreover, overexpression of hepatic ACSL4 expression by pcDNA3.1-ACSL4 plasmid promoted the regulatory effects of DG on LPCAT3 and ALOX15. Our research shows that DG can alleviate NAFLD by regulating the FSP1/COQ10 pathway of the ferroptosis defense system and the ACSL4/LPCAT3/ALOX15 pathway of the ferroptosis execution system. Therefore, DG may serve as a novel inhibitor of ferroptosis for the treatment of NAFLD. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.

AimThis study aimed to investigate the mechanisms through which diosgenin inhibits the pathogenesis of non-alcoholic fatty liver disease, focusing particularly on ferroptosis-related pathways and its reliance on nuclear factor erythroid 2-related factor 2. Materials and MethodsUsing a rat model, we showed diosgenin's efficacy in reducing lipid deposition throughout the body and examined its impact on ferroptosis-related gene expression in vivo. Moreover, in vitro experiments using human hepatocellular liver carcinoma cell line cells were conducted to assess oxidative stress and ferroptosis levels. ResultsDiosgenin decreased lipid accumulation and steatosis; lowered serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, glutamic pyruvic transaminase and glutamic oxaloacetic transaminase; reduced interleukin-1 beta and tumour necrosis factor-alpha; diosgenin decreased malondialdehyde levels; and increased serum superoxide dismutase levels in a rat model of high-fat diet-induced non-alcoholic fatty liver disease. Diosgenin upregulated the expression of nuclear factor erythroid 2-related factor 2 and its downstream ferroptosis-related genes to inhibit ferroptosis in the livers of rats with non-alcoholic fatty liver disease. Diosgenin decreased reactive oxygen species levels and enhanced the expression of ferroptosis-related genes in human hepatocellular liver carcinoma cells induced by free fatty acids, with its effects being dependent on nuclear factor erythroid 2-related factor 2. ConclusionsThis study highlights the potential of diosgenin from Dioscoreaceae plants in mitigating oxidative stress and ferroptosis levels through nuclear factor erythroid 2-related factor 2 regulation, offering novel insights into the treatment of non-alcoholic fatty liver disease and other metabolic disorders through traditional Chinese medicine.

Due to a scarcity of appropriate therapeutic approaches capable of ameliorating or eliminating non-alcoholic fatty liver disease (NAFLD), many researchers have come to focus on natural products based on traditional medicine that can be utilized to successfully treat NAFLD. In this study, we aimed to evaluate the effects exerted by seven natural products (curcumin, silymarin, resveratrol, artichoke leaf extract, berberine, catechins, and naringenin) on patients with NAFLD. For this purpose, PubMed, Embase, Cochrane Library, and Web of Science, were searched for randomized controlled trials (RCTs) exclusively. The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The RCTs from the earliest available date until September 2022 were collected. This process resulted in 37 RCTs with a total sample size of 2509 patients being included. The results of the network meta-analysis showed that artichoke leaf extract confers a relative advantage in reducing the aspartate aminotransferase (AST) levels (SUCRA: 99.1%), alanine aminotransferase (ALT) levels (SUCRA: 88.2%) and low-density lipoprotein cholesterol (LDL-C) levels (SUCRA: 88.9%). Naringenin conferred an advantage in reducing triglyceride (TG) levels (SUCRA: 97.3%), total cholesterol (TC) levels (SUCRA: 73.9%), and improving high-density lipoprotein cholesterol (HDL-C) levels (SUCRA: 74.9%). High-density catechins significantly reduced body mass index (BMI) levels (SUCRA: 98.5%) compared with the placebo. The Ranking Plot of the Network indicated that artichoke leaf extract and naringenin performed better than the other natural products in facilitating patient recovery. Therefore, we propose that artichoke leaf extract and naringenin may exert a better therapeutic effect on NAFLD. This study may help guide clinicians and lead to further detailed studies.

Metabolic-associated fatty liver disease (MAFLD) is one of the most common liver diseases worldwide; however, its pathogenesis and treatment methods have not been perfected. NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) is a promising therapeutic target for MAFLD. Diosgenin (DG) is a natural compound that was identified in a traditional Chinese herbal medicine, which has pharmacological effects, such as anti-inflammatory, antioxidant, hepatoprotective, and hypolipidemic activities. In this study, we examined the effects and molecular mechanisms of DG on MAFLD in vitro and in vivo. We established a rat model by administering a high-fat diet (HFD). We also generated an in vitro MAFLD model by treating HepG2 cells with free fatty acids (FFAs). The results indicated that DG attenuated lipid accumulation and liver injury in both in vitro and in vivo models. DG downregulated the expression of NLRP3, apoptosis-associated speckle-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), gasdermin D (GSDMD), GSDMD-n, and interleukin-1β (IL-1β). In addition, we silenced and overexpressed NLRP3 in vitro to determine the effects of DG on antiMAFLD. Silencing NLRP3 enhanced the effect of DG on the treatment of MAFLD, whereas NLRP3 overexpression reversed its beneficial effects. Taken together, the results show that DG has a favorable effect on attenuating MAFLD through the hepatic NLRP3 inflammasome-dependent signaling pathway. DG represents a natural NLRP3 inhibitor for the MAFLD treatment.

ObjectiveSome previous studies have suggested a potential link between stroke and gastroesophageal reflux disease (GERD). We used a two-sample bidirectional Mendelian randomization (MR) method to explore the causal relationship between stroke and GERD.DesignSummary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for stroke (n = 446,696) and its common subtypes ischemic stroke (IS) (n = 440,328), large vessel stroke (LVS) (n = 410,484), small vessel stroke (SVS) (n = 198,048), and cardioembolic stroke (CES) (n = 413,304) were obtained from the MEGASTROKE consortium. The data on intracerebral hemorrhage (ICH) (n = 721,135) come from the UK Biobank. Instrumental variables (IVs) for lacunar stroke (LS) (n = 474,348) and GERD (n = 602,604) were screened from publicly available genetic summary data. The inverse variance weighted (IVW) method was used as the main MR method. Pleiotropy was detected by the MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis. Cochran Q statistics were used as supplements to detect pleiotropy.ResultsWe found that GERD can causally increase the risk of stroke [IVW odds ratio (OR): 1.22, 95% confidence interval (CI): 1.13–1.32, p = 1.16 × 10−6] and its common subtypes IS (OR: 1.19, 95% CI: 1.10–1.30, p = 3.22 × 10−5), LVS (OR: 1.49, 95% CI: 1.21–1.84, p = 1.47 × 10−4), and LS (OR: 1.20, 95% CI: 1.001–1.44, p = 0.048). Several important risk factors for stroke have also been implicated in the above causal relationship, including type 2 diabetes, sleep apnea syndrome, high body mass index, high waist-to-hip ratio, and elevated serum triglyceride levels. In reverse MR analysis, we found that overall stroke (OR: 1.09, 95% CI: 1.004–1.19, p = 0.039) and IS (OR: 1.10, 95% CI: 1.03–1.17, p = 0.007) have the causal potential to enhance GERD risk.ConclusionThis MR study provides evidence supporting a causal relationship between GERD and stroke and some of its common subtypes. We need to further explore the interconnected mechanisms between these two common diseases to better prevent and treat them.

With the acceleration of people's pace of life, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world, which greatly threatens people's health and safety. Therefore, there is still an urgent need for higher-quality research and treatment in this area. Nuclear factor Red-2-related factor 2 (Nrf2), as a key transcription factor in the regulation of oxidative stress, plays an important role in inducing the body's antioxidant response. Although there are no approved drugs targeting Nrf2 to treat NAFLD so far, it is still of great significance to target Nrf2 to alleviate NAFLD. In recent years, studies have reported that many natural products treat NAFLD by acting on Nrf2 or Nrf2 pathways. This article reviews the role of Nrf2 in the pathogenesis of NAFLD and summarizes the currently reported natural products targeting Nrf2 or Nrf2 pathway for the treatment of NAFLD, which provides new ideas for the development of new NAFLD-related drugs.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide in recent years, causing severe economic and social burdens. Therefore, the lack of currently approved drugs for anti-NAFLD has gradually gained attention. SIRT1, as a member of the sirtuins family, is now the most widely studied in the pathophysiology of many metabolic diseases, and has great potential for preventing and treating NAFLD. Natural products such as Diosgenin (DG) have the potential to be developed as clinical drugs for the treatment of NAFLD due to their excellent multi-target therapeutic effects. In this study, we found that DG can activate the SIRT1/PGC-1α pathway and upregulate the expression of its downstream targets nuclear respiratory factor 1 (NRF1), complex IV (COX IV), mitofusin-2 (MFN2), and PPARα (perox-isome proliferator-activated receptor α) in SD rats induced by high-fat diet (HFD) and HepG2 cells caused by free fatty acids (FFAs, sodium oleate: sodium palmitate = 2:1). Conversely, the levels of dynamin-related protein 1(DRP1) and inflammatory factors, including NF-κB p65, IL6, and TNFα, were downregulated both in vitro and in vivo. This improved mitochondrial dysfunction, fatty acid oxidation (FAO), lipid accumulation, steatosis, oxidative stress, and hepatocyte inflammation. Subsequently, we applied SIRT1 inhibitor EX527 and SIRT1 agonist SRT1720 to confirm further the necessity of activating SIRT1 for DG to exert therapeutic effects on NAFLD. In summary, these results further demonstrate the potential therapeutic role of DG as a SIRT1 natural agonist for NAFLD. (Graphical Abstracts)

Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties.