ID: 41643151
Title: Panaxatriol Improves the Disorder of Lipid Metabolism and Intestinal Flora in Rats Fed With a High-Fat Diet.
Abstract: The ability of ginsenosides to regulate lipid metabolism in vivo and in vitro has been widely studied; however, the effect of panaxatriol (PT) on reducing blood lipids and its impact on intestinal microflora have not been investigated. The results of this study show that PT can not only significantly reduce the level of ALT but also effectively alleviate fatty degeneration and lipid droplet deposition in hepatocytes, thereby improving the pathological damage to the liver. It can also significantly reduce serum TC, TG, and LDL-C levels and increase HDL-C. At the same time, PT can significantly increase SOD activity, decrease MDA content, and inhibit the increase of coagulation factors such as TXB2, thus alleviating vascular endothelial injury. In addition, PT decreased the abundance of intestinal flora, increased the ratio of Firmicutes to Bacteroidetes, increased the abundance of Akkermansia, and decreased the abundance of Prevotella. Our research shows that PT can effectively alleviate the lipid metabolism disorder induced by the high-fat and high-sugar diet by improving liver lipid deposition, enhancing antioxidant capacity, regulating blood coagulation function, and reshaping intestinal flora structure, suggesting that PT has potential application value in the treatment of metabolic syndrome.

ID: 41677682
Title: Fermented Red Ginseng Restores Age-Associated Insulin Homeostasis and Gut Microbiome Balance in Mice.
Abstract: Biological aging disrupts liver-gut intercommunication, resulting in the development of insulin resistance and type 2 diabetes, coupled with the imbalance of gut microbiome composition known as gut dysbiosis. Fermented red ginseng (FRG) is a renowned functional food substance showing its notable anti-inflammatory and anti-diabetic effects owing to its unique bioactive compounds known as ginsenosides. However, whether FRG could impact biological aging and age-related metabolic dysfunction is still unclear. The current study aimed to determine the health benefits of FRG in improving age-associated impaired insulin homeostasis and gut dysbiosis in 19-month-old male mice. Mice were fed with a normal chow diet (NCD) or NCD with FRG (300 mg/kg) for 14 weeks. FRG supplementation significantly improved insulin homeostasis by activating the hepatic protein kinase B (AKT) and proline-rich AKT substrate of 40 kDa (PRAS40). We also observed suppressed mRNA expression of proinflammatory cytokines and diminished inflammatory infiltrates in the liver of FRG-fed mice compared with NCD-only controls. Furthermore, alongside a decreased ratio of Firmicutes to Bacteroidetes, FRG administration enriched beneficial genera, including Muribaculaceae, Borkfalkiaceae, Parasutterella, and Clostridia vadin BB60 group, whereas FRG reduced the abundance of Erysipelotrichaceae and Dubosiella at the genus level. In summary, we suggest that FRG can be a potential anti-aging dietary supplement to manage age-driven dysregulation of insulin homeostasis and gut microbiota composition.

ID: 41788585
Title: Mechanistic insights into the regulation of glucose‒lipid metabolism by the bioactive constituents of ginseng.
Abstract: Panax ginseng Meyer (P. ginseng, PG), a historically used phytotherapeutic agent with a long history and wide-ranging applications, has garnered increasing attention in recent years because of its considerable pharmacological value. Amid the global rise in metabolic disorders, P. ginseng, as a natural product, has been demonstrated to contain various bioactive components-including ginsenosides, P. ginseng polysaccharides, and P. ginseng peptides-that have significant pharmacological effects on glucose and lipid metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). These bioactive compounds modulate glucose and lipid metabolism through multitarget mechanisms, including enhancing glucose uptake and glycogen synthesis, inhibiting gluconeogenesis, and regulating adipocyte differentiation and fatty acid oxidation, as well as through gut microbiota-mediated regulation of glucose‒lipid metabolism. These effects help alleviate pathological conditions such as insulin resistance (IR), inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, involving key signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor gamma (PPARγ). As a result, P. ginseng shows significant promise and holds great potential for preventing and treating glucose‒lipid metabolic disorders. Ongoing advances in research and technology may further elucidate its underlying mechanisms and facilitate clinical translation, paving the way for the development of more effective therapeutics for metabolic regulation.

ID: 41828369
Title: Rice-Fried and Sun-Dried Ginseng: A Comparative Study of Chemical Composition and Protective Effects Against Ulcerative Colitis.
Abstract: Ginseng (Panax ginseng C. A. Mey.), a traditional Chinese medicine, exhibits spleen-fortifying, anti-inflammatory, and anti-ulcerative colitis (UC) effects. Rice-fried ginseng (RFG), prepared by stir-frying with rice together, yields a marked enrichment of rare ginsenosides, which is hypothesized to enhance its anti-inflammatory and anti-UC effects. Therefore, in this study, the chemical compositions of RFG and sun-dried ginseng (SDG) were systematically compared using LC-MS combined with MS-DIAL, and their protective effects against UC were evaluated using lipopolysaccharide (LPS)-induced Caco-2 cells and a dextran sulfate sodium (DSS)-induced UC mouse model. Rice-frying markedly altered the chemical composition of ginseng, and a total of 64 major compounds were identified, of which 31 increased and 33 decreased after processing. These compositional changes were associated with enhanced anti-inflammatory and immunomodulatory effects of RFG. Consistently, RFG enhanced Caco-2 cell viability, decreased TNF-α, IL-1β, and IL-6, and increased ZO-1, occludin, claudin-1, and E-cadherin. In DSS-induced UC mice, RFG attenuated body weight loss, reduced DAI, increased colon length, and decreased the spleen index, accompanied by improved histopathology, reduced pro-inflammatory cytokine levels, and increased expression of tight-junction proteins (TJPs) in a dose-dependent manner. In addition, RFG ameliorated DSS-induced gut microbiota dysbiosis. Metabolomics and network pharmacology analyses highlighted disturbances in linoleic acid and arachidonic acid metabolism and emphasized the involvement of the PI3K-Akt and NF-κB signaling pathways. Western blotting demonstrated decreased phosphorylation of PI3K, Akt, IKKβ, and NF-κB after RFG intervention. Overall, compared with SDG, RFG showed stronger protective effects in vitro and in vivo, accompanied by improved inflammatory readouts, altered lipid-related metabolites and gut microbiota profiles, and reduced phosphorylation of PI3K, Akt, IKKβ, and NF-κB.

ID: 41881903
Title: Healing the heart naturally: The role of bioactive phytocompounds in cardiovascular therapeutics.
Abstract: Cardiovascular diseases remain the leading cause of global mortality, with a consistently rising burden in low- and middle-income countries. Limitations and adverse effects of conventional therapies have increased interest in plant-derived therapeutic alternatives. This review aims to evaluate the therapeutic potential of bioactive phytocompounds from medicinal plants in preventing the development of CVD by promoting cardiovascular health. This proposed study uses a narrative literature review design to examine experimental/clinical findings on plant-based cardioprotective substances. We analysed published preclinical and clinical research on the major active phytochemicals, including curcumin, resveratrol, ginsenosides, berberine, quercetin, and catechins. We discussed their molecular mechanisms, pharmacological actions, and emerging nanotechnology-based delivery systems in detail. We also analysed their impact on gut microbiota-derived metabolites, including TMAO, short-chain fatty acids, and bile acids. Bioactive phytocompounds exerted a pronounced cardioprotective effect by attenuating oxidative stress and inflammation, improving endothelial dysfunction, and restoring lipid metabolism and mitochondrial integrity. These bioactive compounds enhanced nitric oxide bioavailability and effectively regulated calcium signalling, NF-κB, and MAPK pathways, while also modulating microbiota-related metabolites. Nanotechnology-based formulations further improved biocompatibility and tissue specificity. Hypertension, atherosclerosis, myocardial ischemia, and heart failure had strong clinical efficacy and validated safe use. Bioactive phytocompounds offer a holistic and sustainable approach to managing cardiovascular disease. However, standardization, well-designed clinical trials, and regulatory harmonization are still required to facilitate the integration of these therapies into mainstream cardiovascular medicine.

ID: 42098749
Title: Research progress on the mechanisms of Panax ginseng and its active components in maintaining skin homeostasis and disease intervention.
Abstract: Panax ginseng (Panax ginseng C.A. Meyer) is a classic herbal medicine widely utilized in dermatological management, yet its precise therapeutic mechanisms have only recently begun to be fully elucidated. This review systematically synthesizes the pharmacological roles of ginseng's active components, including ginsenosides, polysaccharides, and gintonin, in maintaining skin homeostasis and treating various cutaneous pathologies. Emerging evidence suggests that the efficacy of ginseng extends beyond direct molecular interactions, exhibiting the distinct characteristics of "indirect pharmacology." Specifically, parent ginsenosides function primarily as natural prodrugs that require microbial biotransformation into high-affinity active metabolites, such as Compound K and Rh2, to exert potent therapeutic effects. Functionally, these components regulate skin health by mobilizing endogenous host defense systems, particularly through the activation of the Nrf2/ARE antioxidant pathway and the suppression of inflammatory cascades via the NF-κB, MAPK, and IL-1 signaling networks. Furthermore, they remodel the systemic microenvironment through the gut-skin axis, facilitating metabolic homeostasis to improve skin barrier function. Notably, biotransformation rates and ultimate therapeutic efficacy are highly dependent on individualized variables, such as host age, dietary patterns, and baseline disease states. This systemic regulation has demonstrated robust efficacy in intervening in complex pathologies, including atopic dermatitis, psoriasis, and skin cancer. Additionally, this article addresses the translational bottleneck of low bioavailability and evaluates recent advances in novel skin delivery systems, specifically those utilizing ginseng-derived exosomes. Collectively, this review provides a scientific framework for understanding the systemic actions of ginseng, supporting its development as a precision botanical therapy for dermatological applications.

ID: 42109191
Title: Alleviation of Helicobacter pylori-Induced Pathogenicity and Gastric Inflammation by Majonoside-R2- and Ginsenoside Rg1-Rich Fractions From Panax vietnamensis Ha Et Grushv.: A Metabolomics-Guided Investigation.
Abstract: Helicobacter pylori infection remains a major global health concern due to its association with gastric inflammation, ulceration, and gastric malignancies. This study evaluated the effects of Ngoc Linh ginseng (Panax vietnamensis Ha et Grushv.) root fractions on H. pylori virulence and host inflammatory responses. UHPLC-MS/MS-based metabolomic profiling coupled with feature-based molecular networking was employed to characterize the chemical profiles of different solvent fractions, identifying the dichloromethane (DCM) fraction as enriched in ginsenosides, particularly the ocotillol-type saponin majonoside R2 (MR2). In vitro assays showed that, despite minimal direct antibacterial activity, the DCM fraction at sub-inhibitory concentrations significantly reduced urease activity, acid tolerance, biofilm formation, and the expression of major virulence genes, including vacA and cagA. In H. pylori-infected AGS gastric epithelial cells, the DCM fraction and MR2 decreased VacA and CagA translocation, suppressed pro-inflammatory signaling and cytokine production, restored antioxidant defenses, and alleviated mitochondrial apoptosis. By contrast, ginsenoside Rg1 selectively modulated host inflammatory and oxidative stress responses without affecting bacterial virulence gene expression. These results demonstrate that Ngoc Linh ginseng root fractions mitigate H. pylori-induced pathogenic effects primarily through anti-virulence and host-directed mechanisms, highlighting their potential relevance for the development of gastric health-promoting functional products.

ID: 42141484
Title: Ginsenosides in the management of depression: a comprehensive pharmacological review.
Abstract: Depression is a prevalent and debilitating psychiatric disorder that is frequently accompanied by chronic conditions such as cancer, cardiovascular diseases, and neurological disorders. Despite the availability of various pharmacological treatments, their limited efficacy and frequent side effects have prompted growing interest in natural compounds with antidepressant potential. Panax ginseng, a traditional herbal medicine widely used in East Asia, contains diverse bioactive components, among which ginsenosides are recognized as the principal active constituents. Ginsenosides, primarily classified into dammarane-type and oleanane-type saponins, exhibit antidepressant-like effects through multiple interconnected biological mechanisms. These include modulation of monoaminergic neurotransmission, regulation of the hypothalamic-pituitary-adrenal (HPA) axis, promotion of neurogenesis and synaptic plasticity, mitigation of neuroinflammation and oxidative stress, and restoration of gut microbiota homeostasis. Recent investigations also highlight enhanced bioavailability and therapeutic promises of rare ginsenosides, such as ginsenosides Rg3, Rk1 and Rg5, with fewer sugar moieties, suggesting unique advantages for clinical application. This review consolidates current evidence on the pharmacological activities, molecular targets, and therapeutic potential of ginsenosides in the management of depression. By integrating findings from experimental and limited clinical studies, it aims to provide a rational scientific framework to inform future investigation and development of ginsenoside-based strategies for depression, while emphasizing the need for further rigorous clinical validation.

ID: 42160897
Title: Preclinical investigation and clinical trials of Red ginseng as an immunomodulator: a narrative review from 2015 to 2025.
Abstract: Red ginseng (Ginseng Radix et Rhizome Rubra, RG) is the steamed and dried root of Panax ginseng C.A. Meyer. It has been used for centuries in Asia for Qi tonifying, which has been reported to align with immune regulation in humans. Accordingly, the immune regulatory effects of RG were extensively studied in various health conditions. However, few publications are available retrieving the clinical and preclinical advancements of RG on immunity. This review endeavors to summarize the clinical and preclinical studies conducted to investigate the immunomodulatory effects of RG from 2015 to 2025. The limitations of previous studies and potential future directions are discussed. All relevant clinical and pharmacological studies aimed at elucidating the immune regulatory effects of RG and published from 2015 to 2025 were included. The studies were retrieved from Web of Science, Scopus, PubMed, Springer and Google Scholar. In vitro, in vivo and clinical studies have consistently shown that RG modulates immunity across various species and exhibits bidirectional immunoregulatory effects depending on health status (i.e., good health, sub-health and disease). Major bioactive groups rare ginsenosides, polysaccharides and Arginyl-Fructose endow RG with a regulatory effect on innate immune system (e.g., macrophages, dendritic cells, neutrophils and mucosa cells) and adaptive immune system (e.g., T and B cells). Multiple signaling pathways are involved in the regulatory effects of RG on immune cells, including TLR4/NF-κB, RORγ, glucocorticoid receptors and gut microbiota. It is noteworthy that with the development of separation, purification and detection techniques, an increasing number of researchers are devoting efforts toward uncovering the fine structure of RG polysaccharides, which will help to elucidate the correlation between structure and the immune regulatory effects of RG polysaccharides. Preclinical and clinical studies demonstrated that RG regulates immunity to relieve diseases and enhance body performance, providing scientific evidence for its traditional use as Qi-tonifying agent. Further efforts are needed to elucidate the relationship between the structure and biological activities of RG ingredients, as well as the holistic immune regulatory effects of RG.

ID: 42206644
Title: Research Progress on the Mechanism of Ginsenoside Rg1 in Inflammatory Bowel Disease.
Abstract: Inflammatory bowel disease (IBD), a chronic intestinal inflammatory disorder, has witnessed a rising incidence globally. At present, the primary therapeutic approaches for IBD, such as aminosalicylic acid, glucocorticoids, immunosuppressants, and biologics, often entail notable side effects and limited efficacy. Traditional Chinese medicines (TCMs), particularly ginsenosides, have shown promise in the treatment of IBD. Ginsenoside Rg1 (G-Rg1), a characteristic constituent of ginsenosides, exerts a therapeutic impact on IBD. This review primarily elaborates on how G-Rg1 can restore the equilibrium of inflammatory and anti-inflammatory factors within the intestinal milieu. It achieves this by modifying the structure and metabolism of the intestinal flora, reorganizing the tight junction proteins of the intestinal barrier, and regulating the interplay between signaling pathways and immune cells, ultimately attaining the effect of alleviating IBD.

ID: 42208109
Title: Ginseng-derived cholesterol analogues enhance pulmonary siRNA delivery and alleviate allergic asthma.
Abstract: Asthma patients exhibit elevated airway mucus secretion. Small interfering RNA (siRNA) targeting the mucin MUC5AC delivered by lipid nanoparticles (LNPs) is promising but limited by low transfection efficiency. Protopanaxadiol (PPD), protopanaxatriol (PPT), and ginsenoside Rh2 (GR2) were chosen because their dammarane skeleton preserves membrane-insertion capacity for endosomal escape, whereas bulkier multi-glycosylated ginsenosides adversely affect LNP size and stability. In this study, we designed novel inhaled LNPs incorporating ginseng-derived cholesterol analogs to enhance therapeutic efficacy against asthma. PPD and PPT were used as membrane components to formulate anti-MUC5AC siRNA-loaded LNPs (designated as DLNPs and TLNPs). Flow cytometry and confocal laser scanning microscopy (CLSM) were employed to evaluate the cellular uptake and lysosomal escape of LNPs. An asthmatic mouse model was established to assess therapeutic effects of DLNPs and TLNPs through pathological section analysis and determination of inflammatory cytokine levels. The data showed that these novel formulations enhanced cellular uptake by airway epithelial cells (AECs) and promoted siRNA escape from lysosomes, thereby improving pulmonary delivery efficiency. TLNPs, in particular, demonstrated superior performance. Furthermore, DLNPs and TLNPs exerted multifaceted anti‑asthmatic effects in vivo, as evidenced by significant suppression of MUC5AC overexpression in AECs, attenuation of inflammatory cell infiltration, and reduction in the secretion of the critical cytokines IL‑4 and IL‑13. Overall, our findings indicate that ginseng-derived PPD and PPT effectively enhance siRNA delivery and mitigate asthma symptoms through dual inhibition of MUC5AC overexpression and airway inflammation. These cholesterol analogs represent promising carrier materials for LNP-based pulmonary therapeutics.

ID: 42228830
Title: Characteristics of Anaerobic Bacteroides fragilis CMLF03 and Its Enzymes Involved in the Transformation of Panax notoginseng Saponins.
Abstract: Panax notoginseng saponins (PNS) are bioactive constituents that can be biotransformed by gut microbiota. Anaerobic Bacteroides bacteria are considered the next-generation probiotics. However, little is known about PNS biotransformation by Bacteroides bacteria. The study identified a nonenterotoxigenic Bacteroides fragilis capable of biotransforming PNS. Three family 3 glycoside hydrolases from the strain were heterologously expressed and identified as β-glucosidases GE-270 and GE-710 and β-xylosidase GE-616. The two β-glucosidases catalyzed the conversion of the abundant protopanaxadiol-type ginsenosides Rb2, Rb3, and Rc present in P. notoginseng flowers and leaves to the rare ginsenoside compounds O, Mx1, and Mc1, respectively, and also converted ginsenoside Rb1 to F2. Furthermore, GE-270 converted the protopanaxadiol-type ginsenoside Rg3 to Rh2 and the protopanaxatriol-type notoginsenoside R1 to ginsenoside Rg1. The β-xylosidase GE-616 could convert the ginsenoside Rb3 to Rd. This research provides a novel anaerobic bacterium and its enzymes for PNS biotransformation.

ID: 42276580
Title: A probiotic BL53 enhances the immunomodulatory and neurorestorative activities of red ginseng in cyclophosphamide-exposed mice through the transformation of ginsenosides to compound K.
Abstract: Gut microbiota converts ginsenosides of orally administered red ginseng (RG) into bioactive metabolites such as compound K (CK), with marked interindividual variation. These metabolites exert stronger biological effects than parent ginsenosides. Therefore, we screened probiotic bacteria capable of converting RG ginsenosides to CK and evaluated whether they could enhance the effects of RG on immunosuppression, depression, and cognitive impairment in mice. Bifidobacterium animalis subsp. lactis PB5 and Lactobacillus gasseri PL3, isolated from a human gut microbiota collection, exhibited the strongest ability to convert RG ginsenosides into CK and to increase immune-modulatory and BDNF expression-inducing activity. A (1:4) mixture of PB5 and PL3 (BL53) reduced lipopolysaccharide-induced TNF-α IL-10-1 ratio in macrophages (by 47.8%, P < 0.05) and restored lipopolysaccharide-suppressed BDNF expression in SH-SY5Y cells (by 45.2%, P < 0.05) compared with either PB5 or PL3 alone. Co-administration of BL53 and RG (BRc) enhanced immune responses in cyclophosphamide-exposed mice, compared with either treatment alone, increasing TNF-α, IL-10, and IL-17 levels by 27.0%-96.6% (P < 0.05) and reducing the TNF-α IL-10-1 ratio by 19.5%-27.5% (P < 0.05). BRc also improved cognitive impairment (37.8%) and depression-like behaviors (26.0%-132.0%) and restored hippocampal BDNF (26.9%) (P < 0.05). Plasma CK levels were highest in BRc-treated mice (7.9-fold vs RG, P < 0.05). BRc significantly alleviates immunosuppression and depression- and cognitive impairment-related symptoms in vivo, which may be attributed to the BL53-mediated enhancement of RG efficacy through PB5-driven biotransformation of RG ginsenosides into CK and PL3-mediated immune modulation and BDNF upregulation.

ID: 42280421
Title: Ginseng Bioactive Components as Gut-Brain Axis-Targeted Modulators: Therapeutic Potential and Mechanisms in Multifactorial Diseases.
Abstract: Ginseng (Panax ginseng C. A. Mey.) is a classic traditional Chinese herbal medicine with a history of clinical use that spans millennia. Its utilisation has long been established in the regulation of physical and mental equilibrium, in addition to the amelioration of conditions pertaining to the heart, spleen, and brain. Recent studies have indicated that the core biological activity of the substance under investigation is mediated by key active components such as ginsenosides, polysaccharides, and polyphenols. These components are closely associated with the regulation of the gut-brain axis (GBA). However, extant reviews have predominantly concentrated on individual diseases or specific mechanisms, thereby lacking a thorough investigation into the comprehensive analysis of how ginseng components exert systemic effects via the GBA. This review systematically searched and analyzed published studies in major databases regarding the regulation of the GBA by ginseng bioactive components, summarizing the latest advances in its role as a multifactorial disease intervention regulator targeting the GBA. It has been demonstrated that ginseng components exert a multifaceted GBA regulatory effect through interconnected mechanisms, including modulation of the gut microbiota, protection of the intestinal barrier, anti-inflammatory actions, and regulation of neurotransmitters, showing promising preclinical therapeutic potential in neurodegenerative diseases, mood disorders, metabolic diseases, and gastrointestinal disorders. Contrary to previous reviews, which focused on the description of individual ginseng components or specific diseases, this study provides a comprehensive analysis of how various bioactive components of ginseng modulate the gut-brain axis in relation to multiple disease categories through a systematic review. However, the preponderance of extant evidence derives from preclinical studies and necessitates further validation through clinical trials. This review provides pivotal directions and theoretical underpinnings for the clinical translation of ginseng's bioactive components and the development of disease intervention strategies targeting the gut-brain axis.

ID: 42280449
Title: Ginsenosides for the Management of Metabolic Dysfunction-Associated Fatty Liver Disease: A Research Update.
Abstract: Background: Metabolic-associated fatty liver disease (MAFLD) has a high prevalence of 30-40% in China and Asia, with a complex pathogenesis and no specific therapeutic drugs. Phytochemicals have become a research hotspot for MAFLD prevention, and ginsenosides, the core active components of Panax ginseng, show great potential in anti-MAFLD research. This review aims to comprehensively clarify the key mechanisms and targets of ginsenosides in preventing and treating MAFLD, to provide a theoretical basis for their application in metabolic diseases, and to promote the development of natural phytochemical resources. Method: The literature review method was adopted to sort out the regulatory effects and molecular targets of ginsenosides in multiple pathological processes of MAFLD from published studies. Results: Ginsenosides regulated MAFLD through multi-pathway and multi-target effects: antioxidant regulation occurred via Nuclear factor E2-related factor 2 (Nrf2)/Silent information regulator 1/6 (SIRT1/6) pathways, and anti-inflammatory regulation was achieved by inhibiting the Nuclear factor kappa-B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Additionally, the measures adopted improved insulin resistance and lipid metabolism disorder, suppressed hepatocyte apoptosis/pyroptosis, repaired autophagy, alleviated hepatocyte senescence, and reshaped gut microbiota to restore gut-liver axis homeostasis. Conclusions: Ginsenosides have good potential for MAFLD prevention and treatment, but there is a prominent lack of human clinical evidence as most existing studies are only based on in vitro cell and in vivo animal models, and the synergistic mechanisms among different ginsenoside components remain unclear. Future research needs multi-omics analysis, formulation optimization, and large-sample clinical trials, and ginsenosides have broad application prospects in MAFLD intervention.

ID: 42338888
Title: Interplay between B vitamins, fiber, and Bacteroides abundance: a predictive model for anxiety and depression in amyotrophic lateral sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease that not only affects motor function but is also associated with gastrointestinal and emotional disturbances. Recent research highlights the potential role of gut microbiota and diet in modulating these symptoms, suggesting a complex interaction between nutrition, intestinal health, and presence of anxiety and depression in ALS patients. This study aims to investigate the relationship between dietary intake, gut microbiota composition, and presence of anxiety and depression in patients with amyotrophic lateral sclerosis (ALS). A cross-sectional study conducted with a sample of 48 patients with bulbar-onset or spinal-onset ALS from different regions of Spain. Dietary intake was assessed through 24-h records and food frequency questionnaires, while anxiety and depression were evaluated using validated scales that formed a latent factor called emotional distress. Stool consistency was assessed following the Bristol Stool Scale and the abundance of bacterial microbiota was quantified. Confirmatory factor analysis identified a nutritional factor composed of vitamins B1, B2, B9, C, and fiber, revealing a significant inverse association with anxiety and depression levels. The predictive model revealed both direct and indirect effects of this factor on presence of anxiety and depression, mediated by Bacteroides abundance and stool consistency. This model explained 19% of the variance in psychological distress. Our findings suggest that a diet rich in B vitamins, C vitamin and fiber may help improve emotional well-being in patients with ALS, highlighting the importance of nutritional strategies, as well as the role of Bacteroides related to stool consistency in patients with ALS.

ID: 42346332
Title: Effects of Long-Term Administration of Ginsenosides on the Structure of Intestinal Microflora and the Absorption and Utilization of Saponins in Rats.
Abstract: Background: Ginsenosides are active natural compounds with diverse effects, and their interaction with the gut microbiota can influence microbial composition and abundance, though the long-term effects remain unclear. Methods: This study examines the impact of long-term oral ginsenoside administration on gut microbiota composition and structure in rats, as well as its pharmacokinetics. Twenty healthy male Wistar rats were divided into a control group (CK, receiving distilled water) and a ginsenoside treatment group (PGE, 100 mg/kg) for 30 days. Fecal samples were analyzed using 16S rRNA high-throughput sequencing on the Illumina HiSeq platform to assess microbial diversity. Concurrently, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized to determine the concentrations of ginsenosides in the serum and to investigate their pharmacokinetic properties (p < 0.05). Results: The results indicated that the α-diversity indices of the gut microbiota in the PGE group were significantly higher than in the CK group, suggesting that ginsenosides enhance microbial richness and diversity (p < 0.05). At the phylum level, the relative abundance of Firmicutes in the PGE group increased by 10.6% ± 2.72%, while that of Bacteroidetes decreased by 11.5% ± 3.18%; at the genus level, the proportion of Lactobacillus genus rose by 17.78% ± 4.37% (p < 0.05). Pharmacokinetic analysis revealed that the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of ginsenosides were significantly higher in the PGE group than in the CK group. Conclusions: Chronic oral administration of ginsenosides improves their absorption and utilization through gut microbiota modulation, offering experimental evidence for deeper insight into ginsenoside-microbe interactions.

ID: 42353045
Title: Red Ginseng Ethanolic Extract Alleviates DSS-Induced Colitis in Mice by Suppressing Inflammatory Mediator Production.
Abstract: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by recurrent intestinal inflammation and mucosal injury. This study evaluated the protective potential of red ginseng ethanolic extract (RGEE) using a dextran sulfate sodium (DSS)-induced colitis mouse model and an LPS-stimulated RAW 264.7 macrophage model. Preliminary LC-MS profiling was also performed to characterize the detectable chemical features of RGEE. In vivo, RGEE alleviated DSS-induced body weight loss, disease activity, colon shortening, spleen enlargement, and histopathological injury, with the histopathological score reduced by approximately 51.1%. RGEE also partially improved DSS-induced hematological alterations without causing obvious changes in major organ weights. In vitro, RGEE showed no obvious cytotoxicity up to 250 μg/mL and reduced LPS-induced NO, TNF-α, IL-6, and IL-1β production by approximately 60.0-67.1%. LC-MS analysis putatively annotated several saponin-related features, including notoginsenoside R1 and ginsenosides Rb1, Rb2, Rh1, Rh4, and Rh2. These findings suggest that RGEE has protective potential against DSS-induced colitis, which is associated with the suppression of inflammatory mediator production. Further studies are needed to clarify its active constituents and mechanisms of action.

ID: 42374626
Title: Microbiome and metabolites impact enteric and central nervous systems in ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) has been linked to gastrointestinal symptoms and alterations in the gut microbiota. The enteric nervous system (ENS) coordinates intestinal function and sits at the host-microbe interface. The mechanisms by which luminal changes relay to the central nervous system (CNS), where motor neurons reside, have yet to be completely defined. In this narrative review, we first present evidence from ALS patient cohorts and preclinical models alongside mechanistic studies of infection, dysbiosis, and related neurodegenerative diseases to discuss how the microbiota and its metabolites may affect the ENS and CNS in ALS. Next, we propose a plausible mechanism of ALS pathogenesis through the gut-microbiome-brain axis. We further offer a summary of clinical trials that have studied the impacts of the microbiota on human ALS. Finally, we discuss future directions for studies of microbiota-ENS-CNS interactions in ALS. Better understanding of the dynamic interactions among the microbiota, microbial metabolites, neuroactive metabolites, and inflammation through the ENS/CNS in ALS will provide innovative insights into ALS prevention and treatment.

ID: 42395004
Title: Ginsenosides: potential therapeutic agents against hepatic fibrosis.
Abstract: Hepatic fibrosis, for which no effective pharmacological interventions currently exist, is characterized by progressive scarring and architectural distortion. The pathogenesis involves excessive accumulation of extracellular matrix components, predominantly synthesized by activated hepatic stellate cells (HSCs). HSCs can be activated by inflammatory signals and injured hepatocytes, processes linked to intestinal microbiota dysbiosis. Therefore, HSCs and associated pathways constitute promising therapeutic targets for antifibrotic strategies. Recent evidence suggests that ginsenosides, principal bioactive constituents of Panax ginseng, demonstrate hepatoprotective and antifibrotic properties. Ginsenosides are structurally classified into dammarane-type, ocotillol-type, and oleanane-type saponins, showing favorable safety profiles. Their pharmacological activity is critically dependent on structural features, including the quantity, type, and glycosylation positions of sugar moieties, as well as the stereochemical configuration at the C-20 position. The antifibrotic mechanisms of ginsenosides encompass multiple pathways: suppression of HSC activation, induction of HSC death, amelioration of hepatocellular injury, attenuation of inflammatory responses, and modulation of intestinal microbiota composition. This review aims to evaluate ginsenosides as potential therapeutic agents for hepatic fibrosis and to establish a theoretical framework for their clinical translation in the management of this condition.

ID: 42395006
Title: Microbiome-mediated pharmacology of ginseng: Mechanistic insights into metabolic regulation and therapeutic potential.
Abstract: Ginseng, a traditional medicinal herb with a favorable safety profile, has long been used to promote systemic health. Recent studies reveal that many of its beneficial effects are mediated through interactions with the gut microbiota. Microbial enzymes convert parent ginsenosides into more absorbable and bioactive metabolites such as compound K, while ginseng reciprocally remodels the microbial community and metabolite composition by promoting the growth of beneficial taxa including Akkermansia, Bifidobacterium, and Lactobacillus. These bidirectional interactions modulate host metabolic, immune, and intestinal barrier functions. The ginseng-microbiome interplay regulates microbial and host-derived metabolites such as short-chain fatty acids, bile acids, and indole derivatives, which in turn activate key signaling pathways including FXR/TGR5, FFAR, AMPK, and Nrf2. Through these mechanisms, ginseng improves lipid metabolism, enhances insulin sensitivity, alleviates low-grade inflammation, and ameliorates metabolic abnormalities such as obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). This review provides a comprehensive synthesis of the ginseng-microbiota metabolic axis, focusing on its mechanistic basis in metabolic regulation and related disorders. We also highlight the therapeutic convergence between ginseng and probiotics possessing ginsenoside-hydrolyzing enzymes, discuss strategies for strain selection and co-administration, and outline future directions in precision, microbiome-informed formulations and clinical trial design. Collectively, current evidence supports the ginseng-microbiota interactions as a promising therapeutic platform for restoring metabolic homeostasis and managing metabolic diseases.

ID: 42395015
Title: 20(S)-protopanaxatriol alleviates gastritis by attenuating oxidative stress and inflammatory responses via inhibition of PI3K/AKT and JAK/STAT3 pathways.
Abstract: Inflammation is a fundamental protective response of the body; however, chronic or excessive inflammation can perturb immune homeostasis and elevate the risk of cardiovascular, metabolic, and oncological diseases. Protopanaxatriol (PPT), a principal bioactive metabolite of Panax ginseng ginsenosides, has demonstrated diverse pharmacological activities, including protective effects in colon cancer, dermatological disorders, and hepatic injury. Despite these observations, the molecular mechanisms underlying PPT's modulation of inflammatory processes remain insufficiently characterized. This study aims to evaluate the anti-inflammatory potential of PPT and elucidate mechanistic pathways. Potential targets and signaling pathways were predicted using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The anti-inflammatory activity of PPT was assessed in vitro through nitric oxide (NO) assays, MTT assay, Neutral Red staining, luciferase reporter assays, ROS quantification, RT-PCR, Real-time PCR and Western blotting. In vivo efficacy was examined in an HCl/EtOH-induced gastritis model, with histopathological changes analyzed via hematoxylin and eosin (H&E) staining. PPT markedly attenuated LPS-induced inflammatory responses at non-cytotoxic concentrations, suppressing NO production and reducing expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). In vivo, PPT mitigated gastric mucosal injury in the HCl/EtOH model. Mechanistic investigations revealed that PPT selectively inhibited NF-κB (p65/p50) and AP-1 (c-Jun/c-Fos) activation, downregulation of the JAK-STAT3 pathway, and reduction of ROS accumulation and oxidative stress, collectively mediating its anti-inflammatory effects. PPT exerts potent anti-inflammatory effects by inhibiting PI3K/AKT and JAK-STAT3 signaling and alleviating oxidative stress. These findings support PPT as a promising candidate for the development of novel anti-inflammatory therapeutics.

ID: 42395025
Title: Ginsenosides from Panax ginseng: Their mechanisms, microbiome determinants, and translational strategies in therapeutic activity against cancer.
Abstract: Ginsenosides from Panax ginseng Meyer and their microbiota-derived metabolites have been explored as adjuncts in oncology, with pleiotropic activities across tumor-intrinsic and microenvironmental pathways. This review focuses on representative metabolites (Rg3, Rh2 and compound K) and summarizes mechanistic evidence for apoptosis and cell-cycle control, metabolic reprogramming (Warburg-type glycolysis), and epigenetic regulation (miRNA/lncRNA-linked programs), together with immunomodulatory effects in the tumor microenvironment. A central translational constraint is pharmacokinetics and the "microbiota gatekeeping" effect: many parent ginsenosides show limited oral absorption and require microbiota-mediated deglycosylation, resulting in delayed and variable systemic exposure across individuals. To address this bottleneck, we discuss pragmatic translational directions including bioconversion/pre-transformation to enrich active metabolites, biomimetic delivery platforms such as ginseng-derived exosome-like nanoparticles to improve exposure and tissue uptake, and mechanism-guided combinations (e.g., with immune checkpoint blockade). Finally, we outline how biomarker-informed stratification and AI/ML-enabled, hypothesis-generating optimization of delivery/formulation may support more predictable clinical development.

ID: 42395026
Title: Li-ginseng powder alleviates cancer cachexia in mice by regulating the ubiquitin-proteasome pathway and reducing inflammation.
Abstract: As a debilitating syndrome, cancer cachexia (CC) manifests as ongoing weight reduction and skeletal muscle atrophy, which severely compromise patients' well-being and life expectancy, with no approved treatment available to date. Rare ginsenosides such as Rh2, Rg5, Rk1, and Rh4 have been reported to modulate Nuclear factor kappa-B (NF-κB) and Signal Transducer and Activator of Transcription 3 (STAT3) activity and attenuate inflammatory signaling pathways implicated in CC progression. Li-Ginseng powder (LGP), a specially processed Panax ginseng enriched in rare ginsenosides, including Rk1, Rk3, Rh4, Rg3, and Rg5 represents a potential therapeutic candidate for CC. The anti-cachexia effects of LGP were evaluated in a BALB/c mouse model of CC and in a cellular CC model using mouse myoblast C2C12 cells. Body weight, skeletal muscle atrophy, and histopathological analyses were performed to assess in vivo efficacy. Network pharmacology was applied to predict key regulatory pathways, and mechanistic validation was conducted using Western blotting, immunohistochemistry, and Enzyme-linked immunosorbent assay. LGP treatment significantly attenuated body weight loss and skeletal muscle atrophy in CC mice. Mechanistically, LGP suppressed activation of the ubiquitin-proteasome pathway in the gastrocnemius muscle and reduced systemic and local inflammatory responses. Network pharmacology analysis identified NF-κB and STAT3 signaling as major targets of LGP, which was further confirmed in both muscle tissues and C2C12 cells. Consistently, LGP alleviated myotube atrophy and inhibited UPP, NF-κB, and STAT3 activation in vitro. These findings demonstrate that LGP exerts protective effects against CC by modulating muscle proteolysis and inflammation-related signaling pathways, highlighting its potential as a ginseng-based therapeutic strategy for CC.

ID: 42395029
Title: Panax ginseng as a proteome-metabolome medicinal ecosystem: Reframing pharmacology beyond a strictly saponin-centric paradigm.
Abstract: The pharmacological understanding of Panax ginseng has traditionally focused on ginsenosides (saponins) as the principal bioactive determinants for its anti-inflammatory, metabolic, and anticancer effects. However, advances in multi-omics, high-resolution proteomics, spatial metabolomics, and microbiome analysis are expanding this view beyond a metabolite-exclusive framework. Emerging evidence shows that the ginseng proteome undergoes dynamic remodeling in response to ecological stress, development, and processing, generating glycosylated proteoforms, stress-responsive proteins, and peptide derivatives with biological relevance. Concurrently, microbiome-mediated biotransformation reshapes metabolite bioactivity and immune-metabolic homeostasis. These observations support the consideration of P. ginseng as an expanded, multi-layered system built on the established saponin-centered architecture. While saponins remain the primary signaling axis, the peptide tier, including small proteins, may exert complementary influences through redox buffering, receptor-proximal modulation, and localized stress-response mechanisms. These distinct molecular tiers are thought to converge on shared regulatory hubs, such as nuclear factor-kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), nuclear factor erythroid 2-related factor 2 (Nrf2), inflammasome signaling, and mitochondrial stress pathways. Although some catalytic stress mechanisms need experimental validation, structural and proteomic findings suggest that additional regulatory layers beyond classical signaling modulation merit systematic study. Modern technologies like data-independent acquisition proteomics, peptidomics, spatial omics, and AI-assisted network modeling now enable comprehensive interrogation of this cross-tier structure. Integrating proteomic, metabolomic, and microbiome axes is essential to refine mechanistic understanding, improve multidimensional standardization, and expand translational exploration in botanical pharmacology.

ID: 42411482
Title: Amyotrophic Lateral Sclerosis as a Systemic Disease: Why Integrative and Microbiome-Focused Approaches Deserve Re-Evaluation.
Abstract: Despite decades of intensive research, therapeutic advances in amyotrophic lateral sclerosis (ALS) remain limited. Increasing evidence suggests that ALS is a multisystem disorder involving motor neuron degeneration, immune dysregulation, skeletal muscle pathology, and gastrointestinal dysfunction, thereby challenging the adequacy of current therapeutic strategies. Complementary and alternative medicine (CAM) approaches are widely used by patients with ALS. However, their efficacy remains controversial owing to limited clinical evidence and methodological limitations. The multicomponent herbal medicine and system-level characteristics of CAM conceptually align with the emerging view of ALS as a multisystemic disease. The involvement of gut microbiome dysbiosis in the pathophysiology of ALS has provided a unifying biological framework linking the peripheral, metabolic, and neuroinflammatory processes. These findings suggest that the combination of CAM and conventional therapy may serve as a potential integrative approach to target gut-brain-muscle interactions and systemic disease pathways. This article highlights critical gaps in the existing evidence and proposes that microbiome-focused, biomarker-driven clinical trials are essential to thoroughly evaluate CAM-based interventions in ALS. Embracing a system-oriented therapeutic framework may help address the complexity of ALS beyond traditional neuron-centered approaches.

ID: 42422748
Title: Lactococcus lactis ZB2 from Zhejiang fermented bamboo shoots enhance intestinal barrier and immune homeostasis in mice.
Abstract: Traditional fermented foods harbor functionally diverse microbial communities that represent an underexplored source of probiotic strains. Lactic acid bacteria were systematically isolated from traditionally fermented bamboo shoots collected across Zhejiang Province, China, with the aim of identifying superior probiotic candidates. Among the isolates recovered, Lactococcus lactis ZB2 demonstrated robust gastrointestinal tolerance, favorable adhesion properties, and broad-spectrum antimicrobial activity, consistently matching or exceeding the reference strain Lactobacillus rhamnosus GG across all evaluated in vitro criteria. Molecular identification via 16S rRNA gene sequencing confirmed ZB2 as L. lactis subsp. lactis (>99.7% sequence identity). To evaluate its in vivo effects, ZB2 (1 × 109 CFU/day, 200 μL of bacterial suspension in 0.01 M PBS, pH 7.4) was administered by oral gavage to healthy C57BL/6 J mice for 28 days. ZB2 supplementation significantly reinforced intestinal epithelial barrier integrity, evidenced by reduced serum permeability markers (FITC-dextran flux, DAO, D-lactic acid, and LPS), upregulation of tight junction proteins (ZO-1, Occludin, Claudin-1) and the mucin gene Muc2, and a significant increase in goblet cell number per crypt. Immune homeostasis was modulated toward an anti-inflammatory phenotype, characterized by elevated serum IL-10 and TGF-β, reduced IFN-γ, downregulation of colonic pro-inflammatory cytokines (Tnf-α, Il-6, Il-1β), and upregulation of the antimicrobial peptides Reg3γ and β-defensin 1. 16S rRNA amplicon sequencing revealed selective enrichment of butyrate-producing genera within the Lachnospiraceae family, accompanied by marked increases in fecal short-chain fatty acid concentrations-particularly butyrate and propionate. Systemic antioxidant capacity was also enhanced, as reflected by elevated SOD, CAT, and GSH-Px activities and reduced malondialdehyde. These findings support the characterization of L. lactis ZB2 as a multifunctional probiotic candidate and highlight Zhejiang fermented bamboo shoots as a valuable, underexplored reservoir of superior probiotic strains with broader functional food development potential.

ID: 42436035
Title: Fermentation of plant- and fungal-protein foods: From processing and food properties to gut microbiome and health.
Abstract: The shift toward plant- and fungal proteins is driven by environmental and public-health concerns, but wider adoption is constrained by poor sensory quality, limited techno-functionality, and variable nutritional performance. Fermentation has re-emerged as a versatile processing approach because it can improve flavor and texture while remaining compatible with clean-label food design. Yet the effects of fermentation designed for alternative proteins on host physiology remain largely unexplored. This chapter examines how fermentation modifies plant- and fungal-protein foods at multiple levels and how these changes may translate into health-relevant outcomes. After outlining the major chemical and physical transformations induced by fermentation, the chapter moves beyond the traditional focus on nutrients and bioactive metabolites to consider how fermentation-driven changes in flavor and food structure influence gastrointestinal signaling and digestion. Particular attention is given to how in situ production of exopolysaccharides (EPS) during fermentation reshapes matrix organization and governs the delivery of food components along the gastrointestinal tract, where they can be utilized by the host or serve as substrates for gut microbes in complex trophic chains. Accordingly, the gut microbiome provides a key interface for these processes by integrating both chemical and physical cues from foods after ingestion, while also mediating how these cues translate into physiological responses, thereby serving as a composite readout of food properties and host physiology. By highlighting what is known and where evidence is emerging, this chapter aims to support the future rational design of fermented plant- and fungal-protein foods for both product performance and health.

ID: 42458949
Title: Gut-Brain Axis Mechanisms and Microbiome Abnormalities in Autism Spectrum Disorder and Therapeutic Implications.
Abstract: ASD has been associated with alterations of the microbiota-gut-brain axis, a bidirectional system that links gut microbiota to neural, endocrine, and immune pathways. Multi-omics studies indicate that most of the ASD affected individuals have lower levels of beneficial taxa, including Bifidobacterium, Lactobacillus gemelhinis, Faecalibacterium prausnitzii, and Roseburia species, and also enrichment with potentially pathogenic strains. Dysbiosis likely affects SCFA, especially butyrate, production. Butyrate acts via GPR41 and GPR43, which maintain the gut barrier and reduce inflammation. Lower butyrate and receptor activity can weaken the barrier, leading to systemic and neuroinflammation implicated in ASD. Effects of the microbiota on neurotransmission also seem pertinent, with alteration in tryptophan metabolism being able to affect central nervous system serotonin availability, and imbalance in GABA glutamate signaling potentially playing a role in excitatory inhibitory dysregulation. Immune crosstalk is paramount in these processes, as micro-bial products and SCFAs are able to influence microglial activity and brain-derived neurotrophic factor signaling with consequent impacts on synaptic plasticity and behavior. This narrative review synthesises societal momentum with current understanding and treatment approaches related to the microbiome of ASD. Probiotics, prebiotics, precision nutrition, and faecal microbiota transplanta-tion (FMT) have reported promising evidence of symptom reduction and, in some studies, behavior. Evidence is still mixed because of strain variation, dosing, delivery protocols, and follow-up. We delineate priorities for randomized, adequately powered experiments that incorporate longitudinal multi-omics, immune phenotyping, and standardized neurobehavioral assessments, while taking into account developmental timing and individual variation. Collectively, the current evidence suggests the gut-brain axis as a potential contributor to ASD biology and a potential target of therapy. Customized plans to rehabilitate SCFA production, enhance barrier function, and normalize neuro-immune and neurotransmitter pathways may augment current practice. Establishing causality and determining which patients benefit from which interventions when are the essential next steps.

ID: 42473148
Title: Panax ginseng Extract Alleviates Qi Deficiency Liver Cancer via the Gut-Liver Axis: Insights from Metabolomics and Microbiome.
Abstract: Panax ginseng (PG), a valuable functional food known as the "King of Herbs," demonstrates therapeutic potential in the treatment of Qi deficiency liver cancer (QDLC). Regulating the gut-liver axis (GLA) may be an important mechanism of action of PG in the treatment of QDLC; however, its detailed mechanism remains unclear. This study aimed to elucidate this mechanism in QDLC rats using metabolomics and microbiome analysis. Metabolomics and microbiome experiments demonstrate that PG alleviates QDLC by modulating the composition of the gut microbiota, restoring its diversity, improving metabolic disorders, and increasing short-chain fatty acid levels. Antibiotics cocktail treatment, fecal microbiota transplantation, and probiotic colonization experiments further confirmed that PG's role in alleviating QDLC is gut microbiota-dependent. Additionally, PG alleviated GLA damage in QDLC rats by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Collectively, our study provides a novel interpretation of the natural intervention mechanisms for QDLC and confirms the potential value of PG as a functional food.

ID: 42483913
Title: Biotransformation-Driven Structural Remodeling of Natural Products by Ganoderma lucidum Fermentation: Mechanisms and Enhanced Bioactivities.
Abstract: Ganoderma lucidum fermentation (GLF) serves as a sustainable biotransformation platform that precisely modulates the chemical profiles and bioactivities of natural products through enzymatic hydrolysis, microbial metabolic remodeling, and substrate-microbe crosstalk. This review systematically elucidates the GLF-driven structural modifications of key compounds- including polysaccharides, saponins, triterpenoids, flavonoids, and proteins. These structural optimizations synergistically enhance multiple bioactivities: the increased content of deglycosylated ginsenosides enhances antitumor activity, while the antioxidant and prebiotic effects of polysaccharides are potentiated through the regulation of gut microbiota and short-chain fatty acid (SCFA) production. The core mechanisms involve a sophisticated interplay of specific enzyme catalysis, fungal endogenous biosynthesis, and a dynamic "substrate degradation-product synthesis" metabolic cycle. Finally, we emphasize that integrating multi-omics and synthetic biology is crucial for achieving precision control of GLF and advancing its translation in functional foods and drug discovery.

ID: 42488829
Title: Challenges and opportunities for ginseng-based medicines in treating cardiac fibrosis from mechanistic insights to clinical translation.
Abstract: Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition and progressive myocardial remodeling, is a common pathological outcome of various cardiovascular diseases and lacks effective targeted anti-fibrotic therapies. Panax ginseng and its related preparations, including major ginsenosides (e.g., Rb1, Rg1, and Rg3), standardized extracts, and compound formulas, have garnered growing interest owing to their multi-component, multi-target pharmacological activities and integrative regulatory effects. This review systematically summarizes recent advances in the basic and clinical research of ginseng-based medicines in the prevention and treatment of cardiac fibrosis. Preclinical evidence demonstrates that ginseng and its active constituents attenuate key pathological processes, including oxidative stress, inflammatory responses, apoptosis, and autophagy dysregulation, primarily through modulation of signaling pathways such as TGF-β/Smad, NF-κB, and PI3K/Akt. These regulatory effects collectively contribute to the inhibition of fibroblast activation, reduction of collagen deposition, and improvement of myocardial structure and function. Emerging clinical studies further suggested potential benefits in improving cardiac function and modulating fibrosis-related biomarkers in patients with hypertension, coronary heart disease, and heart failure (HF). Despite these promising findings, several challenges hinder clinical translation, including low oral bioavailability, the mechanistic complexity of compound formulas, and insufficient high-quality clinical evidence. Future investigations should integrate novel drug delivery strategies, systems pharmacology approaches to elucidate holistic mechanisms, and well-designed randomized controlled trials to facilitate the development of ginseng-based medicines as potential therapeutic agents for cardiac fibrosis.

ID: 42497020
Title: Metabolic endotoxemia in metabolic and neurodegenerative diseases.
Abstract: Metabolic diseases, which include obesity, type 2 diabetes, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease (MASLD), are significant global health challenges. Patients with these conditions frequently exhibit gut dysbiosis and compromised gut barrier integrity, which lead to excessive translocation of Gram-negative bacterial lipopolysaccharide (LPS or endotoxin) from the gut lumen into the systemic circulation. This results in chronically elevated systemic LPS levels, a condition termed "metabolic endotoxemia". Gut-derived LPS may stimulate inflammatory responses and oxidative stress when it translocates and is recognized by host Toll-like receptor 4 (TLR4) and caspase-4/-5/-11. Metabolic endotoxemia is a primary trigger for the low-grade inflammation that promotes the development of metabolic diseases. Emerging evidence also indicates that metabolic endotoxemia acts as a key driver in the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease, by promoting chronic neuroinflammation. In this review, we discuss: (1) the molecular structure of LPS that determines its bioactivity and its recognition by host cells, (2) host regulation of its bioactivity, (3) its translocation from the gut lumen into the systemic circulation, and (4) how metabolic endotoxemia contributes to obesity, type 2 diabetes, atherosclerosis, MASLD, and Alzheimer's disease. We conclude by exploring potential interventions aimed at preventing or mitigating metabolic endotoxemia by promoting LPS degradation and inactivation.

ID: 42501555
Title: Gut microbiota and polycystic ovary syndrome: Pathogenesis and novel therapeutic approaches.
Abstract: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women that is characterized by a complex pathogenesis involving multiple mechanisms, including hyperandrogenism, ovulatory dysfunction, insulin resistance (IR), and chronic inflammation. Recent studies have demonstrated that the gut microbiota acts as an important metabolic regulator and may play a pivotal role in the onset and progression of PCOS. Patients with PCOS frequently exhibit gut microbiota dysbiosis, which is characterized by reduced microbial diversity, decreased levels of beneficial bacteria, increased levels of pathogenic bacteria, and altered metabolic byproducts. This imbalance may contribute to IR and ovarian dysfunction by activating the toll-like receptor 4/nuclear factor kappa B inflammatory pathway, inducing oxidative stress, and disrupting Wnt/β-catenin signaling. The Wnt/β-catenin signaling pathway, a key regulator of follicular development, is frequently aberrantly activated in PCOS. In this narrative review, we summarize the recent advances in understanding the roles of the gut microbiota and the Wnt/β-catenin signaling pathway in the pathogenesis of PCOS. To this end, we conducted a comprehensive literature search across PubMed, Web of Science, Embase, and Cochrane Library databases, covering publications from January 2012 to March 2026. Ninety-eight articles were included after screening. We further explored therapeutic strategies based on microbiome modulation and signaling pathway targeting, including probiotics, traditional Chinese medicine, ginsenosides, puerarin, fecal microbiota transplantation, and nanoparticle-based ginseng-derived exosomes, thereby providing novel insights into potential therapies for PCOS.

ID: 42503584
Title: Gut-brain-immune interactions in neonatal hypoxic-ischemic brain injury.
Abstract: Neonatal hypoxia-ischemia (HI) is the leading cause of childhood mortality and neurodevelopmental disability. Despite therapeutic hypothermia as the only clinically established treatment to date, outcomes remain poor for a significant proportion of affected infants. Mechanistic understanding has been brain-oriented in the past, however the gut and immune system are increasingly recognized as active modulators of brain injury, recovery and neurodevelopment. Gut microbiota regulate microglial maturation, myelination and blood-brain barrier integrity. Neonatal HI induces gut dysbiosis and barrier failure, associated with neuroinflammation. First, faecal microbiota transplantation experiments in animal models suggest a causal relationship. Clinical data corroborate microbial perturbations in HIE infants, though antibiotic exposure and the NICU environment represent potential confounders. At the level of the immune system, dysregulated peripheral innate and adaptive immune responses are well documented in HI-affected neonates, with some alterations persisting into school age. The microbiota dimension of these immune responses remains largely unexplored, despite well-characterized microbiota-immune interactions in models of adult stroke. Therapeutic candidates include probiotics, human milk oligosaccharides and butyrate, each with preliminary preclinical support but no completed clinical trials in HIE. Reframing neonatal HI as a systemic gut-brain-immune disease opens up new possibilities for adjunctive therapy and biomarker discovery. Progress requires longitudinal multi-omic clinical cohorts, sex-stratified and disease-phase-resolved preclinical analyses and rigorous evaluation of microbiome-targeted interventions.

ID: 42511307
Title: Dietary and Supplementation Strategies for Modulating Gut Microbiota: A Narrative Review.
Abstract: The composition and balance of the gut microbiota are important for human health, as they are involved in metabolic processes, immune regulation, intestinal barrier function, and gut-brain communication. This narrative review summarizes current evidence on dietary and supplementation-based strategies for modulating the gut microbiota, with particular attention to dietary fiber, fermented foods, prebiotics, probiotics, synbiotics, and postbiotics. The review discusses their potential mechanisms of action, including effects on microbial composition, short-chain fatty acid production, intestinal barrier integrity, immune responses, and metabolic homeostasis. Particular emphasis is placed on the context-dependent nature of microbiota modulation, as the effects of dietary and supplementation strategies may vary according to baseline microbiota composition, health status, habitual diet, probiotic strain, dose, and intervention duration. Overall, current evidence suggests that microbiota-targeted nutritional strategies may support gut homeostasis and selected health-related outcomes; however, their effects are not universal and require more personalized and better-controlled approaches in future research.

ID: 42514363
Title: Ginsenoside Rb1-Enriched Saponin Fraction Inhibits M1 Macrophage Polarization by Suppression of TLR4 Trafficking in Metabolic Dysfunction-Associated Alcoholic Liver Disease.
Abstract: Background/Objectives: Metabolic dysfunction-associated alcoholic liver disease (MetALD) is a serious worldwide health concern, exhibiting metabolic dysfunction-associated lipid accumulation, alcohol-associated oxidative damage, and endotoxin-induced inflammation. Rb1-enriched red ginseng saponin fraction (RGSF) has been known to exhibit anti-inflammatory and anti-oxidative properties, but its role in MetALD remains to be fully elucidated. This study aims to investigate the specific mechanism of RGSF in the MetALD mouse model. Methods: The MetALD mouse model was administered with or without Rb1-RGSF for 7 weeks. Histopathological and molecular analyses, along with primary cell isolation, were conducted for in vivo and ex vivo investigations. M1 macrophage polarization was assessed by analyzing pro-inflammatory cytokine expression. NF-kB/p65 and TLR4 protein expression were measured before being visualized using immunofluorescence assays and confocal microscopy. Results: Histopathological examination revealed that RGSF treatment markedly reduced hepatic steatosis and attenuated inflammatory lesions in MetALD independent of oxidative stress. Notably, RGSF administration suppressed the LPS-induced internalization of surface TLR4. During the early inflammatory phase, RGSF prevented the LPS-mediated loss of the 130 kDa TLR4 form at the cell membrane, thereby limiting the generation of its 110 kDa cytoplasmic form. LPS-binding assay confirmed the direct interactions between TLR4 and RGSF. Conclusions: Collectively, these findings demonstrate that RGSF regulates TLR4 expression and trafficking, leading to the suppression of M1 macrophage polarization by inhibiting LPS-TLR4 surface interactions, thus exhibiting hepatoprotective effects.

ID: 42514986
Title: A Comprehensive Review of the Gut-Microbiota-Brain Axis in Alzheimer's Disease: From Pathophysiology to Potential Therapies.
Abstract: The gut-microbiota-brain axis (GMBA), an intricate network connecting the gastrointestinal (GI) tract and the brain, plays a pivotal role in maintaining overall health and influencing disease processes. The human gut microbiota, comprising over 3000 bacterial species, regulates immune responses, hormonal signals, and metabolite production, maintaining homeostasis under normal conditions. Dysbiosis, or microbial imbalance, has been linked to various central nervous system (CNS) disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and autism spectrum disorder (ASD). Given the growing interest in this topic and the limited effectiveness of current therapeutic strategies for managing patients with AD, the purpose of the current narrative review is to analyze the pathophysiological role of the GMBA in the pathogenesis of AD and assess potential therapeutic strategies targeting the GMBA, particularly the microbiome and its metabolites. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify clinical studies, experimental research, and review articles examining the GMBA in health and AD, as well as related therapeutic strategies. The search terms included "Alzheimer's disease", "neuroinflammation", "amyloid-beta", "tau", "gut-brain axis", "microbiome", "short-chain fatty acids", "probiotics", "prebiotics", and "fecal microbiota transplantation". In AD, altered gut microbiota composition is associated with neuroinflammation, neurodegeneration, and exacerbation of disease progression. Probiotics have shown potential in enhancing cognitive function and reducing neuroinflammation by modulating microbiota composition and influencing brain-derived neurotrophic factor (BDNF) levels. Prebiotics, through their impact on gut microbiota and metabolite production, also offer therapeutic promise by improving cognitive function and mitigating neuroinflammation. With its historical and modern applications, fecal microbiota transplantation (FMT) may represent a potential strategy for addressing dysbiosis and its neurological implications. This manuscript focuses on GMBA and its effects on neuroinflammation, neurodegeneration, and CNS health while emphasizing the need for further research into microbiome-based therapies and the gut-brain relationship in patients with AD.

ID: 42526365
Title: A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS. A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic. A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant. This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder. PROSPERO identifier CRD420251076035.

ID: 42539514
Title: Microbiota-innate immune crosstalk drives atherosclerosis: mechanisms, disease progression, and emerging therapeutic strategies.
Abstract: Atherosclerosis (AS) is a complex cardiovascular disease driven by the interplay of dysregulated lipid metabolism, chronic inflammation, and immune dysfunction. Increasing evidence has revealed that the gut microbiota not only regulates host metabolic homeostasis but also actively contributes to the initiation and progression of AS through intricate interactions with the innate immune system. Microbial-derived signaling molecules, including lipopolysaccharides, outer membrane vesicles, extracellular nucleic acids, and TMAO, can activate Toll-like receptors, the NLRP3 inflammasome, and nucleic acid-sensing pathways, thereby promoting inflammatory cytokine production, endothelial dysfunction, and foam cell formation. In contrast, beneficial microbial metabolites such as short-chain fatty acids, bile acids, and tryptophan-derived metabolites exert immunomodulatory and vasculoprotective effects through signaling pathways involving FFAR2/3, the AhR, the FXR, and TGR5. Conversely, the innate immune system shapes microbial composition and function through barrier defense, phagocytic clearance, and antimicrobial factor production, establishing a dynamic and reciprocal microbiota-immune interaction network. This review systematically summarizes alterations in microbial ecology and innate immune homeostasis associated with atherosclerosis, elucidates the key molecular mechanisms underlying microbiota-innate immune crosstalk, and examines its dynamic involvement across four critical stages of disease evolution: endothelial dysfunction, foam cell formation, plaque progression, and plaque destabilization and rupture. In addition, emerging therapeutic approaches, including microbiota remodeling, modulation of microbial metabolic pathways, and precision microbiome-based interventions, are comprehensively discussed. The microbiota-innate immune axis provides a novel conceptual framework for understanding atherosclerosis pathogenesis and represents a promising target for future disease prevention, risk stratification, and precision therapeutics.

ID: 42539524
Title: Feeding the gut-immune axis: dietary, prebiotic, and probiotic strategies to target persistent inflammation in ART-treated HIV: a narrative review.
Abstract: People living with HIV (PWH) experience ongoing systemic inflammation driven by gut dysbiosis, epithelial barrier disruption, and microbial translocation, despite antiretroviral therapy (ART). This review examines evidence from randomized controlled trials, mechanistic studies, systematic reviews, and meta-analyses evaluating nutritional and microbiome-based interventions to reduce inflammation in PWH. Reduced production of short-chain fatty acids (SCFAs) by the gut microbiota has been observed to precede morbidity and mortality in PWH, with SCFAs, mainly butyrate, exerting immunomodulatory effects through promoting regulatory T-cell differentiation via histone deacetylase inhibition and G protein-coupled receptor 43 (GPR43) and GPR109A signaling, suppressing nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokine production, and enhancing epithelial tight junction integrity. Probiotics, prebiotics, synbiotics, and fecal microbiota transplantation have demonstrated reductions in inflammatory biomarkers including soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), and high-sensitivity C-reactive protein (hsCRP). The Mediterranean diet, omega-3 fatty acids, and polyphenol-rich foods represent an underexplored area as modulators of gut microbiota composition and SCFA production. Existing gaps in the literature include a lack of trials with clinically meaningful endpoints, optimal probiotic strains and doses, and lack of randomized trials evaluating anti-inflammatory dietary patterns in PWH. We propose a research agenda prioritizing Mediterranean diet intervention trials, precision microbiome interventions, and combination approaches integrating dietary modification with microbiome-targeted therapies. Lastly, we provide practical nutritional recommendations for clinicians managing PWH.

ID: 42539626
Title: Sodium oligomannate reduces cerebral infarction and improves neurological function through microbiota remodeling in MCAO/R rats.
Abstract: Ischemic stroke is the second leading cause of death worldwide, characterized by high mortality and a narrow therapeutic window for thrombolysis. Gut microbiota dysbiosis and gliosis following ischemic stroke are key drivers of post-stroke neurological impairment. Sodium oligomannate (GV-971) is a low-molecular-weight acidic oligosaccharide that targets the gut-brain axis. It alleviates gliosis and improves cognitive dysfunction by remodeling gut microbiota in Alzheimer's disease. However, it is still unknown whether GV-971 has pharmacological activity against ischemic stroke. Here, we explore the efficacy of GV-971 on infarct volume, gliosis, blood-brain barrier integrity, gut microbiota composition, and post-stroke cognitive impairment (PSCI) using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male Sprague-Dawley rats. Administer medication before surgery for 4 consecutive days and once after surgery, after stroke 24-hour triphenyltetrazolium chloride (TTC) staining revealed that 0.3 mg/kg GV-971 significantly reduced infarct volume in ischemic brain tissue from 37.81±2.391% to 13.30±4.801% and neurological impairment score of GV-971 treatment significantly decreased from 11.50±0.54 to 7.29±1.47. After stroke 24-hour immunofluorescence analysis of glial activation confirmed that GV-971 significantly reduced central inflammatory responses. Western blot combined with Evans blue staining collectively demonstrated that after stroke 24-hour, GV-971 exerts a significant protective effect on the blood-brain barrier. In the gut, GV-971 reversed microbial dysbiosis, as revealed by shotgun metagenomics, enhanced intestinal barrier integrity, and suppressed colonic inflammation. Antibiotic depletion abolished GV-971's neuroprotective effect, while fecal microbiota transplantation from GV-971-treated donors restored protection, supporting a microbiota-dependent contribution. Furthermore, GV-971-treated rats subjected to MCAO/R exhibited significant improvements in motor and cognitive function. For example, on day 35, Y-maze test results indicated that GV-971 administered either before MCAO/R (pre-treatment) or during the perioperative period (co-treatment) increased spontaneous alternation rate from 60.95±4.91% to 85.60±6.32% and 85.64±5.027%. On day 32, novel object recognition assay results indicated that GV-971 treatment increased new-object exploration from 0.2039±0.03752 to 0.3991±0.1122 (pre-treatment) and 0.5066±0.06982 (co-treatment). On day 42, Barnes maze test results indicated that GV-971 treatment reduced the time required to locate the target hole from 76.45±17.41s to 31.03±20.75 s and 33.37±19.30 s for pre- and co-treatment, respectively. Taken together, GV-971 demonstrated neuroprotective potential in experimental ischemic stroke.

ID: 42540656
Title: Probiotics in Combination with C16 Peptide and Angiopoietin-1 Synergistically Ameliorate Multiple Sclerosis in Mice.
Abstract: Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS), characterized by demyelination, axonal loss, and neuronal injury. At present, effective treatment options remain limited. Prior research demonstrated the protective effects of a compound that consists of C16 peptide and angiopoietin-1 (C16-Ang-1) in experimental autoimmune encephalomyelitis (EAE), a validated animal model of MS. This study aims to investigate the potential synergistic effects of probiotics with C16+Ang-1, and elucidate its underlying mechanisms in mice. C57/BL6 mice were randomly assigned to control, vehicle, probiotics, and C16+Ang-1+probiotics groups. Histological examinations, behavioral tests, and 16S rRNA gene sequencing of fecal samples, were conducted to determine the levels of CNS inflammation, demyelination and axonal loss, neuronal survival, and functional recovery. Compared to the probiotics group, the C16+Ang-1+probiotics group exhibited significant synergistic effects. Specifically, the combined treatment with C16+Ang-1+probiotics had significantly greater effects than probiotics alone in reducing inflammatory severity in the CNS and colon, improving the microenvironment, protecting the gut-blood barrier, and preserving blood-brain barrier integrity. These effects collectively led to the greater amelioration of functional disability in the mouse model of MS. Further mechanistic studies suggested that these effects involved the modulation of the brain-gut axis, and maintenance of gut microbiota homeostasis. These findings demonstrate that the combination of probiotics and C16-Ang-1 acts synergistically to ameliorate MS in mice, resulting in a greater effect. Therefore, this combination therapy warrants further investigation to explore its potential clinical benefits, ultimately improving the care for patients with MS.

ID: 42540768
Title: Allied health use among women with incident Parkinson's disease: Population-based findings from the Australian Longitudinal Study on Women's Health.
Abstract: Allied health interventions benefit people with Parkinson's disease (PD) by reducing symptom severity and improving mobility, mood and quality of life. Yet current evidence suggests low and delayed uptake of allied health among this population. This study aimed to determine the proportion of Australian women with incident PD who accessed allied health and when they did so following diagnosis. Participants of the Australian Longitudinal Study on Women's Health who consented to data linkage were included. From national medication dispensing data, incident PD cases were identified as those taking anti-parkinsonian medications for at least 3 months following a 12-month lookback period. Their allied health use was identified from national primary health and aged care datasets and from hospital admission data from all states and territories. A total of 781 women with incident PD were identified between 2003-2022. Sixty-one percent (n = 477) accessed at least one allied health discipline following diagnosis, with a median time to first use of 282 days (interquartile range 72-880). Half (55%) who accessed allied health did so within one year of diagnosis, with up to 19% showing delayed access >3 years after diagnosis. Despite evidence-based recommendations that people with PD should be referred to allied health upon diagnosis, many are not accessing such care, potentially contributing to the high disability associated with PD. Improving patient education (e.g. through public health campaigns and Parkinson's organisations) and proactive referrals by physicians may improve access and reduce disability for people with PD.

ID: 42541426
Title: Neuroprotective Potential of Spermidine in Drosophila sws Neurodegenerative Model.
Abstract: Neurodegenerative disorders are characterized by progressive neuronal loss and functional decline, yet effective interventions remain limited. The polyamine spermidine was suggested to exert neuroprotective effects, but its concentration-dependent impact on longevity, neuronal integrity, and behavior remains still not well studied. Here, we investigated the effects of spermidine on lifespan, behavioral responses, brain tissue, target gene expression, and antioxidant status in Drosophila melanogaster model of age-dependent neurodegeneration. Wild-type flies and swiss cheese (sws1) mutants were exposed to 0.5, 1, and 5 mM spermidine from early adulthood. Lifespan analysis revealed that high-dose spermidine (5 mM) reduced survival in both wild-type and sws1 mutants, whereas lower doses (0.5 and 1 mM) significantly improved survival in mutants without affecting wild-type flies. Behavioral assays revealed that sws1 flies exhibited reduced climbing ability compared to controls, which was further decreased at 5 mM. Lower concentrations did not significantly affect locomotor performance. Taste preference for trehalose, impaired in untreated sws1 mutants, was partially restored by spermidine at all tested concentrations. Histological analysis of 10-13-day-old mutants showed a concentration-dependent reduction in degeneration zones within the lamina and medulla at 0.5 and 1 mM, whereas 5 mM had no effect. Biochemical assays indicated mild pro-oxidant effects at 5 mM, reflected by increased malondialdehyde (MDA) levels, while 0.5 mM enhanced antioxidant defenses, including catalase activity and Trolox equivalent antioxidant capacity (TEAC). Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector.

ID: 42541645
Title: Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
Abstract: Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.

ID: 42542118
Title: Neuroscience in pictures: Bipolar disorder.
Abstract: Bipolar disorder is a chronic, episodic mood illness characterized by recurrent oscillations between mania, depression, and euthymia, affecting an estimated 2.4% of the global population. This pictorial review explores its pathophysiology through the case of a young individual presenting with a first manic episode with psychotic features. We examine the convergence of genetic loading (∼70-90% heritability), neurodevelopmental vulnerability, and environmental precipitants-including sleep restriction and antidepressant exposure-in unmasking this individual's illness. We review interconnected pathophysiological mechanisms underlying bipolar disorder, including fronto-limbic, reward, and cognitive control circuit dysfunction; opposing catecholaminergic-cholinergic imbalances driving mania vs depression; peripheral and central neuroinflammation; BDNF-mediated synaptic plasticity disruption; hypothalamic-pituitary-adrenal, thyroid, and gonadal axis dysregulation; and circadian rhythm disturbance. Recurrent episodes may drive progressive, heterogeneous brain changes that are potentially modifiable, reinforcing early intervention and adherence. Emerging biomarkers and phase-specific pharmacotherapy reflect progress toward personalized, multimodal treatment integrating mood stabilization with chronobiological and psychosocial optimization.

ID: 42542289
Title: Differential effects of Lactobacillus casei in probiotic and paraprobiotic forms on behavioral performance, oxidative stress, neuroinflammation, and cholinergic dysfunction in a streptozotocin-induced model of sporadic Alzheimer's disease.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, and cholinergic dysfunction. Increasing evidence suggests that gut microbiota disturbances contribute to AD progression, encouraging the investigation of microbiota-modulating approaches such as probiotics and paraprobiotics. This study evaluated the effects of Lactobacillus casei probiotic and its thermally inactivated paraprobiotic on cognitive, behavioral, oxidative, cholinergic, and inflammatory alterations in a sporadic AD model induced by intracerebroventricular streptozotocin (STZ-ICV; 3 mg/3 μL/site) in female rats. From day 4, animals received daily oral treatment with probiotic L. casei (1 × 109 CFU), paraprobiotic (100 mg/kg), or saline for 14 days. Behavioral assessments of memory and exploratory activity were performed alongside biochemical analyses of oxidative stress markers, antioxidant defenses, acetylcholinesterase (AChE) activity, and neuroinflammatory parameters in central and peripheral tissues. STZ-ICV administration induced impairments in working and long-term memory, increased oxidative stress and neuroinflammation, elevated AChE activity, and promoted intestinal and behavioral alterations. Both probiotic and paraprobiotic treatments attenuated memory deficits, reduced lipid peroxidation, inhibited AChE activity, and decreased inflammatory markers. However, their effects differed in magnitude and tissue specificity. The probiotic mainly improved peripheral antioxidant defenses, whereas the paraprobiotic exerted broader neuroprotective effects, reducing cerebral oxidative stress, restoring non-enzymatic antioxidant levels in the hippocampus and colon, improving jejunal catalase activity, and attenuating hippocampal astrogliosis. These findings demonstrate that modulation of the gut-brain axis through L. casei-based interventions mitigates key pathological features of sporadic AD, with paraprobiotics emerging as a promising and stable alternative with enhanced neuroprotective potential independent of bacterial viability.

ID: 42543118
Title: Lineage-calibrated peripheral monocyte-derived myeloid states in neurodegenerative disease: Recruitment, lesion decoding, and state persistence.
Abstract: Peripheral monocytes and monocyte-derived macrophages are increasingly implicated in neurodegenerative disease, yet interpretation remains limited by phenotypic convergence with resident microglia, inconsistent lineage attribution, and strong dependence on experimental model and disease stage. We present a structured, lineage-calibrated framework that separates three linked processes: a recruitment gate controlling access to CNS borders and lesions; a lesion-decoding hub through which aggregate, lipid, cytokine, complement, antigenic, hypoxic, and danger-associated inputs are interpreted; and a state-persistence layer in which metabolic and epigenetic reinforcement stabilizes inflammatory, repair-supportive, or hybrid repair-restrictive programs. To make the framework operational, we first provide a cross-disease synthesis and then map representative models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis to their specific recruitment routes, lesion cues, lineage confidence, and functional outcomes. We also distinguish what single-cell or spatial data can infer from what only origin-resolving approaches can establish, and propose practical terminology for studies that cannot perform fate mapping or parabiosis. A worked therapeutic example illustrates why the same recruitment pathway may be harmful during lesion expansion but useful during debris clearance and recovery. The central question is therefore not whether monocytes are present, but which model, compartment, time point, evidentiary tier, and stabilized state justify a disease-modifying claim. This framework links mechanistic evidence to biomarkers, patient stratification, and stage-aware intervention while reducing over-attribution of peripheral origin.

ID: 42543158
Title: The Role of Gut Microbiota Interventions in the Management of Frailty Syndrome: A Scoping Review and Bibliometric Analysis.
Abstract: The primary aim of this scoping review is to synthesize fragmented evidence on gut microbiota-targeted interventions for frailty. As a complementary objective, we conducted a bibliometric analysis to map the evolving knowledge landscape of this interdisciplinary field, thereby informing the development of future personalized therapeutic strategies and research priorities. We searched nine databases (PubMed, Embase, Web of Science, Scopus, Cochrane Library, CNKI, Wanfang, SinoMed, and VIP) from inception to July 2025 for the scoping review. A dedicated search of the Web of Science Core Collection (up to September 2025) was conducted for the bibliometric analysis to ensure data consistency. Two reviewers independently screened and extracted data. Bibliometric analyses (collaboration networks, keyword co-occurrence, and research trends) and visualizations were performed using CiteSpace (v6.3.R1). The scoping review screened 3216 records and included 10 studies. Interventions-probiotics, prebiotics, synbiotics, and fecal microbiota transplantation-lasted 4 weeks to 6 months. Frailty was mainly assessed using Fried's phenotype, with outcomes covering frailty severity, physical function, gut microbiota composition, and inflammatory/metabolic markers. Bibliometric analysis identified 358 publications, revealing a sharp rise after 2016. China produced the most studies, and the University of Parma was the top institution. Key themes included gut microbiota, frailty, aging, inflammation, and sarcopenia. Given the rapidly growing interest, gut microbiota-targeted interventions represent a promising strategy to slow frailty progression. Future efforts should therefore focus on establishing standardized, multidisciplinary assessment frameworks and elucidating the underlying mechanisms to advance precision nutrition for healthy aging.

ID: 42543301
Title: [Comparative research on efficacy of high-pressure Schisandrae Chinensis Fructus decoction pieces and traditional decoction pieces on nonalcoholic fatty liver disease mice based on gut microbiota and metabolomics].
Abstract: This paper aims to evaluate the feasibility of clinical application of high-pressure Schisandrae Chinensis Fructus decoction pieces(HPSCH) compared with that of traditional Schisandrae Chinensis Fructus decoction pieces(SCH), based on the efficacy of mice with nonalcoholic fatty liver disease(NAFLD) induced by a high-fat diet. The optimal preparation process of HPSCH was investigated by using schisandrin content and total extractive yield as indices. After one week of adaptive feeding, C57BL/6 mice were assigned to a normal control group, while the remaining mice were fed an HFD for eight weeks to establish the NAFLD mouse model. After being successfully modeled, the mice were divided into a blank control group, blank administration group, simple model group, fenofibrate group, SCH group, and HPSCH group. All groups were administered by intragastric administration for four weeks. Body weight changes of mice were recorded, and liver indices were calculated. The levels of blood lipid and liver function index in the serum of mice were measured. Hepatic histopathological changes were observed by using hematoxylin-eosin(HE) staining and oil red O staining. Mice's feces were collected, and the 16S rDNA high-throughput sequencing method was employed to analyze changes in the gut microbiota of mice. Untargeted lipidomic analysis of the liver was conducted by using liquid chromatography-mass spectrometry(LC-MS), and principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA) were adopted to screen and identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes(KEGG) database was used to perform relevant pathway analysis. Integrated analyses of gut microbiota and differential metabolites were performed to compare the similarities and differences in efficacy of HPSCH and SCH. The results show that both the HPSCH group and SCH group exert similar effects on biochemical indices in serum and hepatic pathological changes, lipid metabolism can be regulated, and liver injury in NAFLD mice can be improved. The two groups show similar changes in microbial abundance, trending toward the blank control group and maintaining intestinal homeostasis. Compared with those of the simple model group, the differential metabolites and metabolic pathways of both the HPSCH group and SCH group show similarity, and the differential metabolites are mainly triglycerides, diglycerides, phosphatidylcholines, phosphatidylglycerols, and so on. Metabolic pathways include glycerophospholipid metabolism, choline metabolism, retrograde endocannabinoid signaling, thermogenic lipolysis, and so on. This indicates that HPSCH and SCH share common advantages in improving hepatic function in mice and achieve comparable effects. HPSCH can improve blood lipid and liver function indices in NAFLD mice, attaining the therapeutic effect through the regulation of gut microbiota and lipid metabolism. Notably, HPSCH achieved the same efficacy as SCH at half the conventional dose, demonstrating its feasibility for clinical application. Moreover, the application of HPSCH may contribute to the conservation of medicinal resources.

ID: 42543311
Title: [Mechanism of Tianma Gouteng Yin in treating early-stage Parkinson's disease based on 16S rRNA sequencing and metabolomics].
Abstract: Based on an early-stage Parkinson's disease(PD) rat model, this study employed 16S rRNA sequencing and untargeted metabolomics to investigate the action mechanism of Tianma Gouteng Yin(TGY) in treating early-stage PD. The early-stage PD rat models were established by subcutaneous injection of rotenone for seven days and were randomly divided into a control group, a model group, a positive drug group(levodopa, 50 mg·kg~(-1)), and TGY groups with low, medium, and high doses(9.82, 19.64, and 39.28 g·kg~(-1)), with intragastric administration for seven days during modeling. Behavioral indicators of rats(open field, inclined plane, and pole tests) were determined. The pathological morphology of brain tissue and the expressions of tyrosine hydroxylase(TH) and α-synuclein(α-syn) were detected. The levels of neurotransmitters including dopamine(DA), 5-hydroxytryptamine(5-HT), 3,4-dihydroxyphenylacetic acid(DOPAC), levodopa, and homovanillic acid(HVA) were measured. The inflammatory factors including tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1β(IL-1β) were detected. 16S rRNA sequencing and untargeted metabolomics were conducted on colonic contents to explore the pharmacodynamic effects of TGY and its regulatory mechanisms on gut microbiota and metabolism. RESULTS:: show that TGY can significantly improve motor dysfunction in early-stage PD rats, increase the number of TH-positive cells, inhibit the abnormal aggregation of α-synuclein(α-syn), up-regulate the levels of neurotransmitters, reduce the levels of inflammatory factors in the colon and striatum, thereby exerting a neuroprotective effect. Gut microbiota analysis reveals that TGY can reverse the trends of reduced α-diversity of gut microbiota, increased Firmicutes/Bacteroidetes(F/B) ratio, and increased abundance of pro-inflammatory genera(e.g., Ruminococcus), restore the abundance of beneficial genera(e.g., Bacteroides), and reshape the gut microbiota structure. Metabolomic analysis demonstrates that TGY intervention significantly reverses the differential metabolites in the model group, mainly involving energy and amino acid metabolic pathways such as pyruvate metabolism, β-alanine metabolism, and aminoacyl-tRNA biosynthesis. In conclusion, TGY may exert therapeutic effects on early-stage PD by regulating the axis of microbiota, inflammation, and neuronal injury, with energy and amino acid metabolism as the hub, through these metabolic pathways.

ID: 42543365
Title: [Mechanism of ethanol extract of Cyanotis arachnoidea in improving ischemic stroke: a metabolomics and transcriptomics study].
Abstract: This study aimed to explore the mechanism by which the ethanol extract of Cyanotis arachnoidea(ECA) ameliorates ischemic stroke(IS) in rats, based on metabolomics and transcriptomics. A rat model of middle cerebral artery occlusion(MCAO)-induced IS was established using the modified suture occlusion method. Ninety Sprague-Dawley(SD) rats were randomly divided into the sham operation(sham) group, the model(model) group, ECA low-, medium-and high-dose groups(ECA-L, ECA-M, ECA-H), and the positive drug nimodipine(NMDP) group. The therapeutic effects of ECA were evaluated by neurological deficit scores, 2,3,5-triphenyltetrazolium chloride(TTC) staining, serum biochemical assays, hematoxylin-eosin(HE) staining, and Nissl staining. Transcriptomic and metabolomic analyses were performed on brain tissues from the sham, model, and ECA-H groups. Core gene expression was verified using real-time fluorescence quantitative polymerase chain reaction(RT-qPCR). The results showed that ECA significantly reduced neurological deficit scores and cerebral infarct volume, ameliorated pathological damage in the cerebral cortex, and dose-dependently downregulated the inflammatory factor levels and oxidative stress markers in IS rats. Transcriptomic analysis revealed that ECA-H regulated the expression of 328 differentially expressed genes(DEGs) in the model group, with 129 genes identified as core regulatory targets. Gene Ontology(GO) enrichment analysis showed that these DEGs were mainly involved in IS-related processes, including cerebral cortex development and neuronal development. Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis showed that the DEGs were primarily enriched in pathways such as the calcium signaling pathway and the cyclic adenosine monophosphate(cAMP) signaling pathway. RT-qPCR verification demonstrated that ECA significantly upregulated the relative expression levels of 10 genes related to these two signaling pathways. Metabolomic analysis revealed that ECA-H significantly regulated the levels of 11 differential metabolites in rat brain tissues, mainly involving metabolic pathways such as folate-mediated one-carbon metabolism, lysine degradation, and cysteine and methionine metabolism. In summary, the ECA exerts neuroprotective effects in IS by synergistically activating the calcium and cAMP signaling pathways, targeting the expression of core genes, and regulating key metabolic pathways, thereby inhibiting neuroinflammation, balancing oxidative stress, and alleviating neuronal damage.