Search Results (6,895)

Osteoporosis is characterized by reductions in bone mineral density (BMD) and bone quality. While gut-derived signaling has been increasingly studied in relation to BMD, its contribution to molecular factors associated with bone quality remains less defined. Here, we investigated whether a heat-inactivated, freeze-dried, non-viable preparation of Levilactobacillus brevis AS-1 modulates intestinal epithelial-like cells and thereby promotes lysyl oxidase (LOX), a key enzyme involved in collagen cross-linking. Caco-2 cells were treated using 1 mM sodium butyrate and subsequently stimulated with 100 μg/mL L. brevis AS-1. Supernatants were collected and applied to MG63 cells. Cytokine mRNA expression in Caco-2 cells and LOX responses in MG63 cells were analyzed by qRT-PCR, and bone morphogenetic protein (BMP-1) and transforming growth factor-β (TGF-β)1 protein levels in the supernatant were measured by ELISA. L. brevis AS-1 stimulation up-regulated BMP-1 and TGF-β1 mRNA expression in SB-treated Caco-2 cells and increased BMP-1 protein secretion into the supernatant. LOX mRNA expression and total LOX activity were increased in MG63 cells treated with the conditioned supernatant, and inhibition of BMP-1/procollagen C-proteinase activity (UK383367) attenuated LOX mRNA induction. Collectively, these results suggest that L. brevis AS-1 stimulates intestinal epithelial-like cells to secrete BMP-1, which in turn promotes LOX mRNA expression in osteoblast precursor cells. This in vitro mechanism supports the concept of gut–bone crosstalk regulating molecular factors associated with bone quality. Full article

In this study, Chinese medicinal herbs were evaluated as potential antibiotic substitutes for Chinese soft-shelled turtle (Pelodiscus sinensis). Forty-five herbs were initially screened for antibacterial activity against Salmonella enteritidis, Escherichia coli, and Shigella flexneri. Nine herbs exhibiting broad-spectrum inhibitory effects were selected and subjected to microbial fermentation, after which their antibacterial activities were reassessed and applied as dietary supplements in feeding trials. The results showed that fermentation altered the antibacterial activities of several herbs and enhanced their overall functional performance. Dietary supplementation with fermented Chinese herbal medicine did not adversely affect feed utilization but significantly improved hematological parameters, liver and kidney function indicators, antioxidant capacity, and nonspecific immune responses. Furthermore, turtles fed fermented herbal diets exhibited higher survival rates following bacterial challenge. Intestinal microbiota analysis based on 16S rRNA gene sequencing indicated that fermented herbal supplementation modulated microbial community structure by reducing potential pathogens and increasing beneficial bacterial taxa associated with intestinal health. These findings suggest that microbial fermentation effectively enhances the biological efficacy of Chinese medicinal herbs. Fermented herbal feed additives represent a promising green alternative to antibiotics for soft-shelled turtle aquaculture. The global ban on prophylactic antibiotics drives the need for safe, effective feed alternatives. Microbial fermentation of Chinese herbs (FCM) is proposed to enhance efficacy and detoxification, but its comprehensive effects in aquaculture require deeper investigation. This study evaluated compound unfermented (CM) and fermented (FCM) Chinese herbal supplements on the Chinese soft-shelled turtle (Pelodiscus sinensis). Initial screening showed fermentation generally enhanced the antibacterial activity of the herbs against common enteric pathogens (S. enteritidis, E. coli, S. flexneri). Results indicated that the FCM diet significantly improved physiological status, leading to higher red blood cell counts, better liver/kidney function (reduced ALT/AST, UREA), and stronger immune/antioxidant responses (increased Lysozyme and T-AOC) compared to CM or control diets. Critically, the FCM group achieved the highest survival rates across all single and combined pathogen challenges, demonstrating superior protective efficacy. Furthermore, FCM effectively modulated the gut microbiota, enriching beneficial fermentative bacteria. In conclusion, microbial fermentation significantly amplifies the health-promoting and protective benefits of Chinese herbal supplements in soft-shelled turtles, positioning FCM as a promising green alternative for disease control in aquaculture. Full article

The intestinal epithelial barrier regulates paracellular transport, and its dysfunction is associated with inflammatory and metabolic diseases. Among dietary fibers, inulin has attracted considerable attention due to its beneficial effects on intestinal health. Inulin’s actions have been attributed to protecting the structure and function of gut barrier components against inflammatory-associated damage. This review integrates preclinical and clinical studies evaluating the impact of inulin on intestinal permeability. Evidence from in vitro and in vivo models shows that inulin regulates the expression of tight junction proteins (TJPs), Paneth cell proliferation, and antimicrobial peptides, and modulates inflammatory signaling pathways. In addition, inulin prebiotic activity, via microbiota, stimulates the production of short-chain fatty acids (SCFAs) as butyrate that reinforces the barrier function. Understanding these pathways highlights the therapeutic potential of inulin as a nutritional strategy for treating barrier dysfunction. Clinical studies in obesity, metabolic disorders and inflammatory intestinal disease have associated inulin supplementation with improvements in biomarkers of intestinal permeability. Future studies are needed to test inulin’s safety in order to prevent potential risks and hazards. Full article

Cognitive decline and neurodegenerative disorders represent a growing global health challenge, while effective preventive strategies remain limited. Citrus by-products, particularly grapefruit residues, constitute a rich and underexploited source of polyphenols, including flavonoids with reported antioxidant and neuroprotective properties. In this study, grapefruit-derived stabilized extract (GDSE) was evaluated using an in vitro neuronal model combined with dynamic simulated gastrointestinal digestion to assess the bioaccessibility and retained biological activity of key polyphenolic compounds. The soluble intestinal fraction of the digested formulation significantly reduced oxidative stress in dopaminergic-differentiated SH-SY5Y cells and was associated with changes in the expression of genes associated with neurotrophic support, dopaminergic signalling, and neuronal survival. In parallel, simulated digestion preserved a substantial proportion of major flavonoids, such as naringin and narirutin. Consequently, GDSE retained a moderate level of bioaccessible polyphenols and flavonoids, supporting the maintenance of its biological activity after digestion. Overall, these findings indicate that the formulation retains measurable bioactivity after simulated gastrointestinal digestion and modulates molecular markers associated with neuronal survival in vitro. While further in vivo and clinical studies are needed to fully establish its relevance for neuroprotection, the findings provide evidence that grapefruit-derived polyphenolic preparations could represent a potential source of bioactive compounds for further investigation as nutraceutical ingredients. Full article

Desulfovibrio spp. are sulfate-reducing bacteria (SRB) associated with conditions such as inflammatory bowel disease (IBD) that are linked to intestinal barrier dysfunction (leaky gut). Previously, we reported that Desulfovibrio vulgaris (DSV) caused increased intestinal permeability by upregulating nuclear transcription factor Snail. However, the signaling mechanisms underlying this effect remain unclear. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that maintains intestinal barrier integrity and negatively regulates Snail and promotes its degradation by proteasomes. Rapamycin has been shown to protect the intestinal barrier and is also known to activate GSK-3. In this study, we investigated whether DSV disrupts intestinal barrier function through modulation of GSK-3 signaling and whether rapamycin could counteract these effects. Using a previously established DSV-induced paracellular permeability model using polarized Caco-2 monolayers, here, we showed that DSV induced inhibitory phosphorylation of GSK-3. Pretreatment of cells with rapamycin prevented DSV- induced phospho- inactivation of GSK-3, suppressed Snail expression and nuclear localization, and significantly reduced DSV-induced barrier permeability. Inhibition of proteasomal degradation with MG132 abolished the protective effects of rapamycin on barrier permeability, supporting a role for GSK-3–mediated proteasomal regulation of Snail. Together, these findings identify GSK-3 signaling as a novel mechanism underlying DSV-induced intestinal barrier dysfunction and highlight rapamycin as a potential therapeutic approach strategy to protect intestinal barrier integrity in response to DSV. Specifically, targeting the GSK-3/Snail pathway may represent a promising strategy to mitigate SRB-associated intestinal barrier disruption. Full article

Necrotizing enterocolitis (NEC) is a major cause of illness and death in preterm infants and is increasingly linked to long-term neurodevelopmental issues among survivors. Usually seen as a gastrointestinal disease, NEC is rarely viewed from a brain-centered perspective. In this Perspective, we suggest that NEC should be understood as a disorder of the gut–brain axis affecting neurodevelopment. We combine clinical and experimental evidence showing that intestinal inflammation, microbial imbalance, epithelial barrier failure, and systemic immune activation during NEC all contribute to the disruption of early brain development. We contend that neurodevelopmental damage is a key feature of NEC rather than just a secondary effect of prematurity. Recognizing NEC as a gut–brain axis disorder is crucial for research models, treatment approaches, and assessing long-term outcomes in affected infants. Full article

Momordica charantia L. (MC), also referred to as bitter gourd or bitter melon, is a Cucurbi taceae plant renowned for its medicinal benefits. 5-Fluorouracil (5-FU) is employed as a frontline chemotherapeutic agent, with its antitumor activity mediated through the inhibition of DNA and RNA synthesis. However, its therapeutic efficacy is often compromised by serious adverse effects, particularly gastrointestinal inflammation. Therefore, this research examined the efficacy of the ethanolic extract of Momordica charantia fruit (EMC) in mitigating 5-FU-induced intestinal mucositis in mice. Mucositis was induced in mice by intraperitoneal administration of 5-FU at 50 mg/kg from experimental days 4 to 7, with EMC administered orally at doses of 125 mg/kg and 250 mg/kg once daily for ten consecutive days. 5-FU exposure resulted in severe intestinal injury, manifested by markedly upregulated inflammation and oxidative stress. EMC treatment significantly reversed these pathophysiological alterations, restoring mucosal architecture and function. Furthermore, EMC effectively reduced the 5-FU-induced release of inflammatory mediators and oxidative stress markers. These results demonstrate that EMC acts as a novel protective modulator of 5-FU-induced mucositis, offering substantial translational potential as an adjunctive supportive therapy in colorectal cancer management. Full article

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the “first-in-class” small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC₅₀ = 7.72, pCC₅₀ < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure–activity relationship insights. Full article

Ulcerative colitis (UC) is a highly prevalent chronic non-specific intestinal inflammatory disorder for which effective therapeutic options are urgently needed. The active component cimigenoside (CIM) possesses promising anti-inflammatory bioactivity; however, its therapeutic efficacy and underlying molecular mechanism against UC remain to be fully elucidated. The present study aimed to investigate the effects and possible mechanisms of CIM on dextran sodium sulfate (DSS)-induced UC. Mice received drinking water containing 2.5% DSS to induce a UC model, and were then treated with different dosages of CIM for 10 consecutive days. The results found that CIM restored the colonic length, alleviated pathological damage to the colon, preserved intestinal mucosal barrier integrity, and inhibited colonic oxidative stress and inflammatory responses in DSS-induced mice. Additionally, DSS induction reduced the expression of sirtuin 3 (SIRT3) protein in the colonic tissues of mice; however, this was improved by treatment with CIM. Notably, the above protective roles of CIM on DSS-induced UC were unavailable in SIRT3-knockout (SIRT3-KO) mice. Notably, the docking score of CIM binding to SIRT3 is −11.3 kcal/mol, suggesting that CIM could directly bind to SIRT3. Collectively, CIM directly binds to SIRT3 and upregulates its protein expression, which in turn inhibits colonic inflammation and oxidative stress, thereby exerting anti-UC effects. Full article

Background/Objectives: Doxorubicin is an anthracycline chemotherapeutic agent widely used in the treatment of breast cancer. However, its clinical utility is limited by the drug’s resistance development, low oral bioavailability, and dose-dependent side effects. The semi-essential amino acid, L-arginine, has gained attention as a potential adjuvant that could improve the drug distribution and cytotoxic effectiveness of chemotherapeutics. This study aimed to explore the multifunctional effect of L-arginine on the intestinal absorption and anti-breast cancer activity of doxorubicin. Methods: The rabbit in situ intestinal perfusion technique was employed to investigate the membrane transport parameters of doxorubicin both in the absence and presence of L-arginine. Furthermore, the effect of L-arginine on the cytotoxic activity of doxorubicin against breast cancer cells (MCF-7) was assessed using the MTT assay. Results: Co-perfusion of L-arginine with doxorubicin enhanced the fraction of doxorubicin absorbed, with a recorded 4.3-fold enhancement in the jejuno-ileum and a 1.5-fold enhancement in the colon segment. In MCF-7 cells, co-treatment with L-arginine resulted in a significant potentiation of doxorubicin cytotoxicity. At L-arginine concentrations of 10 μM and 50 μM, the recorded IC₅₀ decreased from 41.3 μM to 8.2 μM and to 22.1 μM, respectively. The superior efficacy of 10 μM L-arginine compared to 50 μM reflected a biphasic concentration-dependent response. Conclusions: L-arginine modulated two critical aspects of doxorubicin efficacy, intestinal absorption and cytotoxic activity. The biphasic response emphasizes the importance of L-arginine dose optimization. These findings support the potential of L-arginine as a safe adjuvant for developing oral doxorubicin formulations. This approach can reduce the dose-related toxicity of doxorubicin and improve therapeutic outcomes. Full article

Ulcerative colitis (UC) is a multifactorial disease characterized by chronic intestinal inflammation and disrupted oxidative balance, significantly impairing patients’ quality of life. Tannins, a class of polyphenolic compounds widely distributed in plants, have demonstrated notable therapeutic potential against UC due to their inherent antioxidant and anti-inflammatory properties. This study employs a systematic literature review of databases, including PubMed and Web of Science, to investigate the molecular mechanisms by which tannins restore intestinal inflammatory and oxidative homeostasis. The findings indicate that tannins directly scavenge reactive oxygen species (ROS) via their polyphenolic structure, mitigate oxidative damage, upregulate antioxidant enzyme expression, suppress pro-inflammatory cytokine secretion, and preserve intestinal barrier integrity. Despite their significant therapeutic promise, challenges such as low bioavailability and structural complexity remain. Future research should prioritize bioavailability enhancement, clarification of structure-activity relationships, and translational studies to facilitate the clinical application of tannin-based therapies for UC. Full article

This review classifies plant-derived functional ingredients in pet food according to phytochemical groups and application forms, including direct oral supplementation and incorporation into complete diets. Polyphenols and plant extracts exert prominent antioxidant (singular), anti-inflammatory, immunomodulatory, and microbiome-regulating effects. Microalgae and omega-3 sources support lipid metabolism, cardiovascular function, and skin integrity. Cannabinoids demonstrate dose-dependent responses in dogs, while cats generally tolerate long-term administration and exhibit notable benefits in chronic pain management. Combinations of botanical extracts with complementary bioactives and fermented botanical preparations exhibit multi-target functionality, with dogs showing pronounced biochemical and microbiome modulation, whereas cats display more behavioral and functional improvements. Phytochemicals operate through integrated multi-level regulation, including activation of antioxidant enzymes, modulation of inflammatory cytokines and T-lymphocyte ratios, microbial metabolic shifts toward short-chain fatty acid production, and regulation of lipid metabolism. Dogs demonstrate marked effects on hepatic function, reproductive resilience, microbiome diversity, CD4+/CD8+ balance, and cholesterol control. In contrast, cats show greater benefits in inflammation reduction, pain relief, intestinal integrity, and long-term safety. These species-specific responses underscore the importance of precision formulation and highlight the emergence of plant-based “pharma-pet nutrition” integrating nutritional and biochemical strategies for targeted health promotion. Full article

This study investigated the effects of dietary lysophospholipids on growth performance, hepatic lipid metabolism, intestinal health, and dietary lipid levels of largemouth bass. The 56-day experiment included five groups: CON (0% lysophospholipids), LL50 (0.05% lysophospholipids), LP50 (0.05% lysophospholipids—0.5% oil), LP100 (0.1% lysophospholipids—1.0% oil), and LP200 (0.1% lysophospholipids—2.0% oil), with 3 replicates (30 fish/replicate) per group. The results showed that compared with the CON group, dietary supplementation of 0.05% lysophospholipid had no significant effect on the growth performance of largemouth bass, but increased the crude protein content and decreased the crude lipid content in the whole body. An amount of 0.05% lysophospholipid improved hepatic lipid utilization efficiency. Specifically, this supplementation level promoted serum lipid transport (increased serum HDL-C content and decreased triglyceride and LDL-C contents), and enhanced hepatic lipid metabolism by regulating the expression of lipid metabolism-related genes (fas, hsl, and acc) and the levels of lipid metabolites (phosphatidylcholine and fatty acids), thereby reducing hepatic triglyceride content. In addition, 0.05% lysophospholipid improved intestinal health by increasing lipase activity and intestinal villus height, up-regulating the expression of the anti-inflammatory gene (tgf-β1) and tight junction protein genes (claudin-1, claudin-4, and zo-1), and down-regulating the expression of the pro-inflammatory gene (tnf-α). In terms of dietary lipid reduction, supplementation with 0.1% lysophospholipid allowed a 1% reduction in dietary lipid level without affecting the growth performance of largemouth bass, whereas at the same level of lysophospholipid supplementation, a 2% reduction in dietary lipid level resulted in decreased growth performance of largemouth bass. These findings provide theoretical support for the practical application of lysophospholipids, and demonstrate that reducing dietary lipid inclusion by adding lysophospholipids helps to reduce feed costs and improve aquaculture economic benefits. Full article

Background: Ulcerative colitis (UC) is an intestinal disease characterized by long-term inflammation. Circadian rhythm disorder (CRD) affects various biological activities and has been linked to several diseases, including UC. This study aimed to investigate the role and significance of CRD in UC. Methods: Bulk RNA-seq data from five independent UC cohorts were obtained from the Gene Expression Omnibus (GEO) database and integrated into a single dataset. The dataset underwent differential analysis to identify differentially expressed genes (DEGs) in association with CRD. Expression levels and pathway enrichment of CRD genes were analyzed, and signature genes were identified using machine learning algorithms. Based on these signature genes, a UC risk prediction model and CRD-related molecular subtypes were established. Furthermore, single-cell RNA-seq data of UC were analyzed to discuss the key role of CRD and signature genes in the UC microenvironment. RT-PCR analysis was employed to validate the expression levels of the identified signature genes. Results: 247 DEGs associated with CRD in UC were identified (referred to as CRD-DEGs). Gene set enrichment analysis (GSEA) revealed a strong association between CRD and inflammation, as well as immune cell infiltration in UC. This association potentially impacts intestinal fibrosis. A comparison of three machine learning algorithms (Lasso, SVM-RFE, and Random Forest) resulted in the identification of 12 signature genes. A UC risk prediction model and two UC CRD subtypes were developed using these genes. Among them, STXBP1 was identified by all three machine learning algorithms and was further analyzed. STXBP1 was predominantly enriched in pathways related to inflammatory response. Elevated levels of STXBP1 are mainly caused by reduced levels of methylation of its gene promoter. RT-PCR confirmed elevated expression of certain genes in mouse UC models. Conclusions: This study is the first to establish a strong association between CRD and the onset of UC. The newly developed UC nomogram based on CRD demonstrated high predictive accuracy, although further clinical validation is required. Understanding the intrinsic relationship between CRD and UC enhances our understanding of the potential pathogenesis of UC. This study introduces novel ideas and methods for early diagnosis, treatment, and prognosis of UC. Full article

The relationship between epilepsy, obesity, and metabolic syndrome (MetS) has emerged as a rapidly evolving area of neurobiology inquiry. Emerging evidence suggests that epilepsy extends beyond neuronal hyperexcitability, reframing it as a systemic condition characterized by significant metabolic dysregulation. Converging supports a bidirectional relationship while seizures, antiseizure medications (ASM), and neuroinflammation induce exacerbate potentiate epileptogenesis through shared molecular pathways. At the cellular level, chronic epileptic activity induces oxidative stress, mitochondrial dysfunction, and the activation of microglia and astrocytes. This, in turn, leads to the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. These mediators traverse the blood-brain barrier (BBB), subsequently modifying insulin signaling, and disrupting glucose homeostasis, which collectively fosters a pro-inflammatory and insulin-resistant environment. Furthermore, antiseizure medications such as valproate can exacerbate these effects by directly impairing insulin receptor signaling and altering adipokine production, ultimately contributing to weight gain and systemic metabolic dysregulation. Obesity and MetS induce neuroinflammatory and excitotoxic states that promote seizure onset via leptin resistance, reduced adiponectin levels, and compromised AMP-activated protein kinase (AMPK) signaling. Emerging evidence emphasizes the gut-brain axis as a crucial regulator in this reciprocal interaction. Dysbiosis, altered microbial metabolites (e.g., short-chain fatty acids), and heightened intestinal permeability facilitate systemic inflammation and BBB disruption, enhancing neuronal excitability. Insulin resistance in the brain disrupts synaptic transmission, impairs mitochondrial biogenesis, and compromises redox equilibrium, perpetuating a pathological cycle linking metabolic stress to epileptic activity. This review synthesizes the cellular, molecular, and systemic pathways connecting epilepsy, obesity, and MetS, and proposes that epilepsy be reconceptualized as a neuro-metabolic disorder. Insights into these convergent pathways provide a rationale for novel therapeutic strategies that simultaneously target seizure control and metabolic regulation, encompassing microbiota modulation, antioxidant therapy, and insulin-sensitizing interventions with the overarching aim of restoring neuro-metabolic homeostasis. Full article