Search Results (232)

Introduction: Osteoarthritis (OA), a leading cause of disability among the elderly, is characterized by progressive joint tissue destruction. Fucoidan, a sulfated polysaccharide with known anti-inflammatory and antioxidant properties, has been investigated for its potential to protect against interleukin-1 beta (IL-1β)-induced articular tissue damage. Methods: Human primary chondrocytes and synovial fibroblasts were pre-treated with 100 μg/mL fucoidan before stimulation with 1 ng/mL of IL-1β. The protective effects of fucoidan were assessed by measuring oxidative stress markers and catabolic enzyme levels. These in vitro findings were corroborated using a rat anterior cruciate ligament transection-induced OA model. To explore the underlying mechanisms, particularly the interaction between microRNAs (miRs) and heme oxygenase-1 (HO-1), five candidate miRs were identified in silico and experimentally validated. Luciferase reporter assays were used to confirm direct interactions. Results: Fucoidan exhibited protective effects against IL-1β-induced oxidative stress and catabolic processes in both chondrocytes and synovial fibroblasts, consistent with in vivo observations. Fucoidan treatment restored HO-1 expression while reducing inducible nitric oxide synthase and matrix metalloproteinase levels in IL-1β-stimulated cells. Notably, this study revealed that fucoidan modulates the miR-22/HO-1 pathway, a previously uncharacterized mechanism in OA. Specifically, miR-22 was upregulated by IL-1β and subsequently attenuated by fucoidan. Luciferase reporter assays confirmed a direct interaction between miR-22 and HO-1. Conclusion: The results demonstrate that fucoidan mitigates OA-related oxidative stress in chondrocytes and synovial fibroblasts through the novel modulation of the miR-22/HO-1 axis. The miR-22/HO-1 pathway represents a crucial therapeutic target for OA, and fucoidan may offer a promising therapeutic intervention. Full article

Diabetes is a risk factor for periodontitis. Increasing evidence suggests that a central player in this link is the vacuolar H+-ATPase (V-ATPase), which provides a physical and functional core for regulation by the catabolic lysosomal AMP-activated protein kinase complex (L-AMPK) and the anabolic mammalian target of rapamycin complex 1 (mTORC1). These complexes detect levels of various cellular nutrients, including glucose at the lysosome, and promote cellular responses to restore homeostasis. The high-glucose conditions of diabetes foster anabolic mTORC1 signaling that increases inflammation and inflammatory bone resorption in response to periodontal infections. Here, we review the structure and composition of V-ATPase, L-AMPK, mTORC1, and other elements of the energy-sensing platform. Mechanisms by which V-ATPase passes signals to the complexes are examined and recent data are reviewed. Current anti-bone resorptive therapeutics, bisphosphonates and denosumab, enhance the risk of medicine-related osteonecrosis of the jaw (MRONJ) and are not used to treat periodontal bone loss. Accumulating data suggest that it may be possible to target inflammatory bone resorption through agents that stimulate L-AMPK, including metformin and glucagon-like peptide-1 agonists. This approach may reduce inflammatory bone resorption without major effects on overall bone remodeling or increased risk of MRONJ. Full article

Autophagy, an evolutionarily conserved self-degradation catabolic mechanism, is crucial for recycling breakdown products and degrading intracellular components such as cytoplasmic organelles, macromolecules, and proteins in eukaryotes. The process, which can be selective or non-selective, involves the removal of specific ribosomes, protein aggregates, and organelles. Although the specific mechanisms governing various aspects of selective autophagy have not been fully understood, numerous studies have revealed that the dysregulation of autophagy-related genes significantly influences cellular homeostasis and contributes to a wide range of human diseases, particularly cancers, neurodegenerative disorders and inflammatory diseases. Notably, accumulating evidence highlights the complex, dual role of autophagy in cancer development. Thus, this review systematically summarizes the molecular mechanisms of autophagy and presents the latest research on its involvement in both pro- and anti-tumor progression. Furthermore, we discuss the role of autophagy in cancer development and summarize advancement in tumor therapies targeting autophagy. Full article

Inflammatory bowel disease (IBD) represents a chronic inflammatory disorder of the gastrointestinal tract with a multifactorial etiology that remains incompletely elucidated. Accumulating evidence implicates dysregulation of the intestinal micro-ecosystem, aberrant neuroimmune interactions, and compromised epithelial barrier integrity as key contributors to IBD pathogenesis. While oral administration remains the predominant therapeutic approach, the acidic gastric milieu and enzymatic catabolism markedly compromise drug efficacy. Consequently, selecting an optimal drug delivery method has become a pressing issue in IBD management. As a drug delivery platform, hydrogels, distinguished by their favorable biocompatibility, biodegradability, and injectability, can shield drugs from the harsh gastrointestinal environment. This review offers an innovative and comprehensive analysis of the interactions among various hydrogel application forms, delivery routes, and loaded substances, summarizing the advantages of different types of hydrogels in terms of their anti-inflammatory properties and maintenance of intestinal flora homeostasis, as well as discussing the limitations of current hydrogel deliver systems and looking to the future. Full article

Vitamin D and its metabolites exert anti-cancer properties in various cancers; however, their effects on cervical cancer remain largely unexplored. To investigate this gap, we exposed HeLa adenocarcinoma cervical cells to physiological and the growth inhibition 20% (GI20) concentration of 25-hydroxycholecalciferol, the precursor hormone of active 1,25-dihydroxycholecalciferol. We then assessed its impact on cell health, and the expression of the genes and proteins involved in the activation and catabolism of vitamin D at the cellular level by autocrine vitamin D metabolism via the vitamin D metabolizing system (VDMS). Cell health was evaluated by crystal violet and alamarBlue assays, while cell cycle progression and apoptotic cell death markers were assessed by flow cytometry. Gross morphology and ultrastructure were observed using brightfield microscopy and transmission electron microscopy. Gene and protein analyses of the autocrine VDMS were assessed using reverse transcription polymerase chain reaction and Western blot, respectively. Our findings reveal that 25(OH)D₃ inhibits cell growth and induces apoptosis in HeLa cervical cells in a dose-dependent manner through the autocrine upregulation of CYP27B1 and VDR. These autocrine effects most likely promote the bioactivation of 25(OH)D₃ and intracellular signaling of pro-apoptotic genomic pathways by liganded VDR. Furthermore, the upregulation of CYP24A1 at GI20 treatment likely increases the catabolism of 25(OH)D₃ and 1,25(OH)₂D_3, and therefore may mitigate the anti-cancer action of the high-treatment dose. In summary, 25(OH)D₃ holds immense potential as a complementary therapeutic treatment for cervical cancer. Full article

β-Hydroxy-β-methylbutyrate (HMB), a metabolite of the essential amino acid leucine, is acknowledged for its powerful role in facilitating muscle protein synthesis, reducing muscle catabolism, and promoting fat-free mass accumulation. With well-documented anticatabolic, anabolic, and lipolytic effects, HMB has been extensively studied in clinical settings and has exhibited potential in mitigating muscle loss induced by aging, cancer cachexia, and sarcopenia. Moreover, HMB finds applications in specialized medical nutrition, sports nutrition, and animal husbandry, with recent research illustrating its benefits in enhancing animal growth and immunity. This review highlights the current understanding of HMB’s physiological mechanisms, its diverse applications, and recent advancements in detection methods such as High-Performance Liquid Chromatography (HPLC), Gas Chromatography (GC), and Liquid Chromatography–Mass Spectrometry (LC–MS). Additionally, it discusses the future prospects of HMB bio-manufacturing. The establishment of standardized guidelines for its safe use and testing is crucial for its broader adoption in the food industry. Future research should focus on further elucidating HMB’s muscle growth mechanisms and broadening its applications across the food, health, and agricultural sectors. In sum, future studies should prioritize mechanistic exploration, safety and synergy, along with standardization to fully harness HMB’s potential. Full article

Background: Autophagy, a catabolic process essential for maintaining cellular homeostasis, declines with age and unhealthy lifestyles, contributing to neurodegenerative diseases. Probiotics, including Milmed yeast, have demonstrated anti-inflammatory and antioxidant properties. This study evaluated the activity of Milmed on BV-2 microglial cells in vitro and in the in vivo model of Caenorhabditis elegans (C. elegans) in restoring autophagic processes. Methods: BV-2 microglial cells were incubated with S. cerevisiae (Milmed treated yeast or untreated yeast) and then stimulated with lipopolysaccharide (LPS). mRNAs of the autophagic factors and antioxidant enzymes were assessed by qPCR; mTOR and NRF2 were evaluated by ELISA. pNRF2 compared with cytosolic NRF2 was evaluated by immunofluorescence. The longevity, body size, and reactive oxygen species (ROS) levels of C. elegans were measured by fluorescence microscopy. Results: Treatment with Milmed YPD cultured yeast or the dried powder obtained from it promoted autophagic flux, as shown by the increased expression of the Beclin-1, ATG7, LC3, and p62 mRNAs and the inhibition of mTOR, as evaluated by ELISA. It also enhanced the antioxidant response by increasing the expression of NRF2, SOD1, and GPX; moreover, pNRF2 expression compared with cytosolic NRF2 expression was enhanced, as shown by immunofluorescence. Milmed dietary supplementation prolonged the survival of C. elegans and reduced the age-related ROS accumulation without changing the expression of gst-4. The pro-longevity effect was found to be dependent on SKN-1/Nrf2 activation, as shown by the absence of benefit in skn-1 mutants. Conclusions: Milmed yeast demonstrates significant pro-autophagy and antioxidant activity with significant pro-longevity effects in C. elegans, thereby extending the lifespan and improving stress resistance, which, together with the previously demonstrated anti-inflammatory activity, highlights its role as a highly effective probiotic for its beneficial health effects. Activation of the SKN-1/NRF2 pathway and the modulation of autophagy support the therapeutic potential of Milmed in neuroprotection and healthy aging. Full article

Background/Objectives: Yersinia pestis is an important zoonotic pathogen responsible for the rare but deadly disease of people with bubonic, septic, or pneumonic forms of plague. The emergence of multidrug-resistant Y. pestis strains has attracted more and more researchers’ attention to the search for molecular targets for antivirulence therapy, including anti-nutritional-virulence therapy. The glnALG operon plays a crucial role in regulating the nitrogen content within a bacterial cell. This operon codes for three genes: the structural gene glnA and the two regulatory genes glnL and glnG. In this study, we tested the effect of the deletion of glnA and glnALG on the pathogenic properties of Y. pestis. Methods: To assess the contribution of nitrogen metabolism to Y. pestis virulence, knockout mutants ΔglnA and ΔglnALG were constructed. The former was unable to synthesize glutamine, while the latter was not only defective in glutamine synthesis but also lacked the two-component sensor–transcriptional activator pair GlnL and GlnG, which could partially compensate for the decrease in intracellular glutamine concentrations by transporting it from the host or by catabolic reactions. For vaccine studies, immunized mice and guinea pigs were injected s.c. with 200 LD₁₀₀ of the wild-type Y. pestis strain. Results: A single knockout mutation in the glnA gene did not affect the virulence of Y. pestis in mice and guinea pigs. Knockout of the entire glnALG gene cluster was required for attenuation in these animals. The ΔglnALG strain of Y. pestis did not cause death in mice (LD₅₀ > 10⁵ CFU) and guinea pigs (LD₅₀ > 10⁷ CFU) when administered subcutaneously and provided 100% protection of animals when subsequently infected with 200 LD₁₀₀ of the Y. pestis virulent wild-type strain 231. Conclusions: Y. pestis, defective in both the glutamine synthetase GlnA and the two-component sensor–transcriptional activator pair GlnL-GlnG, completely lost virulence and provided potent protective immunity to mice and guinea pigs subsequently challenged with a wild-type Y. pestis strain, demonstrating the potential use of the glnALG operon as a new molecular target for developing a safe and efficient live plague vaccine. Full article

The disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury and strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines microglial responses to chemical hypoxia induced by cobalt chloride (CoCl₂) in BV-2 murine microglial cells, focusing on signaling pathways and proteomic alterations. We assessed the protective effects of monoclonal antibodies against TNFα and IL-1β. CoCl₂ exposure led to decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, and activation of inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, and NF-κB/NLRP3. These responses were significantly mitigated by treatment with anti-TNFα and anti-IL-1β, suggesting their dual role in reducing microglial damage and inhibiting inflammatory reactivity. Additionally, these treatments reduced apoptosis by modulating ATF4 and the p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics and Gene Ontology revealed that CoCl₂ exposure led to the upregulation of proteins primarily involved in endoplasmic reticulum and catabolic processes, while downregulated proteins are associated with biosynthesis. Anti-TNFα and anti-IL-1β treatments partially restored the proteomic profile toward normalcy, with network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator in recovery. These findings offer insights into the pathogenesis of hypoxic microglial impairment and suggest potential therapeutic targets. Full article

The gut microbiota influences and contributes to kidney health and disease. Butyrate, a short-chain fatty acid molecule generated via the fermentation of gut bacterial catabolism of nondigestible dietary fiber, has been shown to exert numerous beneficial effects on kidney disorders. The objective of this review was to discuss the latest findings on the protective effects of butyrate on a variety of animal models of kidney injury. We conducted a PubMed search using the title word “butyrate” and keyword “kidney” to generate our literature review sources. The animal models covered in this review include ischemia–reperfusion renal injury, cisplatin- and folic acid-induced kidney injury, septic kidney injury, diabetic kidney disease (DKD), high-fat diet (HFD)-induced glomerulopathy, adenine-induced chronic kidney disease (CKD), high-salt-induced renal injury, and T-2 toxin-induced kidney injury in birds. The protective mechanisms of butyrate that are most shared among these animal model studies include antioxidative stress, anti-fibrosis, anti-inflammation, and anti-cell death. This review ends with suggestions for future studies on potential approaches that may modulate gut microbiota butyrate production for the well-being of kidneys with the kidney disorders covered in this review. Full article

Background: Malnutrition is a clinical condition that leads to unfavourable changes in health. It affects 35–55% of hospitalized patients, and in the case of cancer, this prevalence rises to 40–90% of patients. Screening nutritional status is essential for preventing undernutrition, which is crucial as its treatment. Undernutrition in patients after severe injuries significantly increases catabolic changes. Cytokines and hormones, such as epinephrine, glucagon, and cortisol, are released, which can increase energy expenditure by 50%. Properly conducted nutritional treatment aims to maintain or improve the nutritional status of patients whose nutrition with a natural diet is insufficient, moreover, in some cases, treatment of the underlying disease. Methods: This study is a narrative review focused on immunonutrition. The search for source articles, mainly from the last 10 years, was conducted in the PubMed and Google Schoolar databases, as well as in printed books. The key words used were “malnutrition”, “inflammation”, “clinical nutrition”, “immunomodulatory components”, “nutritional status assessment”, “enteral nutrition”, “parenteral nutrition”, and their combinations. Results: Providing substances such as omega-3 fatty acids, glutamine, arginine, nucleotides, antioxidants, and prebiotic fiber has a beneficial impact on immunological and anti-inflammatory pathways. The above-mentioned ingredients may inhibit the secretion of pro-inflammatory cytokines, activate anti-inflammatory cytokines, stimulate immune cells, and have a beneficial effect in allergic diseases, respiratory infections, or wound healing. Conslusion: Immunonutrition can be administrated via oral, enteral, and parenteral routes. It is crucial to highlight the importance of proper nutritional status in patients. The relationship between inflammation and malnutrition creates a vicious cycle, where one negatively affects the other due to increased metabolic demand, loss of appetite, weakened immune system, and gut dysbiosis. Full article

Vitamin C is an organic compound biosynthesized in plants and most vertebrates. Since its discovery, the benefits of vitamin C use in the cure and prevention of various pathologies have been frequently reported, including its anti-oxidant, anti-inflammatory, anticoagulant, and immune modulatory properties. Vitamin C plays an important role in collagen synthesis and subsequent scurvy prevention. It is also required in vivo as a cofactor for enzymes involved in carnitine and catecholamine norepinephrine biosynthesis, peptide amidation, and tyrosine catabolism. Moreover, as an enzymatic cofactor, vitamin C is involved in processes of gene transcription and epigenetic regulation. The absence of the synthesis of L-gulono-1,4-lactone oxidase, a key enzyme in the pathway of vitamin C synthesis, is an inborn metabolism error in some fishes and several bird and mammalian species, including humans and non-human primates; it is caused by various changes in the structure of the original GULO gene, making these affected species dependent on external sources of vitamin C. The evolutionary cause of GULO gene pseudogenization remains controversial, as either dietary supplementation or neutral selection is evoked. An evolutionary improvement in the control of redox homeostasis was also considered, as potentially toxic H₂O₂ is generated as a byproduct in the vitamin C biosynthesis pathway. The inactivation of the GULO gene and the subsequent reliance on dietary vitamin C may have broader implications for aging and age-related diseases, as one of the most important actions of vitamin C is as an anti-oxidant. Therefore, an important aim for medical professionals regarding human and animal health should be establishing vitamin C homeostasis in species that are unable to synthesize it themselves, preventing pathologies such as cardiovascular diseases, cognitive decline, and even cancer. Full article

High concentrations of free fatty acids (FFAs) caused by negative energy balance render the cow more prone to inflammatory diseases in part due to an imbalance in the types of immune cells and their specific functions. We previously demonstrated that ORAI calcium release-activated calcium modulator 1 (ORAI1) was associated with increased CD4⁺ Th17 content, but the precise mechanisms remain unclear. The purpose of this study was to evaluate the efficacy of FFAs on CD4⁺ T cell inflammatory response. High FFAs in dairy cows caused the transcript level of the pro-inflammatory factor IL-17A, plasma concentration of IL-17A, and amount of intracellular IL-17A to increase while the transcript levels and intracellular amount of the anti-inflammatory factor FOXP3 were downregulated. These changes indicated Th17/Treg imbalance and inflammation in dairy cows with high FFA. Moreover, ORAI1 and SDS abundance was elevated in dairy cows with high FFAs by transcriptomics, QPCR, and Western blot. Knockdown of SDS (siSDS) did not alter ORAI1 expression in CD4⁺ T cells from high-FFA cows, while it decreased the expression of inflammatory factors. Transfection of CD4⁺ T cells using siRNA knockdown for ORAI1 (siORAI1) revealed that SDS and inflammatory factor abundance decreased. Serine can be catabolized to pyruvate by the action of serine dehydratase (SDS). Data from this study suggested that high FFAs caused by negative energy balance after calving regulates the Th17/Treg balance via SDS, but SDS does not regulate ORAI1 abundance. The above data suggested a pro-inflammatory mechanism in CD4⁺ T cells regulated by the ORAI1-sensitive SDS pathway in early postpartum cows experiencing high-FFA conditions. Thus, targeting this pathway may represent a new therapeutic and interventional approach for preventing immune-related disorders around parturition. Full article

Selol is a semi-synthetic mixture of selenized triglycerides. The results of biological studies revealed that Selol exhibits several anticancer effects. However, studies on its potential anti-inflammatory activity are scarce, and underlying signaling pathways are unknown. The aim of our study was to investigate the ability of Selol to exert anti-inflammatory effects in a RAW 264.7 cell line model of LPS (lipopolysaccharide)-induced inflammation. Cells were treated either with Selol 5% (4 or 8 µg Se/mL) or LPS (1 µg/mL) alone or with Selol given concomitantly with LPS. The parameters studied were reactive oxygen species (ROS) production, glutathione and thioredoxin (Txn) levels, and nuclear factor kappa B (NF-κB) activation, as well as nitric oxide/prostaglandin E₂ (NO/PGE₂) production. The presented research also included the effect of Selol and/or LPS on glucose (Glc) catabolism; for this purpose, the levels of key enzymes of the glycolysis pathway were determined. The results showed that Selol exhibited pro-oxidative properties. It induced ROS generation with a significant increase in the level of Txn; however, it did not affect the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. Selol moderately activated NF-κB but failed to affect NO/PGE₂ production. The effect of Selol on glucose catabolism was not significant. However, the simultaneous administration of Selol with LPS exerted a statistically significant anti-inflammatory effect via a decrease in the production of pro-inflammatory mediators and NF-κB activation. Our study also showed that as a result of LPS action in cells, the anaerobic glycolysis activity was increased, and incubation with Selol caused a partial reprogramming of Glc metabolism towards aerobic metabolism. This may indicate different pharmacological and molecular effects of Selol action in physiological and pathological conditions. Full article

Obesity is a chronic disease that profoundly impacts human health, and the role of plant-based formulas (PBFs) in combating obesity has garnered significant interest. Studies have revealed that fermentation significantly enhances the taste, aroma, quality, and health benefits of PBF water extract, with pasteurization being the preferred sterilization technology. However, few studies have investigated the effects of pasteurization on the active components and potential functions of PBF water extract fermentation broth. To examine the impact of pasteurization on fermented water extract of Millettia speciosa Champ (FH08F) and its potential anti-obesity properties, the components of FH08F and thermal-pasteurized FH08F (FH08FS) were analyzed in this study. The analysis revealed a substantial rise in ester content following sterilization. This can be attributed to the acidic environment that promotes the esterification reaction during the heating phase. Network pharmacology was employed to thoroughly examine seven active components of upregulated compounds (URCs) with potential obesity targets, which constituted 92.97% of the total URC content, and four of them were nitrogen-containing aromatic heterocyclic compounds (NAHCs), which accounted for 90.33% of the total URC content. Upregulated NAHCs appear to actively contribute to efficacy against obesity. Molecular docking analyses have shown that theophylline, an NAHC, has the strongest binding affinity with the obesity-related target PTGS2 (Prostaglandin G/H synthase 2, 5FLG). These results imply that theophylline may directly activate PKA/PKG-mediated phosphorylated hormone-sensitive lipase (p-HSL), thereby promoting lipolysis through the cAMP signaling pathway and stimulating the catabolism of triglycerides (TGs) to combat obesity. In conclusion, pasteurization substantially alters the composition of FH08F, and NAHCs are likely to play a significant role in its potential anti-obesity function. These findings provide a scientific foundation for the potential therapeutic effect of FH08FS on obesity and associated metabolic diseases. Full article