Search Results (336)

The incidence of primary liver cancer is increasing annually, with extremely high mortality and suboptimal therapeutic outcomes. The inefficient presentation of tumor antigens and low infiltration of specific cytotoxic T lymphocytes (CTLs) result in insufficient immunogenicity, which limits the efficacy of immunotherapy. Despite the popularity of immune checkpoint inhibitors (ICIs), insufficient immune activation means only a small subset of hepatocellular carcinoma (HCC) patients exhibit clinical responses to ICIs, showing significant inter-individual variability. The activation of the cyclic GMP-AMP synthase(cGAS)- stimulator of interferon genes(STING) pathway initiates the expression of type I interferons (IFNs) and inflammatory cytokines, promoting the formation of a pro-inflammatory environment at the tumor site. This pathway enhances anti-tumor immune responses by facilitating antigen processing and presentation, T cell priming and activation, and remodeling of the immunosuppressive microenvironment. Our research found that cucurbitacin B (CuB), a natural component derived from traditional Chinese medicine, had significant anti-hepatocellular carcinoma properties and exerted anti-tumor effects through the cGAS-STING pathway. Specifically, CuB regulated ferroptosis by down-regulating the expression of Solute Carrier Family 7 Member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) and upregulating the expression of Transferrin Receptor Protein 1 (TFR1) and Long-chain Acyl-CoA Synthetase 4 (ACSL4). These actions involved lipid substrates, iron ion homeostasis, and antioxidant defense systems. The release of mitochondrial DNA (mtDNA) triggered by ferroptosis activated the cGAS-STING immune signaling pathway, leading to the up-regulation of cGAS, phosphorylated STING (p-STING), phosphorylated TANK-binding kinase 1 (TBK1), phosphorylated Interferon regulatory factor3 (IRF3), and Interferon-β (IFN-β). This cascade activation pattern provides new insights into the drug treatment of tumors. Full article

Sarcopenic obesity, characterized by skeletal muscle loss concurrent with adipose tissue accumulation, has emerged as a global health threat. Exercise is established as an effective intervention; however, the molecular mechanisms underlying its protective effects remain incompletely defined. This study investigated whether exercise mitigates high-fat diet (HFD)-induced sarcopenic obesity, and whether the mechanism was related to the activation of the adenosine monophosphate-activated protein kinase (AMPK)/Acetyl-CoA carboxylase pathway (ACC) pathway and the inhibition of ferroptosis. Cell experiments demonstrated that palmitic acid induced ferroptosis in C2C12 mouse myoblasts. Animal experiments confirmed that HFD promoted skeletal muscle ferroptosis in C57BL/6 mice, evidenced by iron metabolism imbalance (solute carrier family 39 member14 upregulation, ferroportin downregulation), impaired antioxidant capacity (reduced glutathione, superoxide dismutase, glutathione peroxidase 4), and elevated lipid peroxidation (increased malondialdehyde). Meanwhile, both flat treadmill running and uphill treadmill running may reverse these changes by activating AMPK/ACC phosphorylation, reducing non-transferrin iron uptake, enhancing iron export and storage, and improving antioxidant status, jointly inhibiting ferroptosis and attenuating muscle mass loss and lipid deposition. These findings confirm that ferroptosis acts as one of the key pathogenic drivers in sarcopenic obesity and suggests that exercise may improve sarcopenic obesity by activating the AMPK/ACC pathway and inhibiting ferroptosis. This study provides novel mechanistic insights into exercise-mediated regulation of iron-lipid metabolism crosstalk and informs targeted interventions for sarcopenic obesity. Full article

Background/Objectives: Ginger (Zingiber officinale Roscoe) is a flowering plant widely used as a spice and natural medicine for millennia. Ginger demonstrates multiple protective effects, regulates cholesterol, and may reduce the risk of cancer and colitis. However, little attention has been paid to its potential to cause herb–drug interactions (HDIs). The aim of this study was to investigate the interaction of ginger extract and its major components [⁶]-gingerol and [⁶]-shogaol with clinically relevant uptake and efflux transporters in vitro. Methods: Transporter-overexpressing cell lines of 25 uptake transporters and inside-out membrane vesicles containing 8 efflux transporters were employed to measure potential interactions. Results: Zingiber officinale extract at 150 µg/mL interacted with 17 of 33 transporters examined. These were further investigated for interactions with the purified active components. Seven and 16 transporters interacted with pure [⁶]-gingerol (100 µM) and [⁶]-shogaol (100 µM), respectively. To evaluate the risk of in vivo inhibition, IC₅₀ values were determined for the affected transporters. Based on standard risk assessment calculations, we confirmed previously reported inhibitory effects of ginger components on MDR1 (67.64 µM) and BCRP (9.931 µM), and revealed novel potential interactions with renal OAT3 (0.956 µM) and URAT1 (5.887 µM), hepatic OCT1 (4.287 µM) and BSEP (25.45 µM), and the ubiquitously expressed ENT1 (11.62 µM) ([⁶]-shogaol IC₅₀ values are shown in parentheses). Strong and isoform-selective inhibition of OAT3 by [⁶]-shogaol is particularly intriguing. Additionally, via cell viability experiments on a set of human cervical, breast, and oropharyngeal cancer cell lines, we demonstrated the antiproliferative effect of [⁶]-shogaol in vitro. Conclusions: Prolonged consumption of high-dose ginger supplements may pose a risk of transporter-mediated HDIs when consumed concomitantly with conventional medications. Our study encourages follow-up of the suspected effects in vivo. Full article

Seventy 28-day-old weaned barrow piglets (Duroc × Landrace × Large White; 7.2 ± 0.20 kg) were used to determine the effects of 25-hydroxyvitamin D₃ (25-OH-VD₃) combined with phytase and probiotics on calcium and phosphorus metabolism and bone development. Five dietary groups were tested: basal diet + 50 µg/kg 25-OH-VD₃ (CON); basal diet with 17% reduced calcium and phosphorus + 50 µg/kg 25-OH-VD₃ (LCP); LCP + 50 mg/kg phytase (LH); LCP + 10 mg/kg probiotics (LC); LCP + 50 mg/kg phytase + 10 mg/kg probiotics (LHC). The experiment lasted for 31 days, including 3 days adaptation period. Apparent phosphorus digestibility was higher in the LH and LHC groups than in the CON group (p < 0.05). Bone mineral density and calcium content in metacarpal and rib bones were also higher in the LHC group compared with the CON, LCP, LC, and LH groups (p < 0.05). The jejunal mRNA expression of solute carrier family 34 members (SLC34A1, SLC34A2, and SLC34A3) members was higher in the LHC group than the CON, LCP, LC, and LH groups (p < 0.05), while the relative protein expression of the calcium-sensing receptor in the kidneys was lower in the CON group than in the LCP, LH, LC, and LHC groups (p < 0.05). Additionally, supplementation with 25-OH-VD₃, either alone or in combination with phytase and probiotics, was associated with an increased abundance of beneficial gut bacteria. Overall, combined supplementation of 25-OH-VD₃, phytase and probiotics enhanced bone development in weaned piglets fed a low-calcium, low-phosphorus diet by improving calcium and phosphorus utilization and calcium–phosphorus metabolic regulation. Full article

Solute carriers (SLCs) mediate cell- and organelle-specific import and export of nutrients and metabolites required for every biochemical process that occurs in a cell. Functional studies have ascribed activities to many human genes annotated as SLCs, but more than 100 SLCs remain orphans. Here, we applied a set of computational tools to characterize the orphan carriers SLC35F4 and SLC35F5. Phylogenetic analysis grouped SLC35F4 sister to SLC35F3, a suspected thiamine transporter, in a clade with SLC35F5, and distinct from an SLC35F6/2/1 clade. Transcriptome datasets revealed a restricted function for SLC35F4 in the cerebellum, in contrast to the more widespread distribution of SLC35F5. Gene ontology identified the Golgi apparatus as the likely residence of both transporters. Conceptual docking of 71 candidate substrates predicted high affinities of SLC35F4 (10–40 nM) and SLC35F5 (0.1–0.4 nM) for flavin adenine dinucleotide (FAD), straddling that of the known FAD transporter SLC25A32 (2–4 nM), while returning much lower affinities (by 30–fold or more) for all other tested substrates. Docking to SLC35F3 returned low affinity for both FAD and thiamine as candidate substrates. Thus, SLC35F4 and SLC35F5 but not closely related SLC35F3 likely import FAD into the Golgi apparatus, where the cofactor serves as the oxidant for disulfide-bond formation during tissue-specific, post-translational modification of secretory proteins. These findings provide strong direction for the definitive experiments yet needed to confirm the carriers’ subcellular localization, transport activities, and contributions to protein maturation and trafficking. Full article

Type 2 diabetes mellitus (T2D) affects hundreds of millions worldwide, with recent estimates indicating approximately 589 million adults living with diabetes, most with type 2 disease. Beyond classical insulin signaling pathways, increasing evidence implicates altered protein glycosylation in metabolic dysfunction. The solute carrier 35 (SLC35) family of nucleotide sugar transporters mediates the import of activated sugars into the endoplasmic reticulum and Golgi lumen, thereby influencing global glycosylation patterns. Dysregulation of these transporters can perturb glucose homeostasis, insulin responsiveness, and nutrient-sensing pathways through changes in glycosylation flux. In this review, we dissect the molecular mechanisms by which these transporters modulate glucose homeostasis, insulin signaling pathways, protein O-GlcN acylation, and broader glycosylation processes. We integrate findings from human genetic studies, rodent models, and in vitro functional analyses to characterize how altered SLC35 activity is associated with T2D and metabolic syndrome. Four members demonstrate particularly compelling evidence: SLC35B4 modulates hepatic glucose metabolism, SLC35D3 mutations impair dopaminergic signaling and energy balance, and SLC35F3 variants interact with high-carbohydrate intake to increase metabolic-syndrome risk. SLC35A3, though less studied, may influence glycosylation-dependent insulin signaling through its role in N-glycan biosynthesis. Beyond these characterized transporters, this review identifies potential metabolic roles for understudied family members, suggesting broader implications across the entire SLC35 family. We also discuss how such alterations can lead to disrupted hexosamine flux, impaired glycoprotein processing, aberrant cellular signaling, and micronutrient imbalances. Finally, we evaluate the therapeutic potential of targeting SLC35 transporters, outlining both opportunities and challenges in translating these insights into novel T2D treatments. Full article

Background/Objectives: Emerging evidence has suggested that choline is an effective treatment for at least some of the neurobehavioral deficits associated with Fetal Alcohol Spectrum Disorders (FASD). However, the mechanism of how choline works to ameliorate ethanol’s teratogenic effects, and whether it acts directly on the fetus or indirectly by altering the uterine environment, remains unknown. Previous work from our lab demonstrated that 4 BXD mouse strains that show high levels of ethanol-induced cell death on embryonic day 9.5 (E9.5) have differential responses to choline supplementation. This differential response in mouse strains highlights a need to further understand the role of genetics in choline metabolism. Because the liver is the central organ for choline metabolism, and the embryonic liver of mice is not functional this early in gestation, we focused on choline metabolism in the liver of the dam. Methods: Using a bioinformatics approach, the goals were to assess whether (1) genetic differences in liver choline metabolism in the dam could affect ethanol-induced cell death in a genotype-specific manner and (2) any of these candidate genes in the liver of the dam could be linked to differential response to choline amongst the strains. By performing a literature review, haplotype analysis among the 4 BXD strains, and liver protein expression analysis among 3 strains, we show that there are genetic differences in choline metabolic genes that are consistent with the hypothesis that maternal choline metabolism could mediate differential sensitivity. Results: While we identified two genes as promising candidates for the variable responses to choline supplementation among the four previously identified BXD strains choline/ethanolamine phosphotransferase 1 (cept1) and choline transporter gene solute carrier family 44 member 1 (slc44a1), the wealth of data on slc44a1 makes it the stronger candidate and suggests that it should be further explored. Conclusions: Genetic differences in maternal choline metabolism are present and may underlie variable therapeutic responses to choline, warranting a hypothesis that requires further investigation across animal models and human populations. Full article

Despite the known antitumor properties of echinacoside (ECH), its specific role and mechanism in hepatocellular carcinoma (HCC) require in-depth exploration. Our study aimed to decipher the mechanism of ECH against HCC through a multi-disciplinary strategy. We first identified tumor protein p53 (TP53) as a key mediator and ferroptosis as a critical process, through network pharmacology and enrichment analyses. The direct interaction between ECH and TP53 was validated by molecular docking and dynamics simulations. In vitro assessments demonstrated that ECH suppresses HCC proliferation by activating ferroptosis, marked by increased intracellular Fe²⁺, lipid peroxidation (LPO), and malondialdehyde (MDA), alongside reduced glutathione (GSH). The ferroptosis inhibitor ferrostatin-1 notably attenuated ECH’s effects, confirming ferroptosis as the primary mode of cell death. Further mechanistic investigation revealed that ECH acts through the TP53/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4) pathway. These results collectively identify ECH as a promising ferroptosis-inducing agent for HCC therapy via TP53 activation. Full article

This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × Large, body weight = 2.58 ± 0.05 kg) were divided into three treatment groups based on similar body weights and equal numbers of males and females: the blank control group (CON group), the PEDV infection group (PEDV group), and the NG intervention + PEDV infection group (NG + PEDV group) (n = 6 per group). The experiment lasted for 11 days, comprising a pre-feeding period from days 0 to 3 and a formal experimental period from days 4 to 10. On days 4–10 of the experiment, piglets in the NG + PEDV group were orally administered NG (10 mg/kg). On Day 8 of the experiment, piglets in the PEDV and NG + PEDV groups were inoculated with PEDV (3 mL, 10⁶ 50% tissue culture infective dose (TCID₅₀) per milliliter). On day 11 of the experiment, piglets were euthanized for sample collection. PEDV infection caused significant intestinal damage, including a decreased (p < 0.05) villus height in the duodenum and ileum and an increased (p < 0.05) crypt depth in all intestinal segments. This intestinal damage was accompanied by an impaired absorptive function, as indicated by reduced (p < 0.05) serum D-xylose. Further results showed that PEDV compromised the intestinal antioxidant capacity by decreasing (p < 0.05) glutathione peroxidase and catalase activities, and it stimulated the intestinal inflammatory response by upregulating (p < 0.05) the expression of key inflammatory genes, including regenerating family member 3 gamma (REG3G; duodenum, jejunum, colon), S100 calcium binding protein A9 (S100A9; ileum, colon), interleukin 1 beta (IL-1β; ileum, colon), and S100 calcium binding protein A8 (S100A8; colon). PEDV also suppressed the intestinal lipid metabolism pathway by downregulating (p < 0.05) the ileal expression of Solute Carrier Family 27 Member 4 (SLC27A4), Microsomal Triglyceride Transfer Protein (MTTP), Apolipoprotein A4 (APOA4), Apolipoprotein C3 (APOC3), Diacylglycerol O-Acyltransferase 1 (DGAT1), and Cytochrome P450 Family 2 Subfamily J Member 34 (CYP2J34). Moreover, PEDV suppressed the intestinal antiviral ability by downregulating (p < 0.05) interferon (IFN) signaling pathway genes, including MX dynamin like GTPase 1 (MX1) and ISG15 ubiquitin like modifier (ISG15) in the duodenum; weakened intestinal water and ion transport by downregulating (p < 0.05) aquaporin 10 (AQP10) and potassium inwardly rectifying channel subfamily J member 13 (KCNJ13) in the duodenum, aquaporin 7 (AQP7) and transient receptor potential cation channel subfamily V member 6 (TRPV6) in the ileum, and TRPV6 and transient receptor potential cation channel subfamily M member 6 (TRPM6) in the colon; and inhibited intestinal digestive and absorptive function by downregulating (p < 0.05) phosphoenolpyruvate carboxykinase 1 (PCK1) in the duodenum and sucrase-isomaltase (SI) in the ileum. Notably, NG effectively counteracted these detrimental effects. Moreover, NG activated the IFN signaling pathway in the jejunum and suppressed PEDV replication in the colon. In conclusion, NG alleviates PEDV-induced intestinal injury by enhancing the antioxidant capacity, suppressing inflammation, normalizing the expression of metabolic and transport genes, and improving the antiviral ability. Full article

Extracellular RNAs are released from cells and circulate stably in biofluids such as blood, cerebrospinal fluid, saliva, and urine via carriers including extracellular vesicles, RNA-binding proteins and lipoproteins. Because transcriptional and metabolic disturbances—notably mitochondrial dysfunction and oxidative stress—often precede protein aggregation, synaptic loss, and structural change in many brain diseases, exRNAs offer minimally invasive access to early disease biology. Mechanistic studies demonstrate selective RNA packaging and delivery: transferred mRNAs can be translated and miRNAs can modulate targets, indicating exRNAs both report intracellular programs and actively influence recipient cells. Clinical and preclinical data support a dual role for exRNAs as biomarkers and as mediators of pathology. Key technical hurdles—pre-analytical variability, isolation heterogeneity, and uncertain cellular origin—limit reproducibility; recommended solutions include standardized workflows, carrier- and cell type-specific enrichment, multimodal integration with proteomics/metabolomics and neuroimaging, and large, longitudinal validation studies. We synthesize mechanistic and clinical evidence for exRNA utility in early detection, prognosis, and therapeutic targeting and outline a roadmap to translate exRNA findings into robust clinical assays and interventions for neurodegenerative and brain disorders. Full article

Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscorea plants, has been shown to effectively inhibit proliferation of prostate cancer cells in vitro and in vivo. However, the mechanism underlying this inhibitory action remains unclear. To elucidate the mechanism, we used mass spectrometry to analyze protein rearrangements in detergent-resistant membranes (DRMs). Ferroptosis-related factors were identified in cells in vitro and in vivo. MPD induced the expression of acyl-CoA synthetase long chain family member 4 and reduced expression levels of glutathione peroxidase 4 and solute carrier family 7 member 11. Following MPD treatment, RB1-inducible coiled-coil 1 (RB1CC1) dissociated from DRMs and translocated from the cytoplasm to the nucleus. This translocation induced the expression of ferroptosis-related protein coiled-coil-helix-coiled-coil-helix domain containing 3, promoting ferroptosis in prostate cancer cells. As the nuclear translocation of RB1CC1 was promoted by the JNK signaling pathway, SP600125, a JNK inhibitor, prevented the MPD-induced RB1CC1 nuclear translocation. In summary, MPD induced the dissociation of RB1CC1 from DRMs and its subsequent nuclear translocation, contributing to ferroptosis of prostate cancer cells. Full article

This study evaluated the formulation and stability of a quadrivalent glycoconjugate Shigella vaccine candidate based on four predominant strains (S. flexneri; 2a, 3a, and 6, and S. sonnei) covering ~64% of global Shigella infections. Each glycoconjugate antigen consists of a strain-specific O-polysaccharide (O-PS) covalently linked to the carrier protein IpaB, a component of the Shigella type III secretion system. First, selective competitive ELISAs were developed to measure antigenicity of the four O-PS-IpaB conjugates formulated with different adjuvants (i.e., Alhydrogel^®, AH; Adju-phos^®, AP; and CpG-1018^®, CpG). Next, the monovalent S. sonnei O-PS-IpaB conjugate was studied to elucidate interactions with aluminum salt adjuvants (AH, AP) under different solution conditions. Third, the stability profiles of AH- or AP-adjuvanted S. sonnei O-PS-IpaB conjugate in various formulations (±CpG) were determined at different temperatures. Interestingly, incubation at 25 °C for 2 weeks resulted in increased antigenicity values when the antigen was bound to AP or AH, suggesting increased epitope exposure upon adjuvant binding. When bound to AP adjuvant at pH 5.8, the best glycoconjugate antigen stability was observed at elevated temperatures. The CpG adjuvant under these conditions, however, displayed incompatibility (i.e., material loss), presumably from precipitation due to lack of interaction with AP and presence of the detergent LDAO from the bulk antigen buffer. In contrast, the glycoconjugate antigen and CpG adjuvant were both bound to the AH adjuvant and stable at 2–8 °C, pH 7.0. This AH-CpG formulation of the O-PS-IpaB conjugate antigens was identified as a promising candidate for future animal immunogenicity testing. Full article

The present study aimed to design a process of brown onion skin transformation by sequential extraction to a cellulose-based immobilization carrier, along with detailed analysis of obtained extracts, pointing to approaching a “zero-waste” model of circular economy. The process of brown onion skin transformation started with semi-continuous sequential subcritical extraction via consecutive use of five solvents of increasing polarity (96, 75, 50, and 25% ethanol and water), followed by alkaline liquefaction of solid residue by 10% aqueous solution of sodium hydroxide. The designed BOS transformation process resulted in 16.62 g of cellulose-based immobilization carrier derived from 100 g of brown onion skin. Extracts obtained by semi-continuous sequential subcritical extraction contained 37 mg/g of proteins, 40 mg/g of sugars, 17.5 mg/g of uronic acids, 28 mg/g of polyphenols, and 36 mg/g of flavonoids, while those obtained by alkaline liquefaction 19 mg/g of proteins, 58 mg/g of sugars, 10 mg/g of uronic acids, 6.6 mg/g of polyphenols, and 0.5 mg/g of flavonoids. The suitability of the cellulose-based enzyme immobilization carrier was evaluated by B. cepacia lipase immobilization by adsorption, where a maximal 31 U of lipase activity per 1 g of wet carrier was achieved. Based on the results obtained, it seems that the proposed process of brown onion skin transformation shows the possibility of being used for the production of a cellulose-based immobilization carrier, approaching the “zero-waste” model of a circular economy. Full article

This review explores the synergistic integration of edible coatings and non-thermal preservation technologies as a multifaceted approach to maintaining food quality, safety, and sustainability. Edible coatings—composed of polysaccharides, proteins, lipids, or composite biopolymers—serve as biodegradable barriers that control moisture, gas, and solute transfer while acting as carriers for bioactive compounds such as antimicrobials and antioxidants. Meanwhile, non-thermal techniques, including high-pressure processing, cold plasma, ultrasound, photodynamic inactivation, modified atmosphere packaging, and irradiation, offer microbial inactivation and enzymatic control without compromising nutritional and sensory attributes. When combined, these technologies exhibit complementary effects: coatings enhance the stability of bioactives and protect surface quality, while non-thermal treatments boost antimicrobial efficacy and promote active compound penetration. The review highlights their comparative advantages over individual treatments—improved microbial inhibition, nutrient retention, and sensory quality. It further discusses the possible mechanisms through which edible coatings and selected hurdles induced microbial decontamination. Finally, the study identified major drawbacks and provided strategic recommendations to overcome these limitations, including optimizing coating formulations for specific food matrices, tailoring process parameters to minimize adverse physicochemical changes, and conducting pilot-scale validations to bridge the gap between laboratory success and industrial application. Full article

Vitamin B12 (B12) is a strong antioxidant and a cofactor for methionine synthase supporting DNA/RNA/protein methylation. We previously demonstrated that oral high-dose B12 supplement mitigates diabetic cardiomyopathy in Akita diabetic mice expressing twice the normal levels of Elmo1 (Engulfment and cell motility 1). To assess how B12 prevents early kidney damage, we treated Elmo1^HH mice and diabetic Elmo1^HH Ins2^Akita/+ mice with or without B12 in drinking water starting at 8 weeks of age. At 16 weeks, markedly reduced mesangial expansion was detected in the B12-treated diabetic kidneys (22% of glomeruli affected vs. 70% in the untreated diabetic kidneys). RNAseq analysis of the kidneys revealed that B12 suppressed expression of genes for adaptive immune response, while it upregulated those for solute carrier transporters and antioxidant genes. Strikingly, B12 treatment suppressed activators of circadian rhythm, Clock and Bmal1, and upregulated repressors like Cry1/2, Per1-3 and Dbp, suggesting a shift in their rhythmicity. B12 also upregulated linker histone H1 variants, and enhanced chromatin stability and cell cycle regulation. In BU.MPT proximal tubular cells in culture, B12 shifted forward the circadian expression phase of Bmal1 and Per1. Taken together, B12 supplement effectively mitigates early development of diabetic nephropathy in diabetic mice, potentially involving regulation of circadian rhythm. Full article