Search Results (455)

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

Quercetin (QE) is a naturally occurring flavonoid found in many fruits, vegetables, and other plant-based foods. It is recognized for its diverse pharmacological activities. Among its many therapeutic potentials, its antidiabetic properties are of particular interest due to the growing worldwide prevalence of diabetes mellitus. QE improves glycemic control by enhancing insulin sensitivity, stimulating glucose uptake, and preserving pancreatic beta cell function. These effects are mediated by the modulation of key molecular pathways, including AMPK, PI3K/Akt, and Nrf2/ARE, as well as by the suppression of oxidative stress and pro-inflammatory cytokines, such as TNF-α and IL-6. Furthermore, QE mitigates the progression of diabetic complications such as nephropathy, retinopathy, and vascular dysfunction, reducing lipid peroxidation and protecting endothelial function. However, the clinical application of quercetin is limited by its low water solubility, poor bioavailability, and extensive phase II metabolism. Advances in formulation strategies, including the use of nanocarriers, co-crystals, and phospholipid complexes, have shown promise in improving its pharmacokinetics. This review elucidates the mechanistic basis of QE quercetin antidiabetic action and discusses strategies to enhance its therapeutic potential in clinical settings. Full article

Background/Objectives: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). Methods: A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. Results: CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. Conclusions: CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. Full article

Background/Objectives: Adequate vitamin D levels are essential for various physiological functions, including cell growth, immune modulation, metabolic regulation, DNA repair, and overall health span. Despite its proven cost-effectiveness, widespread deficiency persists due to inadequate supplementation and limited sunlight exposure. Methods: This systematic review (SR) examines the relationship between vitamin D and the reduction of cancer risk and mortality, and the mechanisms involved in cancer prevention. This SR followed the PRISMA and PICOS guidelines and synthesized evidence from relevant studies. Results: Beyond genomic actions via calcitriol [1,25(OH)₂D]-receptor interactions, vitamin D exerts cancer-protective effects through mitigating inflammation, autocrine, paracrine, and membrane signaling. The findings reveal a strong inverse relationship between serum 25(OH)D levels and the incidence, metastasis, and mortality of several cancer types, including colon, gastric, rectal, breast, endometrial, bladder, esophageal, gallbladder, ovarian, pancreatic, renal, vulvar cancers, and both Hodgkin’s and non-Hodgkin’s lymphomas. While 25(OH)D levels of around 20 ng/mL suffice for musculoskeletal health, maintaining levels above 40 ng/mL (100 nmol/L: range, 40–80 ng/mL) significantly lowers cancer risks and mortality. Conclusions: While many observational studies support vitamin D’s protective role in incidents and deaths from cancer, some recent mega-RCTs have failed to demonstrate this. The latter is primarily due to critical study design flaws, like recruiting vitamin D sufficient subjects, inadequate dosing, short durations, and biased designs in nutrient supplementation studies. Consequently, conclusions from these cannot be relied upon. Well-designed, adequately powered clinical trials using appropriate methodologies, sufficient vitamin D₃ doses, and extended durations consistently demonstrate that proper supplementation significantly reduces cancer risk and markedly lowers cancer mortality. Full article

Background: Obesity is a growing global health concern and a modifiable risk factor for multiple pancreatic diseases, including acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC). While these conditions have distinct clinical courses, obesity contributes to their pathogenesis through shared mechanisms, such as visceral adiposity, systemic inflammation, insulin resistance, and ectopic pancreatic fat deposition. Methods: This narrative review synthesizes current evidence from clinical, epidemiological, and mechanistic studies exploring the relationship between obesity and pancreatic diseases. We also critically evaluate the effects of weight loss interventions—including lifestyle modifications, pharmacologic therapies, endoscopic approaches, and bariatric surgery—on the risk and progression of disease. Results: Obesity increases the risk and severity of AP via mechanisms such as gallstone formation, hypertriglyceridemia, and lipotoxicity. In CP, obesity-related intrapancreatic fat and metabolic dysfunction may influence disease progression, although some data suggest a paradoxical protective effect. In PC, obesity accelerates tumorigenesis through chronic inflammation, adipokine imbalance, and activation of oncogenic signaling pathways. Weight loss interventions, particularly bariatric surgery and incretin-based therapies (e.g., GLP-1 receptor agonists and dual agonists such as tirzepatide), show promising effects in reducing disease burden and improving metabolic and inflammatory profiles relevant to pancreatic pathology. Conclusions: Obesity plays a multifaceted role in the pathophysiology of pancreatic diseases. Therapeutic strategies targeting weight loss may alter disease trajectories, improve outcomes, and reduce cancer risk. Further research is needed to define optimal intervention strategies and to identify and validate biomarkers for personalized risk assessment and prevention. Full article

Background: Pancreatic adenocarcinoma (PAAD) is an aggressive subtype of pancreatic cancer that is estimated to have a 5-year overall survival rate of only 13%. Most patients present with advanced disease with unpredictable outcomes. The identification of prognostic biomarkers is important to accurately stratify these patients. Methods: We investigated the molecular and survival-related role of ENHO in PAAD by analyzing TGCA mRNA and miRNA data. Survival analysis was conducted using TIMER2.0, “survival”, and “survminer”. Gene set enrichment analysis was conducted using enrichr, while miRNA-mRNA interactions were identified using “multiMiR”. Immune infiltration was assessed using CIBERSORT ABS and ImmuCellAI. Results: We observed that ENHO was strikingly downregulated in PAAD tissues (p = 3.68 × 10⁻⁶⁸), and patients with higher ENHO levels enjoyed significantly better overall survival (HR = 0.597; 95% CI: 0.419–0.852; p < 0.01). Pathway analysis showed that genes co-upregulated with ENHO were enriched for insulin secretion and ion channel activity, whereas those co-downregulated were related to epithelial–mesenchymal transition and extracellular matrix remodeling. Higher ENHO also tracked with increased CD8⁺ T-cell infiltration and correlated positively with PDCD1 and LAG3 but negatively with B7-H3, CD70, and NT5E. Conclusions: Our results point to a protective role for ENHO in pancreatic adenocarcinoma. Full article

Ultraprocessed foods (UPFs), now dominant in global diets, pose health risks that go beyond poor nutrition due to the synergistic effects of compounds in their ultracomplex industrial formulations. This narrative review aims to provide researchers and health professionals in the field of cancer with updated and critical information, as they are often unaware of the complex and evolving evidence linking UPFs to carcinogenesis. The review discusses potential mechanisms through which UPFs may contribute to cancer development, including harmful additives, neo-formed contaminants, and packaging-derived substances, as well as the displacement of protective nutrients found in whole foods. Despite limitations in establishing direct causality, epidemiological studies consistently associate high UPF intake with increased incidence of various cancers, notably colorectal, breast, and pancreatic cancers. These findings reflect a broader paradigm shift in nutritional epidemiology, recognizing that food processing is an essential dimension of diet-related health risks. To mitigate the impact of UPFs, the review emphasizes the need for preventive strategies that integrate clear dietary guidelines, regulatory measures on food labeling and additives, and public education campaigns. Successful international experiences in regulating marketing and improving transparency serve as important references. Moreover, eliminating corporate influence and conflicts of interest is crucial to ensure that public health, rather than industry agendas, guides nutrition policy. As scientific research advances to clarify the mechanisms of action and synergistic effects of harmful compounds in UPFs, coordinated efforts are needed to reduce their consumption and ultimately alleviate the global cancer burden. Full article

Andrographolide, fucoidan, or a combination of both compounds were evaluated to determine their effects on the antiviral response in the Atlantic salmon macrophage-like cell line (SHK-1) infected with infectious pancreatic necrosis virus (IPNV). We assessed the transcript expression levels of key molecules involved in the interferon (IFN)-dependent antiviral response, as well as the viral load in cells treated with these compounds. In non-infected cells, incubation with either fucoidan, andrographolide, or a mixture of both resulted in an increase in the transcript expression of IFNα1 and various interferon-stimulated genes (ISGs). In IPNV-infected cells, treatment with either fucoidan or andrographolide separately did not significantly enhance the antiviral response compared to that of infected cells that had not previously been treated with these compounds. In contrast, the combination of andrographolide and fucoidan led to a marked increase in the transcript expression of viperin and a significant reduction in viral load. Overall, combining andrographolide and fucoidan resulted in a greater reduction in IPNV viral load in infected cells than that noted when the compounds were administered individually. Our findings suggest that pre-incubation with this mixture promotes the establishment of a protective antiviral state against IPNV, likely mediated by an IFN-dependent response. Full article

Background/Objectives: Previous studies have shown that unformulated extracts of Passiflora ligularis leaves exhibit promising antidiabetic activity. This research aimed to demonstrate that formulating the extract into a self-emulsifying drug delivery system (PLE-SEDDS) enhanced its antidiabetic activity in a high-fat-diet/streptozotocin-induced diabetic mouse model. Methods: Blood glucose levels (BGLs) of diabetic mice were monitored during 21 days of oral administration of P. ligularis extract (PLE) and PLE-SEDDS. Control groups included metformin (positive control), vehicle, and SEDDS vehicle (negative controls). The animals underwent an oral glucose tolerance test (OGTT). The oxidative stress markers superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation quantified by malondialdehyde (MDA) levels were measured in the kidney, liver, and pancreas, complemented with histopathological analysis. Additionally, plasma lipid profile parameters were evaluated. Results: The PLE-SEDDS formulation demonstrated superior efficacy compared to the PLE extract in improving antidiabetic outcomes. Animals treated with PLE-SEDDS exhibited a minimal increase in blood glucose levels (11.5%) during the OGTT, compared to 27.4% with PLE and over 77% in the vehicle groups. PLE-SEDDS also showed greater enhancement of SOD and CAT activity, along with a more pronounced reduction in MDA levels, indicating stronger protection against oxidative stress. Histological analysis revealed significant preservation of pancreatic islets, and lipid profile analysis showed greater reductions in triglycerides, cholesterol, and LDL-C, alongside increased HDL-C levels. Conclusions: Altogether, these findings suggest that PLE-SEDDS exhibits superior antihyperglycemic, hypolipidemic, and antioxidant effects compared to the unformulated extract, making this novel formulation a promising option for treating type 2 diabetes mellitus. Full article

Mucin, a heavily glycosylated glycoprotein, serves an important function in forming protective and immune defense barriers against the exterior environment on epithelial surfaces. While secreted-type mucins are involved in mucous production, transmembrane mucins, which contain O-glycosylated tandem repeats, play a pivotal role in cellular signaling, especially in immune modulation and mediating inflammatory response. However, dysregulation in mucin expressions, such as MUC1, MUC2, MUC4, MUC5AC, and MUC16, have been observed in many cancer cells. More specifically, alterations in the expression and glycosylation of MUC1 have been associated with the upregulation of pathways involving the cell proliferation, angiogenesis, migration, and invasion of cancer cells. With mucin’s extensive involvement in cancer biology, several mucin biomarkers, such as CA125, CA19-9, and CEA, have been utilized as diagnostic and prognostic monitoring biomarkers in ovarian, pancreatic, and colon cancer. Vaccines and antibody therapy against abnormal mucin glycosylation have also been investigated for potential therapy for mucin-related cancers that are resistant to traditional chemotherapy agents. Despite the lack of specificity in mucin biomarkers and challenges in efficient drug delivery systems, the current advancement in mucin-targeted immunotherapy highlighted the pivotal potential in developing therapeutic targets to improve cancer prognosis. Full article

Macrobrachium nipponense is an important economic freshwater species in China. Previous research has found that M. nipponense can reproduce under salinity conditions of 10 parts per thousand (ppt) and exhibits a strong ability to adapt to salinity changes in the aquatic environment. The aim of the present study was to identify the molecular mechanism of M. nipponense in terms of saline acclimation by identifying changes in immune response, morphology, and gene expression in the gills under a salinity of 10 ppt. The findings revealed that salinity exposure dramatically stimulated the activities of MDA, Ca²⁺Mg²⁺-ATPase, and CAT, reaching a peak on Day 7 (p < 0.05), indicating that these antioxidant enzymes play essential roles in protecting the body from the damage caused by saline treatment. In addition, we found no obvious morphological changes in the gills, indicating that M. nipponense can adapt well to water environments with such salinity. Transcriptome profiling analysis identified 168, 434, and 944 differentially expressed genes (DEGs) when comparing S0 vs. S1, S1 vs. S4, and S4 vs. S7, respectively. Furthermore, lysosome, apoptosis, amino sugar, and nucleotide sugar metabolism; the cGMP-PKG signaling pathway; pancreatic secretion; and the calcium signaling pathway represented the main enriched metabolic pathways of DEGs in the present study. Lysosome, apoptosis, amino sugar, and nucleotide sugar metabolism and the cGMP-PKG signaling pathway are immune-related metabolic pathways, while pancreatic secretion is an energy-metabolism-related metabolic pathway, suggesting that the immune response and energy metabolism play essential roles in the regulation of saline acclimation in this species. The results from the quantitative real-time PCR analyses of the DEGs were consistent with those from RNA-Seq, indicating the accuracy of the present study. This study provides valuable evidence for the acclimation of M. nipponense to high-salinity aquatic environments, thus indicating the potential for this species to be used in aquaculture programs in saline and alkaline water regions. Full article

Background: Thioredoxin-interacting protein (TXNIP) is a major inhibitor of the thioredoxin (TRX) antioxidant system and an important player in the development and aggravation of intracellular oxidative stress. Although first recognized as a metabolic regulator, recent studies have identified the multifaceted role of this protein in other molecular pathways involving inflammation, apoptosis, and glucose metabolism. Methods: This review aims to highlight the importance of TXNIP in diabetes-related pathophysiology and explore the existing evidence regarding TXNIP’s role in GDM-associated pathogenetic mechanisms, revealing common regulatory pathways. Results: Among other complex diseases, TXNIP has been found upregulated in diabetic pancreatic beta cells, thus contributing to diabetes pathogenesis and its related complications. In addition, depletion of TXNIP has been shown to decrease the negative consequences of excessive stress in various cellular systems and diseases, pointing towards a potential therapeutic target. In line with these findings, TXNIP has been investigated in the pathogenesis of Gestational Diabetes Mellitus (GDM), a common pregnancy complication affecting the mother and the neonate. Overexpression of TXNIP has been found in GDM placentas or trophoblast cell lines mimicking GDM conditions and has been associated with key dysregulated mechanisms of GDM pathophysiology, like oxidative stress, inflammation, apoptosis, impaired autophagy, altered trophoblast behavior, and placental morphology. Interestingly, TXNIP has been found upregulated in GDM maternal serum and downregulated in umbilical cord blood, indicating potential compensatory protective mechanisms to GDM-related oxidative stress. Conclusions: Due to its contribution to the regulation of critical cellular processes such as inflammation, metabolism, and apoptosis, TXNIP finds its place in the pathophysiology of gestational diabetes through a currently limited number of scientific reports. Full article

Type 1 Diabetes Mellitus (T1D) is a disease characterized by the destruction of pancreatic beta cells. The subsequent loss of insulin production results in hyperglycemia, muscle wasting, and vascular dysfunction. Due to an inability to appropriately maintain glucose homeostasis, patients afflicted with T1D suffer from increased morbidity and early mortality. Skeletal muscle is the body’s largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream and physical exercise is known to improve and prevent the progression of pathological outcomes, but many T1D patients are unable to exercise at a level that conveys benefit. Thus, directly targeting muscle mass and function may prove beneficial for improving T1D patient outcomes, independent of exercise. A potent negative regulator of skeletal muscle has been identified as being upregulated in T1D patients, namely the myokine myostatin. Our hypothesis is that targeting myostatin (via genetic deletion) will prevent glucose dysfunction in a T1D model, preserve skeletal muscle function, and protect against vascular and renal dysfunction. Our methods utilized adult male mice with (WT) and without myostatin (Myo KO), in combination with the chemical induction of T1D (streptozotocin). Experimental outcomes included the assessment of glucose homeostasis (plasma glucose, HbA1c, IGTT), metabolism, muscle function (in vivo plantarflexion), and skeletal muscle vascular function (ex vivo pressure myography). Our results described systemic benefits from myostatin deletion in the T1D model, independent of insulin, including the following: inhibition of T1D-induced increases in plasma glucose, prevention of functional deficits in muscle performance, and preservation of fluid dynamics. Further, endothelial function was preserved with myostatin deletion. Taken together, these data inform upon the use of myostatin inhibition as a therapeutic target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1D. Full article

Objectives: This study engineered a colon-targeted drug delivery system (CTDS) using the dual pharmaceutical and edible properties of Pueraria lobata to encapsulate Lactobacillus paracasei for Type 2 diabetes mellitus (T2DM) therapy. Methods: The CTDS was designed as a core–shell composite through microwave–hydrothermal engineering, comprising the following: (1) a retrograded starch shell with acid/enzyme-resistant crystallinity to protect probiotics from gastric degradation; (2) a porous cellulose core derived from Pueraria lobata’s natural microstructure, serving as a colonization scaffold for probiotics. Results: Structural characterization confirmed the shell’s resistance to acidic/pancreatic conditions and the core’s hierarchical porosity for bacterial encapsulation. pH/enzyme-responsive release kinetics were validated via fluorescence imaging, demonstrating targeted probiotic delivery to the colon with minimal gastric leakage. In diabetic models, the CTDS significantly reduced fasting blood glucose and improved dyslipidemia, while histopathological analysis revealed restored hepatic and pancreatic tissue architecture. Pharmacologically, the system acted as both a probiotic delivery vehicle and a microbiota modulator, selectively enriching Allobaculum and other short-chain fatty acid (SCFA)-producing bacteria to enhance SCFA biosynthesis and metabolic homeostasis. The CTDS further exhibited direct compression compatibility, enabling its translation into scalable oral dosage forms (e.g., tablets). Conclusions: By integrating natural material engineering, microbiota-targeted delivery, and tissue repair, this platform bridges the gap between pharmaceutical-grade probiotic protection and metabolic intervention in T2DM. Full article

Natural polysaccharides (NPs), as a class of bioactive macromolecules with multitarget synergistic regulatory potential, exhibit significant advantages in diabetes intervention. This review systematically summarizes the core hypoglycemic mechanisms of NPs, covering structure–activity relationships, integration of the gut microbiota–metabolism–immunity axis, and regulation of key signaling pathways. Studies demonstrate that the molecular weight, branch complexity, and chemical modifications of NPs mediate their hypoglycemic activity by influencing bioavailability and target specificity. NPs improve glucose metabolism through multiple pathways: activating insulin signaling, improving insulin resistance (IR), enhancing glycogen synthesis, inhibiting gluconeogenesis, and regulating gut microbiota homeostasis. Additionally, NPs protect pancreatic β-cell function via the nuclear factor E2-related factor 2 (Nrf2)/Antioxidant Response Element (ARE) antioxidant pathway and Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) anti-inflammatory pathway. Clinical application of NPs still requires overcoming challenges such as resolving complex structure–activity relationships and dynamically integrating cross-organ signaling. Future research should focus on integrating multi-omics technologies (e.g., metagenomics, metabolomics) and organoid models to decipher the cross-organ synergistic action networks of NPs, and promote their translation from basic research to clinical applications. Full article