Search Results (2,987)

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic relapsing–remitting condition characterized by systemic and intestinal inflammation and immune dysregulation. Up to 47% of IBD patients develop extraintestinal manifestations, yet kidney and urological involvement remain underrecognized. Accumulating evidence has linked IBD to nephrolithiasis, glomerular diseases, tubulointerstitial nephritis, acute kidney injury, chronic kidney disease, and, rarely, amyloid A amyloidosis. Population studies have consistently shown elevated risks for various important kidney disorders in IBD, with CD generally posing a greater risk than UC. The pathogenesis of kidney complications in IBD reflects complex gut–kidney interactions, including metabolic and absorptive abnormalities, shared genetic and immune pathways, intestinal dysbiosis with nephrotoxic microbial metabolites, systemic inflammation, and drug-related nephrotoxicity. Strategies for kidney protection in IBD include increased awareness, close monitoring of kidney function, urinary metabolic profiling in high-risk patients, and prompt nephrology referral for early detection and treatment. Management should include an effective and sustained control of intestinal inflammation, discontinuation of potential nephrotoxic drugs when indicated, and timely diagnosis and treatment of kidney manifestations, as well as integrating kidney complications into IBD guidelines to enhance awareness, ultimately optimizing both the kidney and overall outcomes for IBD patients. Future studies are needed to validate the potential predictive biomarkers for kidney complications and to develop targeted interventions to address shared gut–kidney pathogenic mechanisms in IBD. Full article

There is a bidirectional relationship between chronic kidney disease (CKD) and an altered gut microbiome, with gut-derived uremic toxins contributing to cardiovascular-kidney-metabolic effects. In this review, we summarize the interplay between diet, the intestinal microbiota and systemic sequelae including CKD progression, cardiovascular morbidity and cognitive decline. We discuss the current state of knowledge regarding microbiota-modulating therapies that have the potential to delay CKD complications such as plant-dominant diets, oral adsorbents, prebiotics/probiotics, fecal microbiota transplantation and exercise. Full article

Background and Objectives: SGLT2 inhibitors increase hemoglobin and hematocrit in multiple clinical settings, an effect increasingly attributed to stimulation of erythropoiesis rather than hemoconcentration. However, most mechanistic evidence derives from diabetic populations, leaving uncertainty as to whether this response depends on diabetes-related metabolic changes. To evaluate whether dapagliflozin stimulates erythropoiesis in non-diabetic patients with heart failure and to determine whether hematologic changes correlate with renal, cardiac, inflammatory, hepatic, or iron-related parameters. Materials and Methods: In this retrospective observational study, each of 68 non-diabetic heart failure patients served as their own control. Hematologic, renal, cardiac, inflammatory, hepatic, and iron parameters were assessed at three time points: one year prior to dapagliflozin initiation, at baseline, and one year after initiation of therapy. Changes were analyzed using paired tests and correlation analyses. Results: Hemoglobin, hematocrit, and red blood cell count were significantly lower at the baseline compared with values recorded one year before dapagliflozin initiation and increased significantly during the year following treatment (all p < 0.001), while mean corpuscular indices remained stable. Serum iron decreased before treatment and increased significantly after dapagliflozin initiation (p < 0.05 vs. baseline); however, changes in serum iron did not correlate significantly with changes in hemoglobin after treatment. Inflammatory markers showed a modest reduction in C-reactive protein after treatment, while composite inflammatory indices remained largely stable. Liver enzymes showed no significant longitudinal changes. Correlation analyses demonstrated no association between changes in hemoglobin and changes in eGFR (ρ = 0.202, p = 0.098) or NT-proBNP (ρ = −0.003, p = 0.981) after treatment. Hematologic variables remained strongly intercorrelated, whereas cross-system correlations were minimal, indicating that erythropoietic stimulation occurred largely independently of renal or cardiac functional trajectories. Conclusions: Dapagliflozin robustly stimulates erythropoiesis in non-diabetic patients with heart failure, independent of improvements in kidney or cardiac function. Although serum iron levels improved after treatment, the absence of a direct correlation with hemoglobin suggests that iron mobilization may act as a permissive rather than a primary driver of erythropoietic response. These findings support the concept that erythropoiesis represents a diabetes-independent pharmacologic action of SGLT2 inhibitors and may involve renal, hepatic, inflammatory, and iron-regulatory pathways beyond those described in diabetic physiology. Dedicated mechanistic studies in non-diabetic populations are warranted. Full article

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on clinical, genetic, and molecular predictors of tirzepatide response and discuss their implications for a precision medicine framework. Data from pivotal clinical trials, post hoc analyses, and relevant preclinical and clinical studies were evaluated to identify determinants of glycemic and weight loss responses, as well as hepatic and renal protective effects. Key clinical predictors include tirzepatide dose, duration of diabetes, β-cell function, baseline glycated hemoglobin, sex, age, race, concomitant therapies, and early treatment response. Genetic factors implicated in treatment variability include variants in GLP-1 receptor, GIP receptor, β-arrestin 1, transcription factor 7-like 2, fat mass and obesity-associated protein, and melanocortin 4 receptor, although tirzepatide-specific validation remains limited. Molecular biomarkers such as branched-chain amino acids, insulin-like growth factor–binding protein-1 and -2, the adiponectin-to-leptin ratio, high-sensitivity C-reactive protein, and interleukin-6 show potential as pharmacodynamic indicators of metabolic response. For organ-specific outcomes, procollagen type III N-terminal peptide and magnetic resonance imaging–proton density fat fraction are supported for assessing hepatoprotective effects, while cystatin C–based estimated glomerular filtration rate and urine albumin-to-creatinine ratio are validated markers of renoprotection. Additional candidates—including tumor necrosis factor receptor 1/2, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin—are promising but require prospective validation. Overall, predicting response to tirzepatide’s multifaceted therapeutic effects necessitates an integrated, multidimensional approach that incorporates clinical characteristics, genetic variation, and molecular profiling. Ongoing validation and harmonization of these predictors may help establish a precision medicine framework for optimizing tirzepatide therapy. Full article

Objectives: Obesity precipitates excessive lipid accumulation within the kidney, culminating in ectopic lipid deposition that compromises target organ function through lipotoxicity. Given the pivotal role of GDF15 in lipid metabolism, this study aims to determine whether GDF15 can ameliorate ectopic lipid deposition and mitigate the resulting renal injury. Methods: C57BL/6J mice were used to establish a high-fat diet-induced obesity model. Based on Lee’s index, the mice were categorized into a diet-induced obesity group and an obesity-resistant group. Subsequently, the diet-induced obesity group received an injection of AAV-shGFRAL to knock down the GFRAL receptor. Results: In obesity resistant mice, ectopic lipid deposition in the kidneys was markedly reduced, accompanied by decreased expression of the renal injury marker KIM-1 and significantly elevated levels of GDF15. Modulation of the GDF15-GFRAL axis demonstrated that reduced autophagy levels led to increased lipid accumulation and exacerbated renal injury. Conversely, GDF15 activates the AMPK/SIRT1 signaling pathway to promote cellular autophagy, thereby mitigating renal damage induced by ectopic lipid deposition. Consistent with this mechanism, the suppression of autophagy results in the aggravation of renal injury caused by ectopic lipid accumulation. Conclusions: GDF15 ameliorates renal injury induced by ectopic lipid deposition in the kidney primarily through activation of autophagy via the AMPK/SIRT1 signaling pathway. Full article

Cardio-renal metabolic (CRM) syndrome, characterized by insulin resistance and dyslipidemia, disrupts renal insulin signaling, enhances oxidative stress, and activates inflammasome pathways, ultimately promoting renal fibrosis and kidney dysfunction. Aberrant renal gluconeogenesis has emerged as a critical contributor to tubular injury under cardiometabolic stress; however, its mechanistic linkage to inflammatory and fibrotic remodeling remains incompletely defined. In this study, ApoE^−/− mice subjected to streptozotocin administration and a high-fat diet developed pronounced cardiometabolic dysfunction, accompanied by elevated blood urea nitrogen, creatinine, uric acid, and glycated hemoglobin levels, as well as severe renal histopathological alterations. N-Acetylcysteine (NAC) supplementation significantly improved metabolic abnormalities and attenuated tubular dilation, glomerular hypertrophy, and mesangial expansion. Mechanistically, NAC suppressed renal gluconeogenesis by downregulating glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression and mitigated epithelial–mesenchymal transition by restoring E-cadherin and reducing vimentin expression, thereby limiting fibrotic remodeling. Consistent with in vivo findings, NAC reduced reactive oxygen species production, restored PI3K/Akt-dependent insulin signaling, and inhibited inflammasome activation in NRK-52E renal tubular cells exposed to high glucose and oleic acid, resulting in attenuation of inflammatory signaling and gluconeogenic activity. Collectively, these results demonstrate that NAC mitigates cardiometabolic stress-induced renal injury by modulating inflammasome activation and gluconeogenic reprogramming, highlighting its potential as a mechanistic modulator of renal fibrosis under CRM conditions. Full article

Background/Objectives: Excessive dietary inorganic phosphate (Pi) as a food additive poses potential health risks. Methods: This study investigated the impact of excessive dietary inorganic phosphate on intestinal and immune homeostasis in mice using gradient Pi exposure combined with an inflammatory model. Results: Pi overload induced atrophy in the thymus, spleen, and kidney; damaged the intestinal barrier; reduced the villus height-to-crypt-depth ratio; and decreased goblet cell numbers. Altered levels of serum sIgA and IgE, as well as intestinal IgA, IgG, IgE, and IgM, together with decreased IFN-α, indicated altered levels of immunoglobulins and cytokines under Pi treatment. Proteomic analysis revealed differential expression of key proteins, including CNTFR and Bcl2l1 in the JAK/STAT pathway and metabolic regulators CPT1α and IDH1, when comparing Pi-treated mice with the control group. Conclusions: These preliminary findings suggest that Pi may affect intestinal mucosal barrier function and systemic immune response through immune regulation and mitochondrial metabolic pathways, providing preliminary insight into the potential health implications of Pi overconsumption in humans. Full article

Acute kidney injury (AKI) lacks targeted pharmacological interventions. While the DanShen–DaHuang (DS-DH) herb pair shows clinical potential for AKI treatment, and our prior study has validated its nephroprotective efficacy in a cisplatin-induced murine model, its specific molecular targets within the renal microenvironment remain undefined. In this study, we integrated network pharmacology and weighted gene co-expression network analysis (WGCNA) to screen AKI-related targets of the DS-DH pair. A multi-algorithmic machine learning pipeline (including LASSO, Boruta, Random Forest, GBM, XGBoost, and Decision Trees) was utilized to calculate feature importance scores and rank core genes. Subsequently, single-cell RNA sequencing (scRNA-seq) data (GSE197266) were analyzed for transcriptomic mapping, pseudotime trajectory, and cell–cell communication. Finally, molecular docking evaluated theoretical binding affinities. After database screening, a total of 603 drug–disease intersecting targets were obtained. Subsequently, 917 module genes significantly associated with AKI were identified by WGCNA, and 62 core candidate genes were determined after intersecting with the above targets. Multi-algorithm machine learning ranked the importance of the 62 targets, with transketolase (TKT) ranking the highest. To elucidate the mechanism of TKT in AKI, scRNA-seq analysis was performed on 77,593 high-quality cells. The results showed that Tkt was specifically enriched in renal macrophages, with the highest expression in the M2-polarized subset. Pseudotime analysis further revealed that Tkt expression dynamics were highly synchronized with the differentiation trajectory of M2 macrophages and positively correlated with the repair markers Arg1 and Mrc1. Cell–cell communication analysis predicted that Tkt⁺ M2 macrophages act as active communication hubs via the Spp1 and Mif signaling axes. Molecular docking validated the favorable binding affinity between core DS-DH compounds and the TKT active pocket. This computational framework predicts that the DS-DH herb pair might mitigate AKI by potentially targeting TKT, a metabolic enzyme closely associated with macrophage M2 polarization. By prioritizing targets via multi-algorithmic scoring, we provide a data-driven rationale and candidate targets for future experimental validation. Full article

Epimedium is a traditional Chinese tonic used to tonify the kidneys, enhance sexual function, and strengthen muscles and bones. However, the potential effects of Epimedium on the semen quality of Bama boars remain incompletely elucidated. The objective of this study was to evaluate the effects of dietary Epimedium ultrafine powder (EP) supplementation on the semen quality of Bama boars and to explore the underlying mechanisms. The objective of this study was to evaluate the effects of dietary EP supplementation on the semen quality of Bama boars and to explore the underlying mechanisms. Eighteen healthy, sexually mature adult male Bama boars were randomly divided into three groups (n = 6) and fed either a basal diet (CON) or the basal diet supplemented with 0.3% (EP3) or 0.5% (EP5) Epimedium ultrafine powder for five weeks. This study employed enzyme-linked immunosorbent assay (ELISA), 16S RNA gene sequencing, non-targeted metabolomics (CON and EP5), and Spearman correlation analysis, among other methods. The results indicated that dietary Epimedium (0.3% and 0.5%) increased the levels of serum TP, FSH, and SOD and decreased the abnormal sperm rate and the levels of serum TBA, TNF-α, and IL-6. Among them, adding 0.5% Epimedium in the diet increased sperm motility and the levels of serum T, LH, and IgG. 16S rRNA gene sequencing analysis revealed that both 0.3% and 0.5% Epimedium supplementation reduced the abundance of Streptococcus. Specifically, the 0.3% dose decreased Prevotella abundance, while the 0.5% dose reduced Escherichia-Shigella abundance. PICRUSt2 analysis revealed that the pathways of phenylalanine, butanoate, biotin, and arachidonic acid metabolism were significantly enriched in the Epimedium group. A non-targeted metabolomics analysis identified that indole-3-acrylic acid, DL-tryptophan, 2-hydroxyphenylalanine, and propionylcarnitine showed significant upregulation after Epimedium supplementation. Spearman correlation analysis indicated that Streptococcus was negatively correlated with sperm motility and serum-related parameters (TP, T, LH, IgM, and IgG). Streptococcus and Escherichia-Shigella were negatively correlated with indole-3-acrylic acid, DL-tryptophan, and biotin. In conclusion, Epimedium has a positive impact on the seminal quality, reproductive hormones, and immune–antioxidant levels of Bama boars by regulating the composition and metabolites of the intestinal microbiota. Full article

Chronic kidney disease–mineral and bone disorder (CKD-MBD) is a major complication of end-stage renal disease and is associated with increased morbidity and mortality. Sclerostin, an osteocyte-derived glycoprotein that inhibits the Wnt/β-catenin signaling pathway, has been implicated in the dysregulation of bone metabolism in dialysis patients. However, comparative data on sclerostin levels and their clinical determinants between hemodialysis (HD) and peritoneal dialysis (PD) patients remain limited, particularly in Southeast Asian populations. This cross-sectional study was conducted at Hue Central Hospital, Vietnam, between June 2023 and January 2026. A total of 89 end-stage renal disease patients were consecutively enrolled (HD: n = 51; PD: n = 38). Median serum sclerostin levels were 584.21 (IQR: 301.18–1479.50) pg/mL in the HD group and 684.21 (IQR: 407.48–940.35) pg/mL in the PD group, with no significant difference between groups (p = 0.839). Serum sclerostin was inversely correlated with PTH in both HD (r = −0.444, p = 0.001) and PD patients (r = −0.341, p = 0.036). In the HD group, total femur BMD showed a significant inverse correlation with sclerostin (r = −0.304, p = 0.030). In multivariable analysis, Log_PTH remained an independent predictor of sclerostin across all three sequential models in the HD group (Model 1: B = −0.340, p = 0.001; Model 2: B = −0.270, p = 0.035; Model 3: B = −0.268, p = 0.039; adjusted R² range: 0.197–0.217) and in the combined HD + PD cohort (Model 1: B = −0.271, p < 0.001; Model 2: B = −0.263, p < 0.001; Model 3: B = −0.249, p = 0.003; adjusted R² range: 0.141–0.158). In the PD subgroup, Log_PTH was significant in Models 1 and 2 but not in Model 3; none of the models reached overall statistical significance (all p ≥ 0.081), and findings should be considered exploratory given the limited sample size. Serum sclerostin levels did not differ significantly between HD and PD patients. PTH was the most consistent independent predictor of sclerostin across dialysis modalities and analytical models, underscoring its central role in CKD-MBD pathophysiology. Larger prospective multicenter studies are warranted to validate these findings and further clarify the clinical utility of sclerostin in dialysis populations. Full article

There are currently no published methods for the controlled introduction of microplastic particles into the European rabbit (Oryctolagus cuniculus) as an animal model. The aim of this pilot study was to establish a novel rabbit-based experimental model for assessing the impact of microplastic particles by evaluating the physiological and biochemical responses to an eight-day oral administration of polystyrene latex (1 and 5 mg/kg/b.w./day), providing a foundation for future studies. This study was also aimed at evaluating the possibility of using Raman spectroscopy and Fourier-transform infrared spectroscopy to analyze the distribution of microplastics in rabbit samples. We observed a dose-dependent decrease in water and food consumption in the high-dose (5 mg/kg) study group. In addition, a decrease in alanine aminotransferase and total calcium levels, along with an increase in phosphorus levels, was detected. The rabbit’s stomach was the only organ where polystyrene microparticles were identified, with the colon, kidneys, ovaries, and uterus not showing any evidence of polystyrene presence. The selected doses of microplastics did not lead to pronounced toxic effects in rabbits and may be used on larger animal samples. Physiological and biochemical data obtained indicate predominantly negative metabolic shifts associated with the intake of microplastics, which warrants further study. Full article

Oxidative stress and inflammation are key drivers of kidney injury and disease progression. In this context, the role of sialic acids emerged as a critical regulatory layer linking redox imbalance, immune activation, and tissue damage. Sialic acids are terminal negatively charged residues that regulate complement activity, immune cell signaling, and the structural integrity of the glomerular filtration barrier. Alterations in sialylation, resulting from impaired biosynthesis or increased sialidase activity, disrupt immune homeostasis, enhance inflammatory responses, and promote complement-mediated injury. In the kidney, these mechanisms contribute to podocyte dysfunction, glomerular inflammation, and fibrosis and are implicated in glomerulopathies, transplantation, and plasma cell dyscrasias. Emerging evidence also highlights the therapeutic potential of targeting sialic acid metabolism through inhibition of desialylation or restoration of sialylation pathways. Overall, sialic acids represent dynamic modulators at the intersection of oxidative stress and immunity, offering novel opportunities for biomarker development and mechanism-based therapies in kidney disease. Full article

Background: In chronic kidney disease (CKD) treatment, a holistic approach, which involves not only nephrologists but also nutritionists, sports physicians, and kinesiologists, is becoming increasingly important, characterized as including not only pharmacological therapy but also integrative treatments, i.e., nutritional therapies (like low protein diet-LPD) and adapted physical exercise (APE) programs. The aim of this study was to evaluate the potential adjuvant therapeutic role of an integrated APE + LPD program on CKD comorbidities, comparing its additional beneficial effects with those induced by the LPD alone. Methods: This clinical study is a randomized controlled trial, where 40 CKD patients (stage G3b-G5) were enrolled and divided into two homogeneous groups: an APE + LPD group, which performed an online APE protocol combined with LPD; and an LPD group, which received only LPD. All enrolled patients were evaluated at baseline (T₀) and after 12 weeks (T₁) for clinical and body composition parameters and for functional assessment and health-related quality of life (HRQoL). Results: Both groups showed a significant reduction in lipid and glucose metabolism parameters. Good adherence to the prescribed LPD led to significantly better control of systolic blood pressure and electrolytes, along with an increase in venous bicarbonate levels. Improvements in body composition and physical performance were also observed. In the APE + LPD group only we observed a significant increase in neutrophil count, serum iron levels, muscle strength, and patients’ HRQoL. Conclusions: Our results suggest that the integrated approach, rather than the LPD alone, is more effective for muscle-related outcomes, HRQoL, and in the positive modulation of the immune system. Full article

Background: Cancer cells exhibit metabolic reprogramming characterized by increased dependence on glutamine to sustain rapid proliferation and biosynthetic demands. Kidney-type glutaminase (KGA), which catalyzes the first and rate-limiting step of glutamine metabolism, represents a promising therapeutic target, particularly in triple-negative breast cancer (TNBC), an aggressive sub-type lacking effective targeted therapies. This study evaluated 2-amino-4-boronobutyric acid (ABBA), a boronic acid-containing glutamine analog, as a potential KGA inhibitor with anticancer activity. Methods: KGA inhibition was assessed using a fluorometric enzymatic assay. Cytotoxic effects were examined in multiple TNBC cell lines. Covalent docking and molecular simulation analysis were performed to characterize interactions between ABBA and the KGA active site. Results: ABBA potently inhibited KGA activity, with an IC₅₀ of approximately 1.0 μM, demonstrating greater efficacy than several non-proteinogenic amino acid analogs. ABBA induced dose-dependent cytotoxicity across multiple TNBC cell lines, with pronounced sensitivity observed in basal sub-type cells and cellular sensitivity correlated with KGA expression levels. Expression of γ-glutamyl transpeptidase 1 (GGT1) was negligible, and, excluding any off-target effects, the observed anticancer effects are primarily attributed to KGA inhibition. Docking analysis indicated that ABBA forms a reversible covalent adduct with the catalytic Ser286 residue of KGA in a boronate tetrahedral geometry resembling transition-state mimics, while molecular simulation demonstrated stabilization of the complex through hydrogen bonding and electrostatic interactions. Conclusions: ABBA is a potent boron-based glutaminase inhibitor with therapeutic potential for targeting glutamine metabolism in TNBC. Further structural optimization and in vivo evaluation are warranted to advance ABBA toward therapeutic development. Full article

Background: Pulmonary fibrosis (PF) is a chronic, progressive lung disease with limited treatment options. Liuweidihuang pill (LDP), a classical formula for kidney-yin deficiency, has been reported to have anti-inflammatory and anti-oxidative activities, suggesting potential relevance to PF. Purpose: This study evaluated whether LDP attenuates bleomycin-induced PF in mice and whether gut microbiota remodeling may contribute to its protective effects. Methods: Mice received intratracheal bleomycin followed by LDP gavage. Lung pathology was assessed by hematoxylin–eosin (HE) and Masson staining. Inflammatory cytokines, hydroxyproline (HYP), and α-SMA were measured. LDP and LDP-containing serum were profiled by UPLC-MS. The gut microbiota was analyzed using 16S rDNA sequencing. To further explore whether microbiota-related changes were associated with the protective phenotype, fecal microbiota transplantation (FMT) and probiotic VSL#3 intervention were performed. In addition, LDP-containing serum was tested in a TGF-β1-induced EMT model in A549 cells. Results: LDP reduced lung index, inflammatory infiltration, interstitial fibrosis, α-SMA expression, HYP content, and pro-inflammatory cytokine levels in bleomycin-treated mice. These effects were accompanied by gut microbiota remodeling and transcriptomic changes related to inflammation, metabolism, and fibrosis. VSL#3 partially reproduced the protective phenotype, whereas FMT showed limited efficacy. LDP-containing serum had a limited inhibitory effect on EMT inhibited EMT in vitro, suggesting that systemic host responses may contribute to the in vivo effect. Conclusions: LDP attenuated early bleomycin-induced PF and was associated with reduced inflammation and gut microbiota remodeling. These findings suggest a possible role for microbiota–host interactions in LDP-associated protection; however, causal directionality, key active effectors, and protein-level pathway validation remain unresolved. Full article