Search Results (1,189)

Background/Objectives: Antimicrobial resistance (AMR) is a critical global public health challenge driven by inappropriate and excessive antimicrobial use (AMU) across human, animal, and environmental sectors. Method: This narrative review synthesizes recent evidence on antimicrobial utilization and resistance patterns. A structured search of PubMed, Scopus, and Web of Science was conducted for studies published between 2015 and 2025. Eligible sources included surveillance reports, registry-based analyses, and clinical studies. Data were qualitatively analyzed to identify key trends and regional variations. Result: Marked geographical variation in AMR was observed. Carbapenem resistance in Escherichia coli remains low globally (2–3%) but is higher in Southeast Asia (17–18%) and India (~40%). Klebsiella pneumoniae shows consistently high resistance (>40% globally; ~54% in India), while Pseudomonas aeruginosa exhibits stable resistance levels (35–45%). Resistance prevalence increases from primary to tertiary care settings, reflecting greater antimicrobial exposure. Vulnerable populations—including pediatric, elderly, pregnant, and immunocompromised patients—face higher risks of antimicrobial exposure and adverse outcomes, including nephrotoxicity, hepatotoxicity, and microbiome disruption. WHO AWaRe data indicate a global shift toward increased use of Watch-category antibiotics. Stewardship interventions, such as audit and feedback, prescribing restrictions, rapid diagnostics, and decision support systems, effectively reduce inappropriate AMU. Conclusions: Integrated, data-driven antimicrobial stewardship and robust surveillance systems are essential to mitigate the global burden of AMR. Full article

Background/Objectives: Non-small-cell lung cancer (NSCLC) involves oxidative stress and inflammation, driving chemoresistance. Paclitaxel (PTX), a first-line chemotherapy, is limited by these factors. Danggui Buxue Tang (DBT), a polyphenolic-rich traditional Chinese herbal formula, was investigated for its ability to potentiate PTX efficacy by inducing ferroptosis via the Nrf2/GPX4 axis. Methods: Effects of DBT + PTX on cell viability, lipid peroxidation, iron accumulation, and Nrf2/GPX4/SLC7A11 expression were evaluated in A549/HCC827 cells with/without ferrostatin-1 (Fer-1). Findings were validated in an A549 xenograft model. Results: DBT significantly enhanced PTX’s anti-tumor effects in vitro and in vivo, an effect reversed by Fer-1. Combination therapy increased ROS, MDA, and iron while suppressing GPX4/SLC7A11 and promoting Nrf2 nuclear translocation. DBT + PTX synergistically reduced tumor volume and proliferation markers (Ki67/PCNA). Crucially, DBT attenuated PTX-induced hepatotoxicity and nephrotoxicity. Conclusions: DBT potentiates PTX efficacy in NSCLC by disrupting the Nrf2/GPX4 axis to induce ferroptosis while mitigating chemotherapy-related toxicity, supporting its potential as an adjuvant strategy targeting oxidative stress pathways. Full article

Paracetamol (PAR) overdose is a major cause of drug-induced liver injury and is also associated with renal toxicity, both involving mitochondrial dysfunction and oxidative stress. This study investigated the dose- and organ-specific effects of the mitochondria-targeted antioxidant MitoTempo (MT) on PAR-induced hepatorenal toxicity in mice. Male C57BL/6J mice received a single toxic dose of PAR (600 mg/kg), either alone or combined with MT (20 or 40 mg/kg). Twenty-four hours after treatment, serum markers of liver and kidney injury were measured, and mitochondrial function was assessed in both organs. PAR administration caused severe liver injury and moderate renal dysfunction, accompanied by increased mitochondrial oxidative stress, glutathione imbalance, mitochondrial permeability transition pore opening, and disruption of electron transport chain (ETC) integrity. MT co-treatment attenuated several PAR-induced mitochondrial alterations in a dose- and tissue-dependent manner; however, MT did not consistently confer protection and, in some settings, exacerbated oxidative stress and bioenergetic dysfunction, particularly in the kidney. Notably, recovery of ETC protein levels by MT was not consistently associated with restoration of enzymatic activity. Overall, these findings demonstrate that MT exerts dual, dose- and organ-specific effects on PAR-induced mitochondrial dysfunction, highlighting that mitochondria-targeted antioxidants are not universally protective. Full article

The dose–response relationship for fluoride (F⁻) exposure remains largely unexplored. Hence, the current study assessed the hepatotoxic and nephrotoxic effects of subacute exposure (28 days) to increasing F⁻ concentrations in Wistar rats via the benchmark dose (BMD5) method. Thirty male rats were assigned to six groups (n = 5): a control group (tap water) along with five groups that received F⁻ via drinking water at increasing concentrations (10, 25, 50, 100, and 150 mg/L). F⁻ toxicity was determined via water intake, weight gain, histological analyses, redox status, and essential element levels. PROASTweb 70.1 software was utilized to investigate the external and internal F⁻ dose–response relationships. Specified major cytoarchitecture damage and superoxide anion (O₂·⁻), total oxidative status (TOS), superoxide dismutase (SOD) activity, total thiol groups (SH), and advanced oxidation protein product (AOPP) level alterations were detected in both sets of tissues. Moreover, F⁻ caused an imbalance in copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn). The most sensitive parameters were O₂·⁻ (0.06 mg F⁻/kg) in the liver and AOPP (6.5 × 10⁻⁶ mg F⁻/L) in the kidneys. These findings contribute to the limited risk assessment of fluorides and highlight the dose-dependent relationship between redox status parameters and bioelements in the liver and kidneys. Full article

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI) and subsequent chronic kidney disease. Nephrotoxicity often develops as a consequence of treatment with commonly prescribed aminoglycoside antibiotics, and remains a significant clinical challenge. One approach to treating AKI and its associated complications is caloric restriction or its pharmacological mimetics. This study aimed to evaluate the effects of caloric restriction mimetic hydroxycitrate (HC) in gentamicin-induced nephrotoxicity, with particular focus on the influence of treatment duration and the underlying molecular mechanisms. In vitro renal tubular epithelial cells models were used to assess HC’s effects on viability, proliferation, and autophagy activation. For in vivo validation, rats with gentamicin-induced AKI received HC treatment via two distinct regimens (3-week and 7-week administration). Experiments on renal tubule cells showed that HC significantly increased cell viability and proliferation and led to the activation of autophagy. In the rat model, only the 7-week administration of HC demonstrated significantly attenuated renal dysfunction in gentamicin-induced AKI. Moreover, it reduced macrophage infiltration, increased renal cell tolerance to apoptosis, activated autophagy, and reduced oxidative stress. Thus, our results indicate that 7-week HC administration could be used as a prophylactic strategy against antibiotic nephrotoxicity, exerting its effects by promoting autophagy, resisting apoptosis, and attenuating oxidative damage. Full article

The aging of the population and the increasing prevalence of multimorbidity contribute to the widespread use of polypharmacotherapy, which in turn elevates the risk of adverse drug reactions and clinically significant drug–drug interactions. One of the key yet frequently underestimated issues in clinical practice is the prescribing cascade, which occurs when an adverse drug reaction is misinterpreted as a new medical condition, leading to the initiation of an additional medication. This phenomenon is particularly relevant in the older population, in whom altered pharmacokinetics and pharmacodynamics, together with reduced organ reserve, increase susceptibility to adverse drug events, including nephrotoxicity (renal impairment is used throughout the review as a clinically relevant example of organ-specific harm resulting from prescribing cascades, rather than as the sole focus of the analysis). This article discusses the mechanisms and clinical consequences of the prescribing cascade—with particular emphasis on renal function deterioration—as well as strategies for its prevention in the geriatric population. Analysis of the literature indicates that prescribing cascades remain insufficiently recognized in clinical practice, despite the availability of pharmacotherapy assessment tools such as The American Geriatrics Society (AGS) Beers Criteria and the STOPP/START criteria. Documented prescribing cascades have been shown to contribute to deterioration in health status and quality of life, an increased frequency of hospitalizations, and a greater burden on healthcare systems. Particularly concerning are cascades involving cardiovascular, neurological, and analgesic medications, which may induce or exacerbate renal injury, ultimately leading to chronic kidney disease and organ failure. Prescribing cascades represent a significant yet frequently underestimated threat to the efficacy and safety of pharmacotherapy in older adults. Their consequences may extend beyond reduced quality of life and increased treatment costs to include serious complications such as the development of renal failure. Enhancing clinicians’ awareness, conducting systematic medication reviews, and employing validated assessment tools are essential for the identification and prevention of prescribing cascades, thereby reducing the risk of renal injury and improving clinical outcomes. Full article

Acute kidney injury (AKI) is a major complication of lupus nephritis and kidney transplantation, inevitably causing ischemia–reperfusion (I/R) injury. We previously confirmed that high-dose voclosporin induces drug nephropathy through aberrant peroxisome accumulation. The latter induces increased renal indole-3-aceticT acid (IAA) production due to the decreased expression of the IAA-degrading enzyme indolethylamine N-methyltransferase (INMT). Conversely, INMT overexpression prevents this nephropathy, suggesting that high-dose voclosporin could enable a novel therapeutic approach. This prompted us to test whether INMT overexpression with high-dose voclosporin could avert nephrotoxicity and protect against I/R injury. Inmt-overexpressing mice treated with high-dose voclosporin exhibited absence of peroxisomal abnormalities and resistance to I/R injury. RNA sequencing revealed the downregulation of tubular injury markers NGAL (Lcn2) and KIM-1 (Havcr1) concurrent with significant cytokine suppression. Mechanistic analysis revealed the robust induction of Regnase-2, an mRNA decay factor, which directly targeted stem–loop structures within the 3′ untranslated region of Lcn2 and Havcr1, thereby promoting their degradation in proximal tubular cells. Importantly, Regnase-2 knockdown mice showed Lcn2 upregulation, mitochondrial dysfunction, and peroxisomal abnormalities culminating in AKI, underscoring its renal protective effects. High-dose voclosporin under Inmt overexpression promoted Regnase-2-mediated mRNA decay to suppress tubular injury. This protective effect extended beyond I/R to rhabdomyolysis- and lipopolysaccharide-induced AKI to prevent nephropathy. Our findings demonstrate the potential transformative therapeutic approach of administering high-dose voclosporin to promote the prophylactic effect of Regnase-2 augmentation against AKI in both native and transplanted human kidneys. Full article

Background: Acinetobacter baumannii is a major global health threat due to its rapid acquisition of multidrug resistance, particularly to carbapenems. Combination antibiotic therapy has been proposed to enhance antimicrobial activity and suppress resistance; however, evidence from randomized trials remains inconclusive. Methods: A systematic review of randomized controlled trials (RCTs) was conducted following PRISMA guidelines to evaluate the efficacy and safety of antibiotic combination therapy versus monotherapy for drug-resistant A. baumannii infections. Searches across MEDLINE, Embase, Global Health, and Cochrane Central (January 2010–June 2025) identified eligible RCTs reporting clinical outcomes. Data on clinical cure, mortality, microbiological eradication, adverse events, and resistance emergence are described narratively. Results: Eight RCTs enrolling 324 participants were included. Most trials investigated colistin-based combinations (e.g., colistin plus rifampicin, meropenem, fosfomycin, or sitafloxacin); one assessed tigecycline plus cefoperazone–sulbactam. No regimen demonstrated a significant mortality or clinical cure benefit over monotherapy, despite some combinations showing earlier or higher microbiological clearance, most notably colistin–fosfomycin and colistin–rifampicin, without corresponding improvement in clinical outcomes. Adverse events, predominantly nephrotoxicity, were common but comparable across groups. Heterogeneity in trial size, infection severity, and resistance mechanisms limited cross-study comparability. Conclusions: Current RCT evidence does not support routine use of combination therapy over monotherapy for drug-resistant A. baumannii infections, particularly in septic ICU populations where host factors dominate outcomes. Future trials should focus on early-stage or non-sepsis infections, incorporate molecular resistance profiling, and evaluate emerging agents such as sulbactam–durlobactam to guide precision therapy. Full article

The common carp (Cyprinus carpio) kidney uniquely integrates excretory nephrons, renal hematopoietic tissue, and hormonally active thyroid follicles, positioning it as a candidate “multipurpose biomarker organ” for pollutants like perfluorooctanoic acid (PFOA), a prototype long-chain PFAS and persistent organic pollutant exhibiting nephrotoxic, immunotoxic, and thyroid-disrupting effects. Building on prior histological, ultrastructural, and morphometric analyses from carp exposed to waterborne PFOA (0, 200 ng L⁻¹, 2 mg L⁻¹ for 56 days), a hierarchical multipurpose index comprising nephrotoxic, immunotoxic, and thyrotoxic subindices was developed from z-scored light-, electron-microscopy, and morphometric features, enabling cross-scale integration; proximal tubule vesiculations and effete rodlet cells (RCs) were newly quantified from archival electron micrographs. The subindices captured PFOA-induced glomerular hyperfiltration with proximal protein reabsorption and collecting duct RCs recruitment (nephrotoxic); hematopoietic tissue RCs recruitment, clustering, and exocytosis (immunotoxic); and increased thyroid follicle abundance/vesiculation, cross-sectional area, and perimeter (thyrotoxic). Quantification of previously only qualitatively assessed features provided statistical validation, while radar plot integration rendered results more intuitively evident—particularly highlighting the non-monotonic thyroid response—condensing organ-level complexity into a coherent framework supporting carp kidney as a translational One Health model for multi-endpoint waterborne pollutant assessment. Full article

Red yeast rice (RYR), a traditional fermented product obtained via rice fermentation with Monascus purpureus, has a millennia-long history of culinary and medicinal use in East Asia and has gained global attention as a prominent functional food ingredient for its well-recognized cholesterol-lowering properties. This review is driven by one core question: How can the dual challenges of standardizing key bioactive constituents, particularly monacolin K (MK), while eliminating the mycotoxin citrinin be addressed through biotechnological and analytical advances? This narrative review consolidates the latest research progress on RYR-derived bioactive compounds, with a specific focus on their production optimization, multifaceted health-promoting potentials, safety regulation, and application prospects in health food development. We elaborate on key advances in fermentation biotechnology and strain engineering for enhancing the yield of the core lipid-lowering component MK while eliminating the nephrotoxic mycotoxin citrinin, and comprehensively summarize the synergistic bioactivities of RYR metabolites beyond MK. The current applications of RYR in functional foods, dietary supplements, and traditional fermented products are detailed, alongside a comparison of the divergent regulatory frameworks for RYR across major global markets. Finally, we identify critical bottlenecks restricting RYR industrialization, including extreme inter-product heterogeneity and global regulatory fragmentation, and propose evidence-based future research directions to facilitate the development of safe, standardized, and effective RYR-based health foods. Full article

Drug-induced kidney injury remains a major clinical challenge associated with diverse therapeutic agents and is an important cause of acute kidney injury, chronic renal dysfunction, and treatment-related morbidity. Growing evidence indicates that nephrotoxicity caused by anticancer, immunosuppressive, and anti-infective drugs is strongly driven by oxidative stress and redox homeostasis disruption. Excessive production of reactive oxygen species (ROS) in renal tubular cells overwhelms endogenous antioxidant defenses and triggers mitochondrial dysfunction, inflammatory signaling, and activation of stress-responsive pathways that culminate in tubular injury and renal functional decline. These processes promote apoptosis, necrosis, microvascular injury, and a reduction in the glomerular filtration rate, while dysregulation of redox-sensitive pathways involved in cell survival and repair further heightens renal vulnerability. This review summarizes current mechanistic insights into oxidative stress-mediated pathways of drug-induced nephrotoxicity, with emphasis on their translational relevance. In addition, it discusses emerging biomarkers for early detection and highlights recent advances in antioxidant-based and redox-modulating strategies that may help prevent renal injury and preserve kidney function. Full article

P-glycoprotein (P-gp), an efflux transporter highly expressed in renal tubules, plays a crucial role in the detoxification and protection of barrier/excretory tissues from harmful xenobiotics. Xanthones and thioxanthones (TXs) are known for their antimicrobial and antitumor activities and for their ability to modulate membrane transporters such as P-gp. Previous studies have reported that (thio)xanthonic derivatives enhance P-gp expression and/or activity in intestinal cells, reducing the intracellular accumulation of toxic substrates; however, their capacity to modulate P-gp in renal cells remains poorly explored. This study aimed to predict, in silico, TXs’ binding sites within P-gp and to evaluate, in vitro, in human kidney (HK)-2 cells, the effects of selected TXs (TX1–5) on P-gp activity and expression, and protection against cisplatin-induced cytotoxicity. Computational studies identified preferential TX1–5 binding to the drug-binding pocket, particularly the rhodamine 123 (R) or modulator (M) sites, and to nucleotide-binding domain 1. In vitro, rhodamine 123 accumulation assays revealed increased P-gp transport activity after 120 min or 24 h exposure to TX1–5, except TX4. TX2 elicited the strongest effect (141% increase, p < 0.0001), upregulated P-gp expression (24 h, p < 0.0001), and significantly protected HK-2 cells from cisplatin-induced cytotoxicity (increased IC₅₀, p < 0.0001). Altogether, these findings position thioxanthones as promising scaffolds for the development of P-gp-targeted strategies to mitigate drug-induced nephrotoxicity. Full article

According to the World Health Organization, antibiotic research remains insufficient, emphasizing the urgent need for new active molecules, particularly against resistant bacteria. Based on known antibacterial scaffolds, new fluoroquinolone derivatives have been synthesized by our research group, including compound 7a, a difluoroboranyl-fluoroquinolone that previously demonstrated activity against sensitive strains. Methods: The minimum inhibitory (MIC) and bactericidal (MBC) concentrations of compound 7a were determined against Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli. The selective development of ciprofloxacin-resistant S. aureus was induced by reseeding the isolate on seven consecutive days with an antibiotic concentration that was not capable of inhibiting its development. Pharmacokinetic and toxicological properties were predicted using SwissADME, Way2Drug, and molecular docking (AutoDock Vina). In vivo toxicity was evaluated in BALB/c mice through histopathological liver and kidney analysis and serum biochemical markers. The antibacterial efficacy of 7a (80 mg/kg/day) was assessed in a murine pneumonia model induced by ciprofloxacin-resistant S. aureus. DNA gyrase inhibition was confirmed through plasmid electrophoresis assays in E. coli DH5-α cells. Results: Compound 7a exhibited both MIC and MBC values of 0.25 μg/mL, while ciprofloxacin-resistant S. aureus strains did not exhibit a detectable MIC within the concentration range tested (up to 1024 μg/mL). In silico predictions revealed favorable ADME profiles, low toxicity, and strong interaction with DNA gyrase. In vivo, 7a showed no signs of hepatotoxicity or nephrotoxicity and effectively reduced pneumonic tissue to 1.99% in infected mice. Electrophoretic assays confirmed DNA gyrase inhibition consistent with the mechanism of fluoroquinolones. Conclusions: Compound 7a evidenced activity against ciprofloxacin-resistant S. aureus in vitro and reduced infection progression in vivo. It also displays favorable drug-like properties, low predicted toxicity, and DNA gyrase inhibition. Full article

Background: Diabetic kidney disease is a major complication of type 2 diabetes mellitus (T2DM) and a leading cause of chronic kidney disease (CKD) worldwide. While diabetes duration is often considered a marker of cumulative metabolic exposure, its independent contribution to renal decline beyond aging and hypertension remains incompletely defined. Methods: We conducted a cross-sectional study including 250 adults with T2DM. Diabetes duration was analyzed both as a continuous variable and across four predefined strata (0–4, 5–9, 10–14, and ≥15 years). The primary endpoint was estimated glomerular filtration rate (eGFR), analyzed as a continuous outcome. Functional CKD was defined as eGFR < 60 mL/min/1.73 m². Linear and logistic regression models were constructed in unadjusted and adjusted forms (age, sex, BMI, hypertension, HbA1c). A sensitivity analysis modeling duration per 5-year increase was performed. Results: Mean eGFR declined significantly across duration strata (82.45, 84.27, 78.72, and 61.57 mL/min/1.73 m², respectively; p < 0.001). The prevalence of functional CKD increased markedly in patients with ≥15 years of diabetes (54.2%) compared with shorter-duration groups (~15–18%; p < 0.001). In linear regression, each additional year of diabetes was associated with a 1.32 mL/min/1.73 m² decline in eGFR (p < 0.001), remaining significant after adjustment (β = −0.85; p < 0.001). In logistic regression, each additional year was associated with a 10.7% increase in adjusted odds of CKD (OR = 1.11; 95% CI 1.04–1.17; p < 0.001). Each 5-year increment conferred a 66% increase in adjusted CKD risk (OR = 1.66; 95% CI 1.25–2.21; p < 0.001). Patients with ≥15 years of diabetes had nearly fourfold higher adjusted odds of CKD compared with those with 0–4 years (OR = 3.90; 95% CI 1.42–10.75; p = 0.008). Conclusions: Diabetes duration is strongly and independently associated with declining kidney function. Prolonged disease exposure confers a substantial increase in CKD risk, even after adjustment for age, hypertension, and metabolic factors. These findings highlight the progressive nephrotoxic impact of cumulative hyperglycemic exposure and underscore the need for early and sustained nephroprotective strategies in T2DM. Full article

Background/Objectives: Chlorpyrifos (CPF), a widely used organophosphate pesticide, has been associated with oxidative stress-mediated renal injury. Prenatal exposure may pose a risk for developmental nephrotoxicity; however, data regarding protective natural agents remain limited. This study evaluated the protective effects of Ganoderma lucidum (GNL) against CPF-induced renal alterations in rat offspring. Methods: Pregnant rats received CPF (5 mg/kg) and/or GNL (400 mg/kg) orally throughout gestation. On postnatal day 28, blood and kidney tissues from male offspring were collected for biochemical, ELISA, histopathological, immunohistochemical, and stereological analyses. Results: Prenatal CPF exposure significantly elevated serum urea and creatinine levels and induced oxidative stress, evidenced by increased malondialdehyde (MDA) and nitric oxide (NO) levels and decreased antioxidant enzyme activities (Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH)) (all p < 0.05). Renal TNF-α and IL-6 levels were significantly increased, indicating inflammatory activation. Apoptotic signaling was enhanced, demonstrated by elevated cleaved caspase-3 levels and an altered Bax/Bcl-2 ratio. Tubular injury biomarkers, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), were markedly increased. Histopathological findings revealed tubular degeneration, while stereological analysis confirmed significant increases in cortical and glomerular volumes. GNL co-treatment attenuated oxidative stress, suppressed inflammatory cytokines, reduced caspase-3 activation, lowered KIM-1 and NGAL levels, and preserved renal structure. Conclusions: Prenatal CPF exposure induces developmental nephrotoxicity through interconnected oxidative, inflammatory, and apoptotic mechanisms. Ganoderma lucidum mitigates these alterations by restoring antioxidant defense systems, modulating the Bax/Bcl-2 apoptotic balance, suppressing pro-inflammatory cytokine production, reducing tubular injury markers, and normalizing stereologically detected renal structural changes. Full article