Search Results (2,181)

The therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) is limited by gastrointestinal and renal adverse effects caused by non-selective COX-1 and COX-2 inhibition. To address this issue, a new series of naproxen–azetidinone hybrids was rationally designed and synthesized to enhance COX-2 selectivity and reduce off-target toxicity. The synthesis involved esterification, hydrazide formation, Schiff base condensation, and intramolecular cyclization with chloroacetyl chloride. Structural characterization was achieved through FT-IR, ¹H NMR, and ¹³C NMR analyses. In silico ADMET profiling confirmed compliance with Lipinski’s rule and predicted favorable gastrointestinal absorption. Molecular docking revealed high COX-2 binding affinities (−11.93 to −9.72 kcal/mol), while MM/GBSA analysis identified compound N4_c (ΔG = −62.27 kcal/mol) as the most stable complex, surpassing meloxicam and naproxen. DFT (B3LYP/6-31G(d,p)) frontier molecular orbital analysis indicated a narrow HOMO–LUMO gap (ΔE = 2.97 eV) for N4_c, suggesting high electronic reactivity and strong enzyme interaction. Molecular dynamics simulations confirmed complex stability. In vivo anti-inflammatory testing using an egg-white-induced rat paw edema model showed that N4_d, N4_e, and N4_f achieved higher inhibition (19.22%, 16.98%, and 16.98%) than naproxen (4.3%). These results highlight 2-azetidinone–naproxen hybrids as promising selective COX-2 inhibitors with enhanced pharmacokinetic and electronic properties. Full article

This study aimed to investigate the role and underlying mechanism of apolipoprotein C2 (APOC2) in the progression of clear cell renal cell carcinoma (ccRCC). Analysis of The Cancer Genome Atlas (TCGA) datasets, combined with validation in ccRCC cell lines, revealed that APOC2 was markedly upregulated in ccRCC tissues and cells and was associated with poor patient prognosis. Functional assays demonstrated that APOC2 knockdown significantly suppressed cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Mechanistic studies showed that silencing APOC2 reduced the phosphorylation levels of key components of the JAK-STAT signaling pathway, including Jak1/2 and STAT3, without affecting their total protein expression. Gene enrichment analysis further indicated the involvement of JAK-STAT signaling, and functional rescue experiments using the STAT3 agonist Colivelin partially reversed the decreased cell viability and increased apoptosis caused by APOC2 knockdown, confirming the pathway’s mediating role. Collectively, these findings suggest that APOC2 promotes ccRCC cell proliferation and inhibits apoptosis, at least in part, through activation of the JAK-STAT signaling pathway, highlighting APOC2 as a novel oncogenic regulator and potential therapeutic target, and providing new insight into the metabolic–inflammatory axis in ccRCC progression. Clinically, APOC2 may serve as a biomarker to identify ccRCC patients with hyperactivated JAK-STAT signaling and could potentially guide combination therapies involving JAK/STAT inhibitors or metabolic-targeted agents. Full article

Here, we show that the aureolic acid-class antibiotic, olivomycin A, exerts potent anticancer activity in renal cell carcinoma (RCC) by disrupting both cell survival and metastatic programs. In A-498 (wild-type p53) and 786-O (loss-of-function in p53 and PTEN) cells, olivomycin A markedly inhibited migratory capacity and reversed epithelial–mesenchymal transition (EMT), as shown by downregulation of nuclear Snail and the mesenchymal marker N-cadherin and restoration of the epithelial markers, E-cadherin and ZO-1. In parallel, olivomycin A induced apoptosis through distinct p53-dependent mechanisms: In A-498 cells, apoptosis was primarily mediated through the intrinsic pathway, characterized by the upregulation of Puma, Bak, and activation of caspase-9. In 786-O cells, caspase-8 activation and Bid truncation were observed alongside mitochondrial involvement, suggesting possible cross-talk apoptotic cascades. Notably, in p53-mutant 786-O cells, treatment with olivomycin A elicited severe genotoxic stress accompanied by robust DNA damage signaling, excessive reactive oxygen species (ROS) accumulation, and lysosomal activation, culminating in extensive mitochondrial removal. Such changes were weaker in p53-wild-type A-498 cells, suggesting that the altered p53 context sensitizes RCC cells to olivomycin A-mediated mitochondrial quality control mechanisms. Collectively, our findings delineate a multifaceted mechanism whereby olivomycin A coordinates EMT suppression, apoptotic induction, and mitochondrial clearance. Thus, olivomycin A has potential as a therapeutic candidate that can target both survival and metastatic pathways in heterogeneous genetic backgrounds. Full article

Herniation of the transplanted ureter into the inguinal canal is an exceptionally rare complication following renal transplantation. Most cases present as delayed-onset obstructions, typically occurring more than one year post-transplant and often involving the ipsilateral inguinal canal. We presented the case of a 49-year-old male kidney transplant recipient who developed obstructive uropathy due to herniation of the graft ureter into the ipsilateral inguinal canal. Diagnosis was confirmed by computed tomography (CT), which proved superior to ultrasonography in delineating the ureteral course. A JJ ureteral stent was successfully placed, followed by inguinal hernia repair using the Lichtenstein technique. The postoperative course was uneventful, with complete resolution of symptoms and preservation of graft function. Transplanted ureteral herniation is a rare but important cause of late post-transplant obstruction. Cross-sectional imaging, particularly CT, offers greater diagnostic accuracy than ultrasound alone in identifying ureteral displacement. When feasible, primary ureteral stenting may obviate the need for nephrostomy, thereby reducing patient morbidity. Full article

Background: Limited real-world data (RWD) may provide important information regarding diagnostic and treatment patterns in patients (pts) with AL Amyloidosis. The aim was to analyze the characteristics, treatment approach and clinical outcome of patients in the real-world settings. Materials and Methods: RWD of 60 pts diagnosed with AL amyloidosis were analyzed. Advanced cardiac involvement, Mayo Clinical Stage (CS) IIIa and IIIb, and Revised-Mayo CS III and IV, has been found in 26.7%, and 16.7%, or 33.3% and 16.7%, respectively. Bortezomib (Bz)-based regimens were applied in 36 pts (60%), and alkylating-based regimens in 24 pts (40%). In 8 pts (13.3%) treated initially with CyBorD induction, high-dose therapy with Melphalan and autologous stem cell transplantation (HDT + ASCT) was applied as the first line of treatment. Results: The overall response rate (ORR, ≥partial response) was achieved in 40 pts (70%). Patients treated with Bz-based induction followed by HDT + ASCT achieved significantly better hematologic (p = 0.001), cardiac (p = 0.004) and renal response rates (p = 0.002) in comparison to CyBorD or Alk-based regimens alone. There was no difference in PFS between those groups (p = 0.733), but patients treated with CyBorD + HDT + ASCT had significantly durable OS (p = 0.039). Univariate analysis pointed out the predictive influence of cardiac involvement (Mayo CS and Revised Mayo CS), ASCT eligibility, and hematologic, cardiac, renal and composite response rates. Conclusions: Advanced cardiac involvement and cardiac and hematologic response still retain adverse prognostic impact on the clinical outcome. Bz-based combinations significantly improved the survival of patients with AL amyloidosis, regardless of HDT + ASCT treatment. Full article

Background/Objectives: In recent decades, chronic kidney disease (CKD) has increased its prevalence in the general population, reaching about 10%. The increasing number of older patients and the expansion of treatment options could necessitate a growing number of nephrologists/nurses. This report aims to estimate the resources required to manage the CKD population and hypothesize possible strategies to address the discrepancy between the estimated need and available resources. Methods: Based on previous reports about CKD in our geographic area and the data reported by the Italian Statistics Institute (ISTAT), we estimated the number of patients who should be referred to a nephrologist in our district, and consequently the number of nephrology consults and the need of nephrologists (considering 14 visits for 5 days/week, 48 weeks/year for each nephrologist). Results: The Padua district has approximately 240,257 inhabitants aged 40 years and older. Of these, 31,139 are estimated to have CKD, and 540 are potentially affected by CKD stage 5. The estimated number of outpatient visits is approximately 178 per day, which would require 12 full-time employed nephrologists. On the contrary, only two nephrologists are currently involved full-time in outpatient clinics, while eight are involved part-time. Finally, 540 CKD G5 surpasses the current available dialysis seats (184 hemodialysis seats and 80 peritoneal dialysis seats). Conclusions: In the Padua Healthcare district, the estimated outpatient clinic demand and the potential need for renal replacement therapy exceed human and facility resources, indicating a need for nephrologists in outpatient clinics that is more than four to six times the current numbers. This discrepancy highlights the need for a multidimensional approach that promotes active collaboration with general practice, telemedicine, and an informative campaign targeting the population. Full article

Background: Metabolic syndrome involves interconnected disturbances in insulin sensitivity, hepatic function, and renal performance. Simple, integrative indices may improve early detection of multisystem metabolic risk. Methods: In this cross-sectional study, adults were stratified into metabolic risk categories (scores 2–11) and evaluated using the triglyceride–glucose (TyG) index, the fibrosis-4 (FIB-4) score, and estimated glomerular filtration rate (eGFR). Correlation analyses and multivariate regression models (HC3 robust standard errors) were applied to identify independent predictors of hepatic (FIB-4) and renal (eGFR) function. Results: TyG and FIB-4 increased significantly with higher metabolic risk (ANOVA p < 10⁻⁶), while eGFR showed a mild, non-significant decline. TyG correlated strongly with triglycerides (r = 0.78) and fasting glucose (r = 0.69), whereas FIB-4 correlated inversely with eGFR (ρ = −0.30). In regression models, age was the strongest predictor of both FIB-4 (β_std = 0.33) and eGFR (β_std = −0.47). Additional predictors of lower eGFR included FIB-4, systolic blood pressure, BMI, and UACR, whereas TyG showed no independent effect after adjustment. Conclusions: The combined use of TyG, FIB-4, and eGFR provides complementary insight into the metabolic–hepatic–renal continuum. These indices highlight progressive insulin resistance, hepatic stress, and subclinical renal involvement, supporting their utility as accessible tools for early identification of high-risk metabolic phenotypes. Full article

Background/Objectives: GPA is a PR3-ANCA–predominant small vessel vasculitis with organ involvement. Real-world, single-centre data are needed to interpret evolving therapies and phenotype patterns in national conditions. Material and Methods: Retrospective cohort study of consecutive GPA patients managed at the National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) from 1 September 2010 to 1 September 2025. Data included demographics, phenotype, BVAS, organ involvement, PR3/MPO-ANCA serology, and induction/maintenance therapies. Results: Fifty patients were included (54.0% men). Mean age was 52.5 years; mean BMI was 26.15 kg/m². Ear-nose-throat (ENT) disease was frequent: rhinosinusitis 76.0%, nasal cartilage destruction 64.0%, subglottic stenosis 34.0%. Pulmonary nodules occurred in 52.0%, cavitation in 28.0%, and diffuse alveolar haemorrhage in 34.0%. Renal involvement included haematuria in 42.0%, chronic kidney disease (CKD) in 32.0%, and rapidly progressive kidney disease in 22.0%. Orbital inflammation was 36.0%, and PR3-ANCA was positive in 70.0%. All patients received glucocorticoids for induction; cyclophosphamide 28/50 (56.0%), rituximab 6/50 (12.0%), and mycophenolate with methotrexate 6/50 (32%). Maintenance therapy included methotrexate (78.0%), mycophenolate (64.0%), rituximab (52.0%), and azathioprine (12.0%). Conclusions: This Polish single-centre cohort shows an ear-nose-throat-lung-kidney (ELK)-dominant, PR3-predominant GPA phenotype and frequent but variable kidney involvement. Over 2010–2025, practice changed toward rituximab-based strategies, steroid minimisation, selective use of plasma exchange, and early avacopan uptake, with tofacitinib for maintenance therapy as a possible new therapeutic option. Full article

Anorexia nervosa (AN) is a severe psychiatric disorder with the highest mortality rate among mental illnesses, characterized by an intense fear of weight gain, persistent restriction of energy intake, and a distorted perception of body image. Despite decades of investigation, the pathogenesis of AN is only partially understood and is recognized as multifactorial, involving genetic, sociocultural, and neurobiological determinants. Beyond its core psychopathological features, AN leads to a wide spectrum of systemic complications, including cardiovascular, renal, skeletal, and endocrine dysfunctions. Increasing evidence implicates autophagy and oxidative stress as key molecular mechanisms underpinning its pathophysiology, while growing attention has been directed toward immune dysregulation and alterations in the gut–brain axis as potential mediators of disease onset and progression. Therapeutic advances, however, remain limited. Current management relies primarily on nutritional rehabilitation and psychotherapeutic interventions, while treatment outcomes are constrained by high relapse rates and the lack of pharmacological agents with proven efficacy. In this context, a more comprehensive understanding of the clinical spectrum and molecular substrates of AN is essential to improving prognosis and guiding the development of novel therapeutic strategies. This narrative review synthesizes current evidence on the non-psychopathological dimensions of AN, encompassing its clinical manifestations, systemic complications, and implicated molecular pathways. It also appraises existing treatment modalities and examines emerging interventions with translational potential. Overall, this review aims to provide clinicians and researchers with an updated and integrative overview of AN, shedding light on novel directions in ongoing research. Full article

Background/Objectives: Protein–energy wasting (PEW) is a common complication in patients with chronic kidney disease (CKD) receiving renal replacement therapy by dialyses. This condition is associated with higher morbidity, mortality, and poorer quality of life. The aim of this systematic review was to evaluate the effectiveness of different nutritional strategies—such as oral nutritional supplements and intra-dialytic parenteral nutrition—in improving the nutritional status of these patients. Methods: A systematic review was carried out in accordance with the PRISMA statement. Searches were performed in PubMed, BVS, and Scopus between January and March 2025. Randomised or controlled clinical trials published in English or Spanish, available in full text, involving adults on haemodialysis (HD) or peritoneal dialyses (PD) were included. Fourteen studies met the inclusion criteria. Results: The nutritional interventions assessed produced consistent benefits in biochemical markers (e.g., serum albumin), muscle mass, inflammatory indices, and perceived quality of life. Intra-dialytic supplementation and multidisciplinary management were particularly effective in patients with moderate-to-severe malnutrition. Conclusions: Malnutrition is frequent and clinically significant in dialyses patients. Nutritional strategies—including oral supplementation, IDPN, and personalised counselling—effectively prevent and treat PEW. Early, tailored, evidence-based, and multidisciplinary implementation could decisively improve clinical prognosis and quality of life in this population. Full article

Brown tumors (BTs) are rare osteolytic lesions that typically occur in association with primary or secondary hyperparathyroidism (PHP and SHP). Excessive secretion of parathyroid hormone induces increased bone resorption, resulting in lesions characterized by fibrosis, vascularization, and hemosiderin deposition. The most common sites include the jaws, ribs, pelvis, and long bones. Clinical manifestations may involve pain, swelling, or pathological fractures. We present the case of a mandibular BT in a 48-year-old female with chronic renal failure and secondary hyperparathyroidism. The patient exhibited progressive mandibular swelling with radiological features resembling an aggressive odontogenic or malignant lesion. Laboratory analysis confirmed markedly elevated parathyroid hormone levels, while scintigraphy demonstrated increased focal uptake in the mandible and ribs. Histopathological evaluation revealed multinucleated giant cells within a fibrous stroma, consistent with BT. Despite initiation of systemic endocrine therapy, the lesion continued to enlarge, necessitating complete surgical excision of the mandibular mass. This case underscores the diagnostic dilemmas of mandibular BT, which may closely mimic aggressive jaw pathologies. Importantly, while many BTs regress after systemic management of hyperparathyroidism, this case illustrates that surgical excision may be unavoidable in patients with unstable systemic status or progressive local disease. Comprehensive clinical, radiological, laboratory, and histopathological evaluation remains essential to ensure timely diagnosis and appropriate treatment. Full article

Preeclampsia (PE) is characterized by maternal hypertension accompanied with multi-organ dysfunction, such as maternal hepatic and renal dysfunction. Abnormal placental conditions may play a key role in regulating maternal organ function by promoting systemic inflammation. This study aimed to test the hypothesis that placenta-derived secretions contribute to hepatic and renal injury through interorgan communication using a PE-like mouse model. Pregnant mice were infused with angiotensin II (Ang II) from gestational day (GD) 12 (GD1 defined as the day of plug detection). Ang II infusion induced maternal hypertension, as well as liver injury (elevated serum amyloid A [SAA] secretion and alanine aminotransferase levels) and kidney injury (tubular damage with KIM-1 protein expression and immune cell infiltration). Treatment with placental-conditioned medium (CM) from Ang II-infused mice, but not from the control mice, stimulated SAA expression in liver cells. On the other hand, the effects of placental-CM from both the control and Ang II groups on kidney tubular cells were comparable. These findings suggest that placenta-derived secretions in the Ang II-induced PE-like phenotype specifically promote excessive SAA production in the liver. Furthermore, SAA administration in pregnant mice did not cause tubular injury but did promote renal immune cell infiltration, indicating that elevated hepatic SAA levels may contribute to maternal kidney inflammation. Taken together, these results suggest the presence of an in vivo organ network involving the placenta, liver, and kidneys during pregnancy, where dysfunction in one organ may exacerbate the pathogenesis of PE. Full article

The accumulation of advanced glycation end products (AGEs) is a hallmark of prolonged high glucose levels in diabetes mellitus. We have previously reported that hypoxia and AGEs cause epigenetic modification of the repressive mark H3K27me3 in podocytes by downregulation of enhancer of zeste homolog 2 (EZH2) and nuclear inhibitor of protein phosphatase 1 (NIPP1). However, their impact on proximal tubular cells remains unclear. The aim of this study was to investigate the role of AGEs and diabetes on the epigenetic modifications of EZH2 and H3K27me3 in proximal tubular cells and in diabetic (db/db) mice. Our results show that AGEs reduced EZH2 expression in TKPTS cells, thereby decreasing the tri-methylation of H3K27. qRT-PCR analysis revealed upregulation of genes known to contribute to diabetic nephropathy and kidney injury as Ctgf, Snai1, and p27^Kip1. Consistently, immunofluorescent staining of renal sections from db/db mice confirmed the reduction in H3K27me3 levels in proximal tubules compared to non-diabetic controls. In summary, we show that AGEs induce epigenetic changes in proximal tubular cells by suppressing EZH2, thereby facilitating the transcription of genes involved in progression of diabetic nephropathy. These results provide new insights into metabolic memory, a process in which prior poor glucose control triggers ongoing renal damage despite current normoglycemia. Full article

Background/Objectives: Cardiac surgery, particularly procedures performed with cardiopulmonary bypass (CPB), carries a high risk of neurological complications, including postoperative delirium (POD), which affects 16–73% of patients and increases the likelihood of long-term cognitive impairment. Brain-derived neurotrophic factor (BDNF), a neurotrophin involved in neuronal function, synaptic plasticity, and inflammatory regulation processes, including its Val66Met polymorphism, has been implicated as a potential predictor of POD. This study aimed to evaluate the relationship between perioperative plasma BDNF levels, the BDNF Val66Met polymorphism, and the incidence of POD in patients undergoing elective cardiac surgery with CPB. Methods: This prospective observational single-center study enrolled 287 adults scheduled for elective isolated coronary artery bypass grafting (CABG) with CPB, of whom 107 met all inclusion criteria for final analysis. Exclusion criteria included urgent surgery and pre-existing cognitive or psychiatric disorders. Preoperative evaluation included cognitive testing (MoCA), laboratory and biochemical analysis, and genotyping for BDNF Val66Met. Postoperatively, patients were assessed for POD using the CAM-ICU scale for the first three consecutive days. Cognitive function (using MoCA) and other neurological complications were evaluated during hospitalization, at 30-day and 12-month follow-up. Associations between biomarkers, genetic factors, and clinical outcomes were analyzed. Results: POD occurred in 19.6% of patients who were older, had higher EuroSCORE II, greater coronary disease burden, more frequent prior stroke and chronic kidney disease, and lower neutrophil counts. POD was significantly associated with prolonged hospital stay, need for continuous renal replacement therapy, and reoperation. The BDNF Val66Met polymorphism was present in 31.8% of patients but was not associated with POD, although carriers exhibited higher plasma BDNF concentrations across all time points. Conclusions: Perioperative plasma BDNF concentrations and the BDNF Val66Met polymorphism were not independently associated with the occurrence of POD in elective CABG patients. However, POD was significantly linked to prolonged hospitalization and reoperations. Neurological complications remain an important challenge in cardiac surgery, emphasizing the need for further research and early identification strategies to improve postoperative outcomes. Full article

Background/Objectives: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) and chronic obstructive pulmonary disease (COPD) are linked to multi-organ vulnerability involving the lungs, heart, and kidneys. This study aimed to compare the annual changes in pulmonary, cardiac, and renal parameters in patients with SSc-ILD and COPD across three consecutive years, using both individual biomarkers and integrated composite profiles. Methods: This observational longitudinal study included repeated assessments in 2023, 2024, and 2025. Functional, laboratory, and imaging parameters were collected: 6-min walk test (6MWT), SpO₂ (pre-/post-exercise), spirometry/CT lung volumes, gas exchange (pO₂/pCO₂/lactate), echocardiography [left ventricular ejection fraction (LVEF), estimated systolic pulmonary artery pressure (sPAP)], cardiac biomarkers (NT-proBNP, MR-proANP, hsTnT), renal markers [eGFR, creatinine, albuminuria, albumin-to-creatinine ratio (ACR)], heart rate variability (HRV), and renal CT densitometry. All markers were standardized (z-scores, higher values = worse). Subprofiles were generated and aggregated into three integrated profiles (cardiac, renal, pulmonary). Within-group dynamics were analyzed using the Wilcoxon signed-rank test (year-to-year deltas), between-group comparisons with the Mann–Whitney U test, effect sizes via Cliff’s delta, and multiple testing correction with the Benjamini–Hochberg false discovery rate (FDR). Results: Exercise tolerance declined in both groups: by 2025, 6MWT distance decreased by −10 m in SSc-ILD (p = 0.006; q = 0.010) and −20 m in COPD (p = 0.002; q = 0.004); post-exercise SpO₂ fell in both cohorts (both p < 0.001; q < 0.001). MR-proANP remained consistently higher in SSc-ILD across all years (p ≤ 0.005; q ≤ 0.028). sPAP increased in both groups, reaching higher values in COPD by 2025 (p = 0.007; q = 0.033). NT-proBNP and hsTnT increased over time, while eGFR declined, and ACR rose in both cohorts (both p < 0.001; q < 0.001). HRV (HF/total power) decreased by 2025. Composite profiles showed: in 2023, the cardiac profile was worse in SSc-ILD (δ ≈ 0.27; p = 0.011; q = 0.048), but differences diminished by 2025; the renal profile was initially worse in SSc-ILD but later shifted unfavorably in COPD; the pulmonary profile showed no consistent between-group differences. Conclusions: Over three years, patients with SSc-ILD and COPD exhibited concordant deterioration in pulmonary, cardiac, and renal function. Distinct leading markers emerged: desaturation during exercise and neurohormonal activation (MR-proANP) in SSc-ILD, versus reduced 6MWT and higher sPAP in COPD. These findings support the need for integrated monitoring of the cardio–pulmo–renal continuum. Limitations include the observational design, multiple comparisons, and absence of advanced repeated-measures modeling. Full article