Search Results (795)

Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed straight-tubules observed in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca²⁺ entry (SOCE): STIM1 Ca²⁺ sensor proteins in the sarcoplasmic reticulum (SR) and Ca²⁺-permeable ORAI1 channels in the surface membrane. Here, we assessed the therapeutic potential of endurance exercise in the form of voluntary wheel running (VWR) in mitigating TAs and muscle weakness in Orai1^G100S/+ (GS) mice harboring a gain-of-function mutation in the ORAI1 pore. Six months of VWR exercise significantly increased specific force production, upregulated biosynthetic and protein translation pathways, and normalized both mitochondrial protein expression and morphology in the soleus of GS mice. VWR also restored Ca²⁺ store content, reduced the incidence of TAs, and normalized pathways involving the formation of supramolecular complexes in fast twitch muscles of GS mice. In summary, sustained voluntary endurance exercise improved multiple skeletal muscle phenotypes observed in the GS mouse model of TAM. Full article

Rhabdomyolysis is characterized by the breakdown of skeletal muscle tissue, frequently leading to acute kidney injury (AKI). Traditional conservative treatments have shown limited effectiveness in modifying the disease course, thereby necessitating targeted pharmacological approaches. Zileuton (Z), a selective inhibitor of 5-lipoxygenase (5-LOX), has demonstrated efficacy in enhancing renal function recovery in animal models of AKI induced by agents such as cisplatin, aminoglycosides, and polymyxins. The present study aimed to evaluate the therapeutic potential of a single dose of Z in mitigating rhabdomyolysis-induced AKI (RI-AKI) via modulation of myeloid-derived suppressor cells (MDSCs). Male C57BL/6 mice were assigned to four experimental groups: Sham (intraperitoneal administration of 0.9% saline), Z (single intraperitoneal injection of Z at 30 mg/kg body weight), glycerol (Gly; single intramuscular dose of 50% glycerol at 8 mL/kg), and glycerol plus Z (Z + Gly; concurrent administration of glycerol intramuscularly and Z intraperitoneally). Animals were sacrificed 24 h post-glycerol injection for analysis. Zileuton administration significantly improved renal function, as indicated by reductions in blood urea nitrogen (BUN) levels (129.7 ± 17.9 mg/dL in the Gly group versus 101.7 ± 6.8 mg/dL in the Z + Gly group, p < 0.05) and serum creatinine (Cr) levels (2.2 ± 0.3 mg/dL in the Gly group versus 0.9 ± 0.3 mg/dL in the Gly + Z group p < 0.05). Histopathological assessment revealed a marked decrease in tubular injury scores in the Z + Gly group compared to the Gly group. Molecular analyses demonstrated that Z treatment downregulated mRNA expression of macrophage-inducible C-type lectin (mincle) and associated macrophage infiltration-related factors, including Areg-1, Cx3cl1, and Cx3CR1, which were elevated 24 h following glycerol administration. Furthermore, the expression of NLRP-3, significantly upregulated post-glycerol injection, was attenuated by concurrent Z treatment. Markers of mitochondrial biogenesis, such as mitochondrial DNA (mtDNA), transcription factor A mitochondrial (TFAM), and carnitine palmitoyltransferase 1 alpha (CPT1α), were diminished 24 h after glycerol injection; however, their expression was restored upon simultaneous Z administration. Additionally, Z reduced protein levels of BNIP3, a marker of mitochondrial autophagy, while enhancing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), suggesting that Z ameliorates RI-AKI severity through the regulation of mitochondrial quality control mechanisms. Zileuton also decreased infiltration of CD11b(+) Gr-1(+) MDSCs and downregulated mRNA levels of MDSC-associated markers, including transforming growth factor-beta (TGF-β), arginase-1 (Arg-1), inducible nitric oxide synthase (iNOS), and iron regulatory protein 4 (Irp4), in glycerol-injured kidneys relative to controls. These markers were elevated 24 h post-glycerol injection but were normalized following concurrent Z treatment. Collectively, these findings suggest that Zileuton confers reno-protective effects in a murine model of RI-AKI, potentially through modulation of mitochondrial dynamics and suppression of MDSC-mediated inflammatory pathways. Further research is warranted to elucidate the precise mechanisms by which Z regulates MDSCs and to assess its therapeutic potential in clinical contexts. Full article

Background: Ischemia–reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI). While the precise mechanisms of AKI are still incompletely defined, extensive evidence highlights tubular cell injury and death as key factors in its development. Necroptosis has recently emerged as a critical pathway in the pathogenesis of ischemia–reperfusion-induced AKI (IR-AKI). Although sex differences in susceptibility to IR-AKI have been reported, it remains unclear whether there are sex differences in necroptosis dynamics and whether these differences underlie the observed sexual dimorphism in kidney IRI. This study aimed to address these questions. Methods: male and female C57BL/6 J mice were subjected to AKI via ischemia induced by bilateral renal pedicle clamping for 18 min at 37 °C. Plasma, urine, and kidney samples were collected at 0 h, 3 h, 6 h, 12 h, 24 h, 48 h, and 72 h post-reperfusion. Kidney injury and function were assessed by measuring plasma creatinine (PCr), blood urea nitrogen (BUN) levels, and histological damage (PAS and cleaved caspase3 staining). Necroptosis activation was assessed by quantifying phosphorylated forms of key markers: p-RIPK1 and p-MLKL. To explore the role of sex hormones in regulating necroptosis dynamics, ovariectomized female mice were subjected to the same IR-AKI protocol, and their kidney injury and functional outcomes were compared with those of intact counterparts. Results: The PCr was 0.35 ± 0.04 and 0.32 ± 0.06 mg/dL for males and females, respectively, at 3 h of IR. The levels exponentially increased to 2.05 ± 0.18 at 48 h post-reperfusion in the males but only gradually to 0.94 ± 0.13 mg/dL in females. Necroptosis activation began as early as 3 h post-IR in males but was delayed until ~6 h in females. Males exhibited stronger and more sustained necroptosis activation than females, showing elevated phosphorylation levels of pRIPK1 and pMLKL in Western blot. Female sex hormone deficiency exacerbated the female response to IR-induced injury, which reduced the sex difference in the dynamic of the necroptotic activation and subsequent kidney injury. To our knowledge, this is the first study to characterize sex differences in the initiation and progression of necroptosis and subsequent injury in a mouse model of IR-AKI. Conclusions: Our findings reveal distinct temporal patterns of programmed cell death between sexes. Necroptosis-targeted therapies require early intervention in males, which can be delayed in females after IR-AKI, highlighting the need for sex-specific therapeutic windows. Full article

The rapid development of the nuclear industry and mining has increased environmental radioactive contamination, posing potentially ecological risks and health threats to humans. Uranium compounds are known to exhibit selective nephrotoxicity, but their toxicological processes and mechanisms still remain poorly understood and controversial. In this study, the uranyl-induced toxicity in human renal tubular epithelial cells (HK-2) were explored using flow cytometry, DAPI staining, and comet assays. Our results demonstrate that uranium exposure primarily triggers apoptosis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and protein–protein interaction (PPI) analyses revealed significant associations with DNA damage. Moreover, aberrant expression of ABC transporters (e.g., ABCB7) and mitochondrial-related proteins confirms uranium-induced mitochondrial dysfunction. Gene Ontology functional annotation implicated extrinsic apoptotic signaling pathways in uranium-induced cell death. The downregulation of the UBL5 protein also pointed to endoplasmic reticulum stress-mediated apoptosis. In summary, uranium exposure can induce the apoptosis of HK-2 cells through intrinsic pathways by damaging DNA and mitochondria and disrupting protein synthesis, with secondary contributions from endoplasmic reticulum stress and extrinsic apoptotic signaling. Full article

Diffuse correlation tomography (DCT) is an emerging technique for detecting diseases associated with localized abnormal perfusion from near-infrared light intensity temporal autocorrelation functions (g₂(τ)). However, a critical drawback of traditional reconstruction methods is the imbalance between optical measurements and the voxels to be reconstructed. To address this issue, this paper proposes Conv-TransNet, a convolutional neural network (CNN)–Transformer hybrid model that directly maps g₂(τ) data to blood flow index (BFI) images. For model training and testing, we constructed a dataset of 18,000 pairs of noise-free and noisy g₂(τ) data with their corresponding BFI images. In simulation validation, the root mean squared error (RMSE) for the five types of anomalies with noisy data are 2.13%, 4.43%, 2.15%, 4.05%, and 4.39%, respectively. The MJR (misjudgment ratio)of them are close to zero. In the phantom experiments, the CONTRAST of the quasi-solid cross-shaped anomaly reached 0.59, with an MJR of 2.21%. Compared with the traditional Nth-order linearization (NL) algorithm, the average CONTRAST of the speed-varied liquid tubular anomaly increased by 0.55. These metrics also demonstrate the superior performance of our method over traditional CNN-based approaches. The experimental results indicate that the Conv-TransNet model would achieve more accurate and robust reconstruction, suggesting its potential as an alternative for blood flow imaging. Full article

In the Japanese Multi-Centered Environmental Toxicant Study (JMETS) conducted in five areas across Japan, we demonstrated that bone mineral density (BMD) in female farmers without renal tubular dysfunction was not adversely affected by exposure to low to moderate levels of cadmium (Cd). We then expanded JMETS to the most Cd-polluted area in northern Japan, Akita prefecture, with area A as the control and areas B and C as Cd-polluted areas (Cd exposure levels: B < C), which also covered more female farmers with a wider age range (20–82 years) and Cd exposure sufficient to induce renal tubular dysfunction. We selected 1267 eligible subjects in the three areas and classified them by age and menstrual status. The distribution of blood and urinary Cd levels over the areas was A < B < C (blood Cd: 2.10, 3.78, and 3.39 µg/L, and urinary Cd: 3.02, 4.29, and 6.15 µg/g cr., respectively; p < 0.05), with the steepest age-dependent increase in area C, particularly in older postmenopausal subjects with a urinary Cd level around the threshold for renal tubular dysfunction. Urinary α1-microglobulin (α1MG) and ß2-microglobulin (ß2MG) levels in the three areas also showed age-dependent increases, with higher levels being observed in areas B and C than in area A. Furthermore, ß2MG levels in older postmenopausal subjects were significantly higher in area C than in area A (273 and 157 μg/g cr., respectively, p < 0.05). Age-dependent decreases in BMD were noted in all areas, with rapid reductions from peri- to postmenopausal subjects; however, marked differences in each age class were not observed among the three areas. In multiple regression models of BMD in all subjects using age, body weight, grip, urinary creatinine, urinary α1MG or ß2MG, and blood or urinary Cd as independent variables, urinary α1MG and ß2MG levels correlated with BMD, whereas blood and urinary Cd levels did not. Moreover, age and body weight correlated more strongly with BMD than blood and urinary Cd levels. Therefore, Cd, not only at a low level but also at a level that was sufficient to deteriorate renal tubular function, did not affect bones. These results provide further support for Cd exposure itself not directly affecting bones. Full article

This study aims to compare the carbon footprints associated with the fabrication of two types of alumina-based tubular ceramic membranes used in microfiltration (MF): a multichannel membrane produced by extrusion and dip-coating, and an asymmetric hollow fiber membrane fabricated via phase inversion. The multichannel process involves two sintering steps but uses no organic solvents, whereas the phase-inversion method simplifies production through single-step shaping and sintering but requires organic solvents that increase environmental burdens. Using a functional unit of 1 m² effective membrane area, carbon emissions were quantified from raw material extraction to waste disposal. The results showed total emissions of 8.57 kg CO₂-eq/m² for the multichannel membrane and 10.67 kg CO₂-eq/m² for the hollow fiber membrane. Although the hollow fiber process consumed less energy, its extensive use of solvents, particularly NMP, led to significantly higher emissions. This study provides the first quantitative comparison of these two common ceramic membrane fabrication routes and underscores the importance of considering both energy use and solvent impacts when evaluating the environmental sustainability of membrane production. A sensitivity analysis further evaluated the influence of key parameters, including alumina emission factor, regional electricity carbon intensity, alumina recycling, and solvent substitution or NMP recycling. The analysis demonstrated that each factor could significantly influence the total carbon footprint and, under favorable conditions, narrow or even reverse the gap between the two fabrication routes. This study provides the first quantitative comparison of these two common ceramic membrane fabrication methods and highlights the importance of considering energy use, solvent impacts, and potential mitigation strategies when assessing the environmental sustainability of ceramic membrane production. Full article

Acute kidney injury (AKI) is a serious clinical condition that is linked to markedly higher rates of morbidity and mortality in cirrhosis patients. Its diagnosis is challenging due to overlapping clinical and laboratory features among causes such as hepatorenal syndrome (HRS), acute tubular injury (ATI), and prerenal hypovolemia. In order to address the distinct pathophysiology and clinical context of cirrhosis, the definitions and classification of AKI have changed over time, moving from RIFLE and AKIN to KDIGO and ICA-AKI. Because cirrhosis patients have altered muscle mass and fluid retention, traditional markers like serum creatinine (sCr) and urine output have significant limitations. Neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and cystatin C (CysC) are some of the new biomarkers that have shown promise in early AKI detection and in differentiating structural from functional kidney injury. NGAL and KIM-1 are sensitive indicators of tubular damage with potential prognostic implications. IL-18 reflects inflammatory injury, and CysC offers a more reliable measure of glomerular filtration. Incorporating these markers may improve early diagnosis, risk stratification, and treatment decisions, representing a key direction for future research in managing AKI in cirrhosis. Full article

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA–B-Raf–MEK–ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD’s complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD. Full article

The cross-sectional dimensions of structural elements in a structure are design elements that need to be carefully designed and are related to the stiffness of the structure. Various optimization processes are applied to determine the optimum cross-sectional dimensions of beams or columns in structures. By repeating the optimization processes for multiple load scenarios, it is possible to create a data set that shows the optimum design section properties. However, this step means repeating the same processes to produce the optimum cross-sectional dimensions. Artificial intelligence technology offers a short-cut solution to this by providing the opportunity to train itself with previously generated optimum cross-sectional dimensions and infer new cross-sectional dimensions. By processing the data, the artificial neural network can generate models that predict the cross-section for a new structural element. In this study, an optimization process is applied to a simple tubular column and an I-section beam, and the results are compiled to create a data set that presents the optimum section dimensions as a class. The harmony search (HS) algorithm, which is a metaheuristic method, was used in optimization. An artificial neural network (ANN) was created to predict the cross-sectional dimensions of the sample structural elements. The neural architecture search (NAS) method, which incorporates many metaheuristic algorithms designed to search for the best artificial neural network architecture, was applied. In this method, the best values of various parameters of the neural network, such as activation function, number of layers, and neurons, are searched for in the model with a tool called HyperNetExplorer. Model metrics were calculated to evaluate the prediction success of the developed model. An effective neural network architecture for column and beam elements is obtained. Full article

Background and Objectives: The long-term renal and cardiovascular effects of neonatal acute kidney injury (AKI) in preterm infants remain unclear. This study investigated whether neonatal AKI leads to persistent subclinical kidney injury and blood pressure changes in school-aged children born preterm. Methods: In this prospective cohort, preterm-born children (≤35 weeks’ gestation) with (n = 19) and without (n = 38) neonatal AKI were evaluated at 7–12 years. A term-born control group (n = 44) was included for biomarker comparison. Assessments included perinatal data, anthropometry, office and ambulatory blood pressure monitoring (ABPM), and renal ultrasonography. Kidney function was evaluated using serum creatinine (sCr), cystatin C, and estimated glomerular filtration rate (eGFR). Tubular injury was assessed using urinary kidney injury molecule-1/Cr (KIM-1/Cr), neutrophil gelatinase-associated lipocalin/Cr (NGAL/Cr), and trefoil factor 3/Cr (TFF3/Cr) ratios, as well as serum TFF3. Results: Conventional kidney function markers were similar among groups. However, the AKI group had higher serum cystatin C, lower cystatin C–based eGFR, and elevated urinary KIM-1/Cr and NGAL/Cr compared to no-AKI and term controls. Serum TFF3 was also higher in the AKI group. ABPM revealed higher nocturnal systolic blood pressure and blood pressure load in the AKI group. Kidney size did not differ between preterm subgroups. Conclusions: Neonatal AKI in preterm infants is associated with subtle alterations and potential renal stress or injury at school age, detectable only with sensitive biomarkers and ABPM. Further prospective studies are needed to validate these biomarkers and determine their role in predicting long-term outcomes in preterm infants with neonatal AKI. Full article

Background: During infection with the cytomegalovirus (CMV), the membrane system of the infected cell is remodelled into a megastructure called the assembly compartment (AC). These extensive changes may involve the manipulation of the host cell proteome by targeting a pleiotropic function of the cell such as ubiquitination (Ub). In this study, we investigate whether the Ub system is required for the establishment and maintenance of the AC in murine CMV (MCMV)-infected cells Methods: NIH3T3 cells were infected with wild-type and recombinant MCMVs and the Ub system was inhibited with PYR-41. The expression of viral and host cell proteins was analyzed by Western blot. AC formation was monitored by immunofluorescence with confocal imaging and long-term live imaging as the dislocation of the Golgi and expansion of Rab10-positive tubular membranes (Rab10 TMs). A cell line with inducible expression of hemagglutinin (HA)-Ub was constructed to monitor ubiquitination. siRNA was used to deplete host cell factors. Infectious virion production was monitored using the plaque assay. Results: The Ub system is required for the establishment of the infection, progression of the replication cycle, viral gene expression and production of infectious virions. The Ub system also regulates the establishment and maintenance of the AC, including the expansion of Rab10 TMs. Increased ubiquitination of WASHC1, which is recruited to the machinery that drives the growth of Rab10 TMs, is consistent with Ub-dependent rheostatic control of membrane tubulation and the continued expansion of Rab10 TMs. Conclusions: The Ub system is intensively utilized at all stages of the MCMV replication cycle, including the reorganization of the membrane system into the AC. Disruption of rheostatic control of the membrane tubulation by ubiquitination and expansion of Rab10 TREs within the AC may contribute to the development of a sufficient amount of tubular membranes for virion envelopment. Full article

Chloride, long considered a passive extracellular anion, has emerged as a key determinant in the pathophysiology and management of heart failure (HF) and cardiorenal syndrome. In contrast to sodium, which primarily reflects water balance and vasopressin activity, chloride exerts broader effects on neurohormonal activation, acid–base regulation, renal tubular function, and diuretic responsiveness. Its interaction with With-no-Lysine (WNK) kinases and chloride-sensitive transporters underscores its pivotal role in electrolyte and volume homeostasis. Hypochloremia, frequently observed in HF patients treated with loop diuretics, is independently associated with adverse outcomes, diuretic resistance, and arrhythmic risk. Conversely, hyperchloremia—often iatrogenic—may contribute to renal vasoconstriction and hyperchloremic metabolic acidosis. Experimental data also implicate chloride dysregulation in myocardial electrical disturbances and an increased risk of sudden cardiac death. Despite mounting evidence of its clinical importance, serum chloride remains underappreciated in contemporary risk assessment models and treatment algorithms. This review synthesizes emerging evidence on chloride’s role in HF, explores its diagnostic and therapeutic implications, and advocates for its integration into individualized care strategies. Future studies should aim to prospectively validate these associations, evaluate chloride-guided therapeutic interventions, and assess whether incorporating chloride into prognostic models can improve risk stratification and outcomes in patients with heart failure and cardiorenal syndrome. Full article

Hypertension and diabetes mellitus are key contributors to kidney damage, with the renal tubule playing a central role in the progression of kidney disease. MicroRNAs have important regulatory roles in renal injury and are among the most abundant cargos within extracellular vesicles (EVs), emerging as novel kidney disease biomarkers and therapeutic tools. Previously, we identified miR-200a-3p and its target SIRT1 as having a potential role in kidney injury. We aimed to evaluate miR-200a-3p levels in EVs from patient’s urine and delve into its function in causing tubular injury. We quantified miR-200a-3p urinary EV levels in hypertensive patients with and without diabetes (n = 69), 42 of which were with increased urinary albumin excretion (UAE). We analysed miR-200a-3p levels in EVs and cellular pellets, as well as their targets at mRNA and protein levels in renal tubule cells (RPTECs) subjected to high glucose and Angiotensin II treatments, and observed their influence on apoptosis, RPTEC markers and tubular injury markers. We conducted microRNA mimic and inhibitor transfections in treated RPTECs. Our findings revealed elevated miR-200a-3p levels in increased UAE patient urinary EVs, effectively discriminating UAE (AUC of 0.75, p = 0.003). In vitro, miR-200a-3p and renal injury markers increased, while RPTEC markers, SIRT1, and apoptosis decreased under treatments. Experiments using miR-200a-3p mimics and inhibitors revealed a significant impact on SIRT1 and decrease in tubular damage through miR-200a-3p inhibition. Increased levels of miR-200a-3p emerge as a potential disease marker, and its inhibition provides a therapeutic target aimed at reducing renal tubular damage linked to hypertension and diabetes. Full article

Background/Objectives: Early graft loss within the first year is a rare complication of renal transplantations. In some cases, venous congestion may cause renal dysfunction, but, so far, this syndrome has been assessed by the presence of the triad of an unexplained decrease in renal function together with severe volume overload, relevant heart disease, and a typical histopathological pattern of tubular injury. This study aimed to determine the proportion of patients with early allograft loss due to venous congestion within the first year after transplantation. Additionally, we characterized typical renal vein flow profiles to identify patients at risk of early graft loss due to postrenal venous congestion and prerenal perfusion deficit. Methods: In this retrospective, single-center study, patients who underwent kidney transplantations between 2010 and 2020 and experienced early graft loss within the first year after transplantation were included. Clinical data and renal vein blood flow profiles were collected retrospectively. Results: A total of 579 patients received kidney transplants between 2010 and 2020. Of these, 43 patients (7.4%) lost their grafts within the first year of transplantation. Nine of these 43 patients (20.9% with early graft loss) lost their graft due to a suspected cardiorenal syndrome. Besides graft loss, cardiorenal patients had a significantly higher risk of death than other patients. All cardiorenal patients could be identified using a distinct renal vein blood flow profile (100%). Conclusions: We characterized the typical renal vein blood flow profiles in patients at risk of premature graft loss due to venous congestion. The early identification of such patients is crucial in improving outcomes after renal transplantation. Full article