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Naunyn-Schmiedeberg's Archives of... Jun 2024Renal fibrosis is the common endpoint of nearly all chronic and progressive nephropathies. Cell death and sterile inflammation are the main characteristics of renal...
Sorafenib and edaravone protect against renal fibrosis induced by unilateral ureteral obstruction via inhibition of oxidative stress, inflammation, and RIPK-3/MLKL pathway.
Renal fibrosis is the common endpoint of nearly all chronic and progressive nephropathies. Cell death and sterile inflammation are the main characteristics of renal fibrosis, which can lead to end-stage renal failure. The inflammatory reaction triggered by tissue damage is strongly related to necroptosis, a type of caspase-independent, regulated cell death. Using an animal model of unilateral ureteral obstruction (UUO), the anti-fibrotic effects of sorafenib (SOF), a multi-kinase inhibitor, and edaravone (EDV), a potent antioxidant and free radical scavenger, were examined in rats with obstructive nephropathy. Experimentally, animals were divided randomly into five groups: sham; UUO; UUO + SOF (5 mg/kg/day, P.O.); UUO + EDV (20 mg/kg/day, P.O.); and UUO + SOF + EDV groups. The kidney function biomarkers, oxidant/antioxidant status, renal mRNA expressions of TNF-α, collagen-1α, protein expressions of RIPK-1, RIPK-3, MLKL, caspase-8, HYP, MPO, and TNF-α were all significantly modulated by UUO. Administration of either SOF or EDV significantly attenuated cellular and molecular changes induced by UUO. Also, histopathological changes were improved. Moreover, SOF in combination with EDV, significantly improved UUO-induced renal fibrosis compared with each drug alone. Collectively, administration of either SOF or EDV or both of them significantly attenuated the rats with obstructive nephropathy, possibly by blocking the RIPK-3/MLKL necroptotic pathway and suppressing renal oxidative stress and inflammation.
PubMed: 38874805
DOI: 10.1007/s00210-024-03146-z -
Animal Models and Experimental Medicine Jun 2024Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as...
BACKGROUND
Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis; therefore, inhibition of ASK1 kinase activity can protect cells from pathological injury. In this study, we designed and synthesized a novel selective ASK1 inhibitor, CS17919, and investigated its pharmacological effects in various animal models of metabolic injury.
METHODS
First, we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib (GS-4997), a phase III ASK1 inhibitor. We then conducted pharmacokinetic (PK) studies in mice. Finally, we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH).
RESULTS
Compared to GS-4997, CS17919 demonstrated comparable inhibition of ASK1 in vitro, exhibited lower toxicity, and provided greater protection in palmitic acid-treated LO2 cells. CS17919 also showed pronounced pharmacokinetic properties such as a high plasma concentration. In the unilateral ureteral obstruction model (UUO), CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis. In the diabetic kidney disease (DKD) model, CS17919 significantly improved serum creatinine and glomerular sclerosis. In the NASH model, the combination of CS17919 and a THRβ agonist (CS27109) was found to significantly improve liver inflammation and substantially reduced liver fibrosis.
CONCLUSIONS
CS17919 showed cell protective, anti-inflammatory, and antifibrotic effects in vitro and in vivo, suggesting its therapeutic potential for metabolic-related kidney and liver diseases.
PubMed: 38873818
DOI: 10.1002/ame2.12437 -
PloS One 2024Renal fibrosis is the most common pathway in progressive kidney diseases. The unilateral ureteral obstruction (UUO) model is used to induce progressive renal fibrosis....
Renal fibrosis is the most common pathway in progressive kidney diseases. The unilateral ureteral obstruction (UUO) model is used to induce progressive renal fibrosis. We evaluated the effects of irisin on renal interstitial fibrosis in UUO mice. The GSE121190, GSE36496, GSE42303, and GSE96101 datasets were downloaded from the Gene Expression Omnibus (GEO) database. In total, 656 differentially expressed genes (DEGs) were identified in normal and UUO mouse renal samples. Periostin and matrix metalloproteinase-2 (MMP-2) were selected to evaluate the effect of irisin on renal fibrosis in UUO mice. In UUO mice, irisin ameliorated renal function, decreased the expression of periostin and MMP-2, and attenuated epithelial-mesenchymal transition and extracellular matrix deposition in renal tissues. In HK-2 cells, irisin treatment markedly attenuated TGF-β1-induced expression of periostin and MMP-2. Irisin treatment also inhibited TGF-β1-induced epithelial-mesenchymal transition, extracellular matrix formation, and inflammatory responses. These protective effects of irisin were abolished by the overexpression of periostin and MMP-2. In summary, irisin treatment can improve UUO-induced renal interstitial fibrosis through the TGF-β1/periostin/MMP-2 signaling pathway, suggesting that irisin may be used for the treatment of renal interstitial fibrosis.
Topics: Animals; Ureteral Obstruction; Fibrosis; Fibronectins; Mice; Matrix Metalloproteinase 2; Signal Transduction; Transforming Growth Factor beta1; Cell Adhesion Molecules; Epithelial-Mesenchymal Transition; Male; Humans; Kidney Diseases; Kidney; Mice, Inbred C57BL; Cell Line; Disease Models, Animal; Periostin
PubMed: 38870184
DOI: 10.1371/journal.pone.0299389 -
American Journal of Physiology.... Jun 2024Biliary atresia (BA) is the leading indication for pediatric liver transplantation. Rhesus rotavirus (RRV) induced murine BA develops an obstructive cholangiopathy that...
Biliary atresia (BA) is the leading indication for pediatric liver transplantation. Rhesus rotavirus (RRV) induced murine BA develops an obstructive cholangiopathy that mirrors the human disease. We have previously demonstrated the "SRL" motif on RRV's VP4 protein binds to heat shock cognate 70 protein (Hsc70) facilitating entry into cholangiocytes. In this study, we analyzed how binding to Hsc70 affects viral endocytosis, intracellular trafficking, and uniquely activates the signaling pathway that induces murine BA. Inhibition of clathrin- and dynamin-mediated endocytosis in cholangiocytes following infection demonstrated blocking dynamin decreased the infectivity of RRV whereas clathrin inhibition had no effect. Blocking early endosome trafficking resulted in decreased viral titers of RRV while late endosome inhibition had no effect. Following infection, TLR3 expression and p-NF-κB levels increased in cholangiocytes, leading to increased release of CXCL9 and CXCL10. Infected mice knocked out for TLR3 had decreased levels of CXCL9 and CXCL10, resulting in reduced NK cell numbers. Human BA patients experienced an increase in CXCL10 levels, suggesting this as a possible pathway leading to biliary obstruction. Viruses that utilize Hsc70 for cell entry exploit a clathrin-independent pathway and traffic to the early recycling endosome uniquely activating NF-κB through TLR3, leading to the release of CXCL9 and CXCL10, and inducing NK cell recruitment. These results define how the "SRL" peptide found on RRV's VP4 protein modulates viral trafficking, inducing the host response leading to bile duct obstruction.
PubMed: 38860860
DOI: 10.1152/ajpgi.00308.2023 -
World Journal of Critical Care Medicine Jun 2024Discerning the etiology of acute kidney injury (AKI) in cirrhotic patients remains a formidable challenge due to diverse and overlapping causes. The conventional... (Review)
Review
Discerning the etiology of acute kidney injury (AKI) in cirrhotic patients remains a formidable challenge due to diverse and overlapping causes. The conventional approach of empiric albumin administration for suspected volume depletion may inadvertently lead to fluid overload. In the recent past, point-of-care ultrasonography (POCUS) has emerged as a valuable adjunct to clinical assessment, offering advantages in terms of diagnostic accuracy, rapidity, cost-effectiveness, and patient satisfaction. This review provides insights into the strategic use of POCUS in evaluating cirrhotic patients with AKI. The review distinguishes basic and advanced POCUS, emphasizing a 5-point basic POCUS protocol for efficient assessment. This protocol includes evaluations of the kidneys and urinary bladder for obstructive nephropathy, lung ultrasound for detecting extravascular lung water, inferior vena cava (IVC) ultrasound for estimating right atrial pressure, internal jugular vein ultrasound as an alternative to IVC assessment, and focused cardiac ultrasound for assessing left ventricular (LV) systolic function and identifying potential causes of a plethoric IVC. Advanced POCUS delves into additional Doppler parameters, including stroke volume and cardiac output, LV filling pressures and venous congestion assessment to diagnose or prevent iatrogenic fluid overload. POCUS, when employed judiciously, enhances the diagnostic precision in evaluating AKI in cirrhotic patients, guiding appropriate therapeutic interventions, and minimizing the risk of fluid-related complications.
PubMed: 38855271
DOI: 10.5492/wjccm.v13.i2.93812 -
Cell Death & Disease Jun 2024The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting...
The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2 mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2 BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-β1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.
Topics: Animals; Apoptosis; Macrophages; Receptors, Immunologic; Membrane Glycoproteins; Mice; Signal Transduction; STAT Transcription Factors; Mice, Inbred C57BL; Janus Kinases; Kidney; Mice, Knockout; Male; Fibrosis; Reperfusion Injury; Ureteral Obstruction; Cell Polarity; TOR Serine-Threonine Kinases; Acute Kidney Injury
PubMed: 38849370
DOI: 10.1038/s41419-024-06756-w -
Cell Biology International Jun 2024W. Xi, X. Zhao, M. Wu, W. Jia, and H. Li, "Lack of MicroRNA-155 Ameliorates Renal Fibrosis by Targeting PDE3A/TGF-β1/Smad Signaling in Mice with Obstructive...
W. Xi, X. Zhao, M. Wu, W. Jia, and H. Li, "Lack of MicroRNA-155 Ameliorates Renal Fibrosis by Targeting PDE3A/TGF-β1/Smad Signaling in Mice with Obstructive Nephropathy", Cell Biology International 42, no. 11 (2018): 1523-1532. https://doi.org/10.1002/cbin.11038 The above article, published online on 6 August 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Sergio Schenkman; the International Federation for Cell Biology; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Several flaws and inconsistencies between results presented and experimental methods described were found. Furthermore, several image elements in Figure 2 A were found to have been published previously in a different scientific context. Thus, the editors consider the conclusions of this article to be invalid. The authors have been informed of the decision of retraction but were not available for a final confirmation.
PubMed: 38845116
DOI: 10.1002/cbin.12194 -
Southern African Journal of Infectious... 2024HIV patients frequently develop acute kidney injury (AKI) because of sepsis and diarrhoeal disease. Here, we report a case of an HIV-positive man with partially treated...
UNLABELLED
HIV patients frequently develop acute kidney injury (AKI) because of sepsis and diarrhoeal disease. Here, we report a case of an HIV-positive man with partially treated sinonasal plasmablastic lymphoma (PBL) and unexplained AKI. A kidney biopsy revealed two pathological processes.
CONTRIBUTION
While urinary tract obstruction is the most common mechanism by which PBL causes AKI, maintaining a high level of suspicion for multiple pathological processes in cases involving light chain producing PBL.
PubMed: 38841341
DOI: 10.4102/sajid.v39i1.637 -
Cureus May 2024Obstructive sleep apnea (OSA) has been a significant contributor to mortality all across the globe. The most attributing factors to pathogenesis are metabolic syndrome,...
A Comprehensive Analysis of Clinical, Biochemical, and Polysomnographic Characteristics in Patients With Type 2 Diabetes Mellitus With and Without Obstructive Sleep Apnea.
BACKGROUND
Obstructive sleep apnea (OSA) has been a significant contributor to mortality all across the globe. The most attributing factors to pathogenesis are metabolic syndrome, obesity, diabetes, and so on, but the indicators of its early detection are still elusive.
OBJECTIVE
The study aimed to compare the clinical, biochemical, and polysomnographic characteristics of type 2 diabetes patients with and without OSA.
DESIGN AND METHODS
This cross-sectional study was conducted at the Department of Medicine and Endocrinology Unit of Dayanand Medical College and Hospital, Ludhiana. A total of 584 patients with type 2 diabetes were assessed using the Berlin questionnaire, with 302 fulfilling the criteria for a high risk of OSA. Out of 302 patients who met the criteria for the high-risk category, 110 patients underwent a sleep study.
RESULTS
Three hundred and two patients satisfying the inclusion and exclusion criteria were enrolled in the study. A total of 110 patients underwent a sleep study, of which 68 (61.8%) had evidence of OSA. The waist-to-hip ratio was considerably higher in the OSA patients than in the non-OSA group (1.09 vs 0.930, p = 0.001). HbA1c >7% was found in 58.8% of OSA patients contrary to 38.1% of non-OSA patients. Fasting plasma glucose levels (>126 mg/dl) were identified in a substantially larger proportion of OSA patients than the non-OSA patients (64.7% vs 45.2%, p = 0.04). Similarly, peripheral neuropathy was found more commonly in the OSA patients than in the non-OSA patients (47% vs. 26.1%, p = 0.02). Prevalence of retinopathy, nephropathy, coronary artery disease, stroke, heart failure, and peripheral vascular disease did not differ significantly between the two groups.
CONCLUSIONS
OSA frequently occurs among individuals diagnosed with type 2 diabetes mellitus. The prompt identification of OSA within this demographic is imperative to pinpoint those at an elevated risk of succumbing to conditions such as peripheral neuropathy, the exacerbation of glycemic control, and the onset of unmanaged hypertension. Moreover, there exists a positive correlation between the waist-to-hip ratio and the prevalence of OSA in persons with type 2 diabetes mellitus, highlighting the critical role of waist-to-hip ratio assessments in this patient population.
PubMed: 38841011
DOI: 10.7759/cureus.59734 -
BMC Medical Informatics and Decision... Jun 2024Diagnosis can often be recorded in electronic medical records (EMRs) as free-text or using a term with a diagnosis code. Researchers, governments, and agencies,...
BACKGROUND
Diagnosis can often be recorded in electronic medical records (EMRs) as free-text or using a term with a diagnosis code. Researchers, governments, and agencies, including organisations that deliver incentivised primary care quality improvement programs, frequently utilise coded data only and often ignore free-text entries. Diagnosis data are reported for population healthcare planning including resource allocation for patient care. This study sought to determine if diagnosis counts based on coded diagnosis data only, led to under-reporting of disease prevalence and if so, to what extent for six common or important chronic diseases.
METHODS
This cross-sectional data quality study used de-identified EMR data from 84 general practices in Victoria, Australia. Data represented 456,125 patients who attended one of the general practices three or more times in two years between January 2021 and December 2022. We reviewed the percentage and proportional difference between patient counts of coded diagnosis entries alone and patient counts of clinically validated free-text entries for asthma, chronic kidney disease, chronic obstructive pulmonary disease, dementia, type 1 diabetes and type 2 diabetes.
RESULTS
Undercounts were evident in all six diagnoses when using coded diagnoses alone (2.57-36.72% undercount), of these, five were statistically significant. Overall, 26.4% of all patient diagnoses had not been coded. There was high variation between practices in recording of coded diagnoses, but coding for type 2 diabetes was well captured by most practices.
CONCLUSION
In Australia clinical decision support and the reporting of aggregated patient diagnosis data to government that relies on coded diagnoses can lead to significant underreporting of diagnoses compared to counts that also incorporate clinically validated free-text diagnoses. Diagnosis underreporting can impact on population health, healthcare planning, resource allocation, and patient care. We propose the use of phenotypes derived from clinically validated text entries to enhance the accuracy of diagnosis and disease reporting. There are existing technologies and collaborations from which to build trusted mechanisms to provide greater reliability of general practice EMR data used for secondary purposes.
Topics: Humans; Cross-Sectional Studies; General Practice; Electronic Health Records; Victoria; Chronic Disease; Clinical Coding; Data Accuracy; Population Health; Male; Female; Middle Aged; Adult; Australia; Aged; Diabetes Mellitus, Type 2
PubMed: 38840250
DOI: 10.1186/s12911-024-02560-w