Tubular insulin-induced gene 1 deficiency promotes NAD+ consumption and exacerbates kidney fibrosis.

Profibrotic proximal tubules (PT) were identified as a unique phenotype of proximal tubule cells (PTCs) in renal fibrosis by single-cell RNA sequencing (scRNA-seq). Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insulin-induced gene 1 (Insig1) is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered that tubular Insig1 deficiency, rather than fibroblast Insig1 deficiency, plays a detrimental role in the pathogenesis of renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Mechanistically, Insig1 deletion in PTCs boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, as well as accelerating renal fibrosis. We also identified nicardipine as a selective inhibitor of Aldh1a1, which could restore NAD+ and maintain ER homeostasis, as well as improve renal fibrosis. Together, our findings support tubular Insig1 as a new therapeutic target for chronic kidney disease (CKD).

Inhibition of RAC attenuates Adriamycin-induced podocyte injury.

Minimal Change Disease (MCD), which is associated with podocyte injury, is the leading cause of nephrotic syndrome in children. A considerable number of patients experience relapses and require prolonged use of prednisone and immunosuppressants. Multi-drug resistance and frequent relapses can lead to disease progression to focal and segmental glomerulosclerosis (FSGS). To identify potential targets for therapy of podocyte injury, we examined microarray data of mRNAs in glomerular samples from both MCD patients and healthy donors, obtained from the GEO database. Differentially expressed genes (DEGs) were used to construct the protein-protein interactions (PPI) network through the application of the search tool for the retrieval of interacting genes (STRING) tool. The most connected genes in the network were ranked using cytoHubba. 16 hub genes were selected and validated by qRT-PCR. RAC2 was identified as a potential therapeutic target for further investigation. By downregulating RAC2, Adriamycin (ADR)-induced human podocytes (HPCs) injury was attenuated. EHT-1864, a small molecule inhibitor that targets the RAC (RAC1, RAC2, RAC3) family, proved to be more effective than RAC2 silencing in reducing HPCs injury. In conclusion, our research suggests that EHT-1864 may be a promising new molecular drug candidate for patients with MCD and FSGS.

Monogenic Causes Identified in 23.68% of Children with Steroid-Resistant Nephrotic Syndrome: A Single-Centre Study.

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of end-stage kidney disease in children, mostly associated with focal segmental glomerulosclerosis (FSGS). Advances in genomic science have enabled the identification of causative variants in 20-30% of SRNS patients. Methods: We used whole exome sequencing to explore the genetic causes of SRNS in children. Totally, 101 patients with SRNS and 13 patients with nephrotic proteinuria and FSGS were retrospectively enrolled in our hospital between 2018 and 2022. For the known monogenic causes analysis, we generated a known SRNS gene list of 71 genes through reviewing the OMIM database and literature. Results: Causative variants were identified in 23.68% of our cohort, and the most frequently mutated genes in our cohort were WT1 (7/27), NPHS1 (3/27), ADCK4 (3/27), and ANLN (2/27). Five patients carried variants in phenocopy genes, including MYH9, MAFB, TTC21B, AGRN, and FAT4. The variant detection rate was the highest in the two subtype groups with congenital nephrotic syndrome and syndromic SRNS. In total, 68.75% of variants we identified were novel and have not been previously reported in the literature. Conclusion: Comprehensive genetic analysis is key to realizing the clinical benefits of a genetic diagnosis. We suggest that all children with SRNS undergo genetic testing, especially those with early-onset and extrarenal phenotypes.

Clinical manifestations and risk factors of shock in children with multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a novel disease associated with COVID-19. The COVID-19 epidemic peaked in May 2022 in Taiwan, and we encountered our first case of MIS-C in late May 2022. We aimed to present patients' clinical manifestations and identify risk factors for shock. METHODS: We included patients diagnosed with MIS-C at two medical centers from May 2022 to August 2022. We separated those patients into two groups according to whether they experienced shock. We collected demographic, clinical manifestation, and laboratory data of the patients and performed statistical analysis between the two groups. RESULTS: We enrolled 28 patients, including 13 (46 %) with shock and 15 (54 %) without shock. The median age was 6.4 years (IQR: 1.9-7.5). In single variable analysis, patients with shock tended to be older, had more neurological symptoms, more conjunctivitis and strawberry tongue, lower lymphocyte count, lower platelet counts, and higher C-reactive protein, higher procalcitonin, higher ferritin, and higher D-dimer levels than those without shock. The area under the ROC curve that used procalcitonin to be the risk factor of shock with MIS-C was 0.815 (95 % CI 0.644 to 0.987). The cutoff value obtained by ROC analysis of procalcitonin was 1.68 ng/mL. With this cutoff, the test characteristics of procalcitonin were as follows: sensitivity 77 %, specificity 93 %, positive predictive value 91 %, negative predictive value 82 %. Multivariable analysis revealed that procalcitonin was the only independent risk factor of shock with MIS-C on admission (OR, 26.00, 95 % CI, 1.01-668.89). CONCLUSIONS: MIS-C patients with high initial procalcitonin levels have higher risks of experiencing shock and may need ICU admission.

Association of organophosphate flame retardants with all-cause and cause-specific mortality among adults aged 40 years and older.

The longitudinal associations of urinary concentrations of diphenyl phosphate (DPHP), bis(2-chloroethyl) phosphate (BCEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCPP) with all-cause, cardiovascular, and cancer mortality in a population of adults aged 40 years and older are still unclear. A total of 3238 participants were included in this cohort study. Urinary BCEP levels were positively associated with all-cause mortality and cardiovascular mortality. Specifically, a logarithmic increase in BCEP concentration was related to a 26 % higher risk of all-cause mortality and a 32 % higher risk of cardiovascular mortality. No significant associations were observed for DPHP and BDCPP in relation to mortality. Doseresponse analysis confirmed the linear associations of BCEP with all-cause and cardiovascular mortality and the nonlinear inverted U-shaped association between DPHP exposure and all-cause mortality. Notably, the economic burden associated with BCEP exposure was estimated, and it was shown that concentrations in the third tertile of BCEP exposure incurred approximately 507 billion dollars of financial burden for all-cause mortality and approximately 717 billion dollars for cardiovascular mortality. These results highlight the importance of addressing exposure to BCEP and its potential health impacts on the population. More research is warranted to explore the underlying mechanisms and develop strategies for reducing exposure to this harmful chemical.

Plk1 promotes renal tubulointerstitial fibrosis by targeting autophagy/lysosome axis.

The prevalence of chronic kidney disease (CKD) has been increasing over the past decades. However, no effective therapies are available for delaying or curing CKD. Progressive fibrosis is the major pathological feature of CKD, which leads to end-stage renal disease (ESRD). The present study showed that Polo-like kinase 1 (Plk1) was upregulated in the kidneys of CKD patients and mice subjected to unilateral ureteral obstruction (UUO) with location in proximal tubules and tubulointerstitial fibroblasts. Pharmacological inhibition, genetic silencing or knockout of Plk1 attenuated obstructive nephropathy due to suppressed fibroblast activation mediated by reduced autophagic flux. We found Plk1 plays a critical role in maintaining intralysosomal pH by regulating ATP6V1A phosphorylation, and inhibition of Plk1 impaired lysosomal function leading to blockade of autophagic flux. In addition, Plk1 also prevented partial epithelial-mesenchymal transition (pEMT) of tubular epithelial cells via autophagy pathway. In conclusion, this study demonstrated that Plk1 plays a pathogenic role in renal tubulointerstitial fibrosis by regulating autophagy/lysosome axis. Thus, targeting Plk1 could be a promising strategy for CKD treatment.

TRAF1 improves cisplatin-induced acute kidney injury via inhibition of inflammation and metabolic disorders.

BACKGROUND: Cisplatin-induced acute kidney injury (AKI) is a severe clinical complication with no satisfactory therapies in the clinic. Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) plays a vital role in both inflammation and metabolism. However, the TRAF1 effect in cisplatin induced AKI needs to be evaluated. METHODS: We observed the role of TRAF1 in eight-week-old male mice and mouse proximal tubular cells both treated with cisplatin by examining the indicators associated with kidney injury, apoptosis, inflammation, and metabolism. RESULTS: TRAF1 expression was decreased in cisplatin-treated mice and mouse proximal tubular cells (mPTCs), suggesting a potential role of TRAF1 in cisplatin-associated kidney injury. TRAF1 overexpression significantly alleviated cisplatin-triggered AKI and renal tubular injury, as demonstrated by reduced serum creatinine (Scr) and urea nitrogen (BUN) levels, as well as the ameliorated histological damage and inhibited upregulation of NGAL and KIM-1. Moreover, the NF-κB activation and inflammatory cytokine production enhanced by cisplatin were significantly blunted by TRAF1. Meanwhile, the increased number of apoptotic cells and enhanced expression of BAX and cleaved Caspase-3 were markedly decreased by TRAF1 overexpression both in vivo and vitro. Additionally, a significant correction of the metabolic disturbance, including perturbations in energy generation and lipid and amino acid metabolism, was observed in the cisplatin-treated mice kidneys. CONCLUSION: TRAF1 overexpression obviously attenuated cisplatin-induced nephrotoxicity, possibly by correcting the impaired metabolism, inhibiting inflammation, and blocking apoptosis in renal tubular cells. GENERAL SIGNIFICANCE: These observations emphasize the novel mechanisms associated to metabolism and inflammation of TRAF1 in cisplatin-induced kidney injury.

Clinical characteristics and factors associated with severe COVID-19 in hospitalized children during the SARS-CoV-2 Omicron pandemic in Taiwan.

BACKGROUND: Since April 2022, a notable increase in COVID-19 cases with the rapid spread of the SARS-CoV-2 Omicron variant has been reported in Taiwan. In the epidemic, children were one of the most vulnerable groups, so we analyzed their clinical presentations and factors associated with severe complications of COVID-19 in children. METHODS: We included hospitalized patients under 18 years old with lab-confirmed SARS-CoV-2 infection from March 1, 2022, to July 31, 2022. We collected the demographic and clinical characteristics of the patients. Patients requiring intensive care were defined as severe cases. RESULTS: Among the 339 enrolled patients, the median age was 31 months (interquartile range (IQR), 8-79.0 months); and 96 patients (28.3%) had underlying diseases. Fever was noted in 319 patients (94.1%) with a median duration of two days (IQR 2-3 days). Twenty-two patients (6.5%) were severe cases, including 10 patients (2.9%) with encephalopathy with abnormal neuroimaging and ten patients (2.9%) with shock. Two patients (0.6%) died. Patients with congenital cardiovascular disease (aOR: 21.689), duration of fever up to four days or more (aOR: 6.466), desaturation (aOR: 16.081), seizure (aOR: 20.92), and procalcitonin >0.5 ng/mL (aOR: 7.886) had a higher risk of severe COVID-19. CONCLUSIONS: Vital signs need close monitoring, early management and/or intensive care may be applied in COVID-19 patients with congenital cardiovascular diseases, fever lasting ≥4 days, seizures, desaturation and/or elevated procalcition since they are at higher risks of severe diseases.

TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5.

Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent injury to renal tubular epithelial cells and activation of fibroblasts chiefly determine the extent of renal fibrosis. In this study, the role of tumor protein 53 regulating kinase (TP53RK) in the pathogenesis of renal fibrosis and its underlying mechanisms is investigated. TP53RK is upregulated in fibrotic human and animal kidneys with a positive correlation to kidney dysfunction and fibrotic markers. Interestingly, specific deletion of TP53RK either in renal tubule or in fibroblasts in mice can mitigate renal fibrosis in CKD models. Mechanistic investigations reveal that TP53RK phosphorylates baculoviral IAP repeat containing 5 (Birc5) and facilitates its nuclear translocation; enhanced Birc5 displays a profibrotic effect possibly via activating PI3K/Akt and MAPK pathways. Moreover, pharmacologically inhibiting TP53RK and Birc5 using fusidic acid (an FDA-approved antibiotic) and YM-155(currently in clinical phase 2 trials) respectively both ameliorate kidney fibrosis. These findings demonstrate that activated TP53RK/Birc5 signaling in renal tubular cells and fibroblasts alters cellular phenotypes and drives CKD progression. A genetic or pharmacological blockade of this axis serves as a potential strategy for treating CKDs.

Reduction of NADPH oxidase 4 in adipocytes contributes to the anti-obesity effect of dihydroartemisinin.

Artemisinin derivatives have been found to have anti-obesity effects recently, but the mechanism is still controversial. Herein, long-term DHA treatment in obese mice significantly reduced the body weight and improved glucose metabolism. However, short-term DHA treatment did not affect glucose metabolism in obese mice, suggesting that the improved glucose metabolism in mice with DHA treatment could be secondary to body weight reduction. Consistent with previous reports, we observed that DHA inhibited the differentiation of adipocytes. Mechanistically, DHA significantly reduced the expression of NADPH oxidase 4 (NOX4) in white adipose tissue (WAT) of mice and differentiated adipocytes, and using NOX4 siRNA or the NOX4 inhibitor GKT137831 significantly attenuated adipocyte differentiation. Over-expression of NOX4 partially reversed the inhibition effect of DHA on adipogenic differentiation of preadipocytes. In addition, targeted proteomics analysis showed that DHA improved the abnormality of metabolic pathways. In conclusion, DHA significantly reduced fat mass and improved glucose metabolism in obese mice, possibly by inhibiting NOX4 expression to suppress adipocyte differentiation and lipid accumulation in adipocytes.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in male mice.

Kidney injury initiates epithelial dedifferentiation and myofibroblast activation during the progression of chronic kidney disease. Herein, we find that the expression of DNA-PKcs is significantly increased in the kidney tissues of both chronic kidney disease patients and male mice induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. In vivo, knockout of DNA-PKcs or treatment with its specific inhibitor NU7441 hampers the development of chronic kidney disease in male mice. In vitro, DNA-PKcs deficiency preserves epithelial cell phenotype and inhibits fibroblast activation induced by transforming growth factor-beta 1. Additionally, our results show that TAF7, as a possible substrate of DNA-PKcs, enhances mTORC1 activation by upregulating RAPTOR expression, which subsequently promotes metabolic reprogramming in injured epithelial cells and myofibroblasts. Taken together, DNA-PKcs can be inhibited to correct metabolic reprogramming via the TAF7/mTORC1 signaling in chronic kidney disease, and serve as a potential target for treating chronic kidney disease.

NSC228155 alleviates septic cardiomyopathy via protecting mitochondria and inhibiting inflammation.

Septic cardiomyopathy is a lethal symptom of sepsis. Discovery of effective therapy that prevents cardiac injury in sepsis is critical in the clinical management of sepsis. NSC228155 is a novel compound with therapeutic potential on acute kidney injury by preventing apoptosis and protecting mitochondria. Whether NSC228155 protects against septic cardiomyopathy is unclear. In the present study, adult C57BL/6J mice were i.p injected with 5 mg/kg/day NSC228155 for 2 days before 10 mg/kg lipopolysaccharide (LPS) injection. Cardiac functional testing and sampling for serum and tissue were performed 12 and 24 h post LPS injection, respectively. NSC228155 significantly improved cardiac function examined by echocardiography, decreased the serum lactate dehydrogenase (LDH) and creatine kinase-MB, and pathologically alleviated cardiac injury in LPS mice. Accordingly, NSC228155 attenuated cardiomyocytes' mitochondrial damage as shown by decreased damaged mitochondrial ratio and activated signals for mitochondrial biogenesis, dynamics and mitophagy in LPS mice model. Metabolomics analysis demonstrated that NSC228155 corrected the metabolic disturbance involved in oxidative stress and energy metabolism, and decreased tissue injury metabolites in LPS-stimulated cardiac tissue. In the LPS-stimulated cardiac cell culture derived from human induced pluripotent stem cells, NSC228155 effectively restored the beating frequency, decreased LDH release, and protected mitochondria. NSC228155 also inhibited inflammation shown by decreased pro-inflammatory mediators in both serum and cardiac tissue in LPS model. Taken together, NSC228155 significantly improved cardiac function by directly preventing against cardiac cell injury and inhibiting inflammation in LPS model, hence may be a potential novel therapy against septic cardiomyopathy.

Anti-inflammatory role of fenofibrate in treating diseases.

Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic drug for treating hyperlipidemia. In addition to its lipid-lowering effect, fenofibrate has also been reported to exert anti-inflammatory effects with complicated underlying mechanisms of action. In general, the anti-inflammatory effect of fenofibrate is secondary to its lipid-lowering effect, especially for the inflammation caused by hyperlipidemia in the circulatory system. Some anti-inflammatory actions may also come from its regulatory effects on intracellular lipid metabolism by activating PPAR-α. In addition, some roles in anti-inflammation might be mediated by its direct regulation of inflammatory signaling pathways. In order to understand anti-inflammatory activities and the underlying mechanisms of fenofibrate action in disease better, we herein reviewed and discussed the anti-inflammatory roles and its subserving mechanisms in various diseases of different organ systems. Thus, this review offers insights into the optimal use of fenofibrate in the clinical setting.

A Potential Therapy Using Antisense Oligonucleotides to Treat Autosomal Recessive Polycystic Kidney Disease.

(1) Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by progressively enlarged kidneys with fusiform dilatation of the collecting ducts. Loss-of-function mutations in the PKHD1 gene, which encodes fibrocystin/polyductin, cause ARPKD; however, an efficient treatment method and drug for ARPKD have yet to be found. Antisense oligonucleotides (ASOs) are short special oligonucleotides which function to regulate gene expression and alter mRNA splicing. Several ASOs have been approved by the FDA for the treatment of genetic disorders, and many are progressing at present. We designed ASOs to verify whether ASOs mediate the correction of splicing further to treat ARPKD arising from splicing defects and explored them as a potential treatment option. (2) Methods: We screened 38 children with polycystic kidney disease for gene detection using whole-exome sequencing (WES) and targeted next-generation sequencing. Their clinical information was investigated and followed up. The PKHD1 variants were summarized and analyzed, and association analysis was carried out to analyze the relationship between genotype and phenotype. Various bioinformatics tools were used to predict pathogenicity. Hybrid minigene analysis was performed as part of the functional splicing analysis. Moreover, the de novo protein synthesis inhibitor cycloheximide was selected to verify the degraded pathway of abnormal pre-mRNAs. ASOs were designed to rescue aberrant splicing, and this was verified. (3) Results: Of the 11 patients with PKHD1 variants, all of them exhibited variable levels of complications of the liver and kidneys. We found that patients with truncating variants and variants in certain regions had a more severe phenotype. Two splicing variants of the PKHD1 genotypes were studied via the hybrid minigene assay: variants c.2141-3T>C and c.11174+5G>A. These cause aberrant splicing, and their strong pathogenicity was confirmed. We demonstrated that the abnormal pre-mRNAs produced from the variants escaped from the NMD pathway with the use of the de novo protein synthesis inhibitor cycloheximide. Moreover, we found that the splicing defects were rescued by using ASOs, which efficiently induced the exclusion of pseudoexons. (4) Conclusion: Patients with truncating variants and variants in certain regions had a more severe phenotype. ASOs are a potential drug for treating ARPKD patients harboring splicing mutations of the PKHD1 gene by correcting the splicing defects and increasing the expression of the normal PKHD1 gene.

Flavonoid derivative DMXAA attenuates cisplatin-induced acute kidney injury independent of STING signaling.

Cisplatin-induced nephrotoxicity is the main adverse effect of cisplatin-based chemotherapy and highly limits its clinical use. DMXAA, a flavonoid derivative, is a promising vascular disrupting agent and known as an agonist of STING. Although cGAS-STING activation has been demonstrated to mediate cisplatin-induced acute kidney injury (AKI), the role of DMXAA in this condition is unclear. Here, we defined an unexpected and critical role of DMXAA in improving renal function, ameliorating renal tubular injury and cell apoptosis, and suppressing inflammation in cisplatin-induced AKI. Moreover, we confirmed that DMXAA combated AKI in a STING-independent manner, as evidenced by its protective effect in STING global knockout mice subjected to cisplatin. Furthermore, we compared the role of DMXAA with another STING agonist SR717 in cisplatin-treated mice and found that DMXAA but not SR717 protected animals against AKI. To better evaluate the role of DMXAA, we performed transcriptome analyses and observed that both inflammatory and metabolic pathways were altered by DMXAA treatment. Due to the established role of metabolic disorders in AKI, which contributes to kidney injury and recovery, we also performed metabolomics using kidney tissues from cisplatin-induced AKI mice with or without DMXAA treatment. Strikingly, our results revealed that DMXAA improved the metabolic disorders in kidneys of AKI mice, especially regulated the tryptophan metabolism. Collectively, therapeutic administration of DMXAA ameliorates cisplatin-induced AKI independent of STING, suggesting a promising potential for preventing nephrotoxicity induced by cisplatin-based chemotherapy.

LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease.

Mitochondria comprise the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). Here, we studied Lon protease 1 (LONP1), a major mitochondrial protease, as its role in CKD pathogenesis is unclear. LONP1 expression was decreased in human patients and mice with CKD, and tubular-specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction in two different models of CKD, but these outcomes were aggravated by Lonp1 deletion. These results were confirmed in renal tubular epithelial cells in vitro. Mechanistically, LONP1 downregulation caused mitochondrial accumulation of the LONP1 substrate, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which disrupted mitochondrial function and further accelerated CKD progression. Finally, computer-aided virtual screening was performed, which identified a novel LONP1 activator. Pharmacologically, the LONP1 activator attenuated renal fibrosis and mitochondrial dysfunction. Collectively, these results imply that LONP1 is a promising therapeutic target for treating CKD.

Novel function of Roxadustat (FG-4592) as an anti-shock drug in sepsis by regulating mitochondrial oxidative stress and energy metabolism.

BACKGROUND: Septic shock is a serious clinical syndrome leading to high mortality. A new anti-anemia drug Roxadustat (FG-4592) protected against cardiac injury and hypertension. However, its effect and mechanism on shock and cardiac dysfunction induced by sepsis require to be investigated. METHODS: C57BL/6j mice received FG-4592 (10 mg/kg/day) by i.p injection, followed by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) treatment. Mortality and shock status were monitored during the experiment. Cardiac function was assessed using echocardiography and serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) assay. TEM, COX-SDH staining and ATP production were used to evaluate mitochondrial function. A non-targeted metabolomic analysis was performed to evaluate the metabolic disorders. RESULTS: Both pre- and post-treatment of FG-4592 could improve the survival rate in LPS- and CLP-induced sepsis mice with a better effect in pre-treated animals. Meanwhile, FG-4592 improved systolic blood pressure and body temperature drop in septic mice along with alleviated cardiac dysfunction (as shown by the restoration of decreased LVEF and LVFS and increased LDH and CK-MB) and inflammation. Interestingly, we observed that FG-4592 improved mitochondrial oxidative stress possibly by upregulating the anti-oxidative enzymes of SOD2 and HO-1. Furthermore, FG-4592 improved the energy supply and glycerophospholipid metabolism in cardiomyocytes, possibly through upregulating the HIF-1α-targeted genes of LDHA and PDK1 in glycolysis and CHK-α, respectively. CONCLUSIONS: FG-4592 protected against mortality and shock in septic animals possibly by antagonizing mitochondrial oxidative stress and metabolic disorders. GENERAL SIGNIFICANCE: This study provides a potential of FG-4592 as a novel drug for treating septic shock.

The identification of a novel CCNQ gene tail extension variant contributing to syndactyly, telecanthus and anogenital and renal malformations syndrome.

The "toe syndactyly, telecanthus and anogenital and renal malformations" (STAR) syndrome is a rare X-linked dominant inherited kidney ciliopathy caused by CCNQ gene mutations. Here, we investigated the genotype and phenotype in the first two twin sisters with a novel tail extension CCNQ variant in Asia. Genetic variants of the pedigree were screened using whole-exome sequence analysis and validated by direct Sanger sequencing. The genetic function was investigated through cultured cells and zebrafish embryos transfected with mutant. The proband is suffered from end-stage renal disease, telecanthus, scoliosis, anal atresia, bilateral hydronephrosis pyeloureter dilation and hearing loss, while her twin sister had milder phenotypes. A novel heterozygous variant c.502_518delinsA (p.Val168SerfsTer173) in CCNQ gene was identified in the twins and their asymptomatic mosaic mother. The concurrent deletion of 17 bases and insertion of one base variant led to the loss of 5 amino acids, subsequently caused a 96 more amino acids tail extension delaying the appearance of stop codon. The loss-of-function variant of CCNQ not only led to the impaired expression of cyclin M but also increased the binding affinity of CDK10-cyclin M complex, which is different from the previous study. The research expanded the genotypic and phenotypic spectrum of STAR syndrome.

Hemoperfusion and intravenous immunoglobulins for refractory gastrointestinal involvement in pediatric Henoch-Schönlein purpura: a single-center retrospective cohort study.

BACKGROUND: Henoch-Schönlein purpura (HSP) with refractory gastrointestinal (GI) symptoms is always difficult to handle because of its resistance to supportive therapies and glucocorticoid. This study aimed to evaluate the efficacy of hemoperfusion (HP) and intravenous immunoglobulins (IVIG) therapies in this population. METHODS: Sixty-four HSP patients with refractory GI involvement (R-GI group) and 64 cases with mild GI symptoms (control group) were retrospectively analyzed in our center from March 2016 to October 2019. In R-GI group, 42 cases (subgroup A) were treated with IVIG and steroid, 13 cases (subgroup B) used HP and steroid, 9 cases (subgroup C) executed a combination of IVIG, HP and steroid. Demographic characteristics, clinical features, laboratory indexes and treatment outcomes were recorded. t-test, One-way ANOVA, Mann-Whitney U test, and multivariate logistic regression were used in comparing differences among subgroups and predicting independent risk factors. RESULTS: Compared with the control group, R-GI cases experienced higher risk of renal involvement (P = 0.000), more steroid exposure (P = 0.000), six times expenses (P = 0.000) and 2.3 times length of hospitalization (P = 0.000). The independent risk factors of R-GI group were elevated neutrophils (OR 1.250 [95% CI 1.130-1.383]) and the percentage of B lymphocytes (OR 1.100 [95% CI 1.026-1.179]) as well as decreased IgG (OR 0.847 [95% CI 0.732-0.98]). In R-GI group, increased age (OR 1.039 [95% CI 1.016-1.062]) and IgM (OR 5.994 [95% CI 1.403-27.611]) were verified to be risk factors of HSP nephritis. All three subgroups could alleviate the symptoms effectively. Compared with those in subgroup A, patients in subgroup B were elder (P = 0.004), had less relapse (P = 0.002), steroid exposure (P = 0.033) and expenses (P = 0.031), more significant decrease of WBC (P = 0.026) after treatment. CONCLUSION: The HSP with refractory GI involvement had much higher risk of medical burden and renal involvement. Both IVIG and HP therapies could ameliorate refractory GI symptoms efficiently. HP therapy tended to reduce the relapse, costs and steroid exposure in its audiences who were cooperated and with stable hemodynamics, while IVIG had better use in younger children.

Acetaminophen-induced reduction of NIMA-related kinase 7 expression exacerbates acute liver injury.

Background & Aims: Acetaminophen (APAP)-induced acute liver injury (ALI) is a global health issue characterised by an incomplete understanding of its pathogenesis and unsatisfactory therapies. NEK7 plays critical roles in both cell cycle regulation and inflammation. In the present study, we investigated the role and mechanism of NEK7 in APAP-induced ALI. Methods: In mice with NEK7 overexpression (hydrodynamic tail vein injection of NEK7 plasmids), hepatocyte-specific NEK7 knockout (cKO), and inducible NEK7 knockout (iKO), an overdose of APAP was administered to induce ALI. Liver injury was determined by an analysis of serum liver enzymes, pathological changes, inflammatory cytokines, and metabonomic profiles. In vitro, hepatocyte damage was evaluated by an analysis of cell viability, the reactive oxygen species levels, and mitochondrial function in different cell lines. Hepatocyte proliferation and the cell cycle status were determined by Ki-67 staining, EdU staining, and the cyclin levels. Results: NEK7 was markedly downregulated in APAP-induced injured liver and damaged hepatocytes. NEK7 overexpression in the liver significantly alleviated APAP-induced liver injury, as shown by the restored liver function, reduced pathological injury, and decreased inflammation and oxidative stress, which was confirmed in a hepatocyte cell line. Moreover, both NEK7 cKO and iKO mice exhibited exacerbation of APAP-induced ALI. Finally, we determined that cyclin B1-mediated cell cycle progression could mediate the protective effect of NEK7 against APAP-induced ALI. Conclusions: Reduced NEK7 contributes to APAP-induced ALI, possibly by dysregulating cyclins and disturbing cell cycle progression. Lay summary: Acetaminophen-induced acute liver injury is one of the major global health issues, owing to its high incidence, potential severity, and limited therapeutic options. Our current understanding of its pathogenesis is incomplete. Herein, we have shown that reduced NEK7 (a protein with a key role in the cell cycle) exacerbates acetaminophen-induced acute liver injury. Hence, NEK7 could be a possible therapeutic target for the prevention or treatment of this condition.