Serum HMGB-1 released by ferroptosis and necroptosis as a novel potential biomarker for systemic lupus erythematosus.

High mobility group box proterin-1 (HMGB-1) is a multifunctional protein that can be released by various programmed cell deaths (PCDs), such as necroptosis and ferroptosis. PCDs play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the role of HMGB-1 in the process of SLE remains unclear. This study aims to demonstrate the potential diagnosing role of serum HMGB-1 in SLE that released by necroptosis and ferroptosis. We found that the serum levels of HMGB-1, receptor-interacting protein kinase 3 (RIPK3) /mixed lineage kinase domain-like protein (MLKL) related with necroptosis, and metabolites associated with ferroptosis were significantly upregulated in SLE patients compared to HC individuals. These serum levels were positively correlated with SLE disease activity. Additionally, the serum level of HMGB-1 showed a strong positive correlated with the levels of RIPK3/MLKL and ferroptosis metabolites. Moreover, the serum level of HMGB-1 was correlated with renal involvement and high-antinuclear antibodies (ANA) titer. After SLE serum and interferon γ (IFN-γ) treatment in vitro, the level of necroptosis and ferroptosis markers were activated and HMGB1 was released both in HEK293 and HK2 cells. Clinically, HMGB-1 was considered as a significant independent risk factor in SLE serum by binary logistic assay. Notably, HMGB-1 exhibited outstanding diagnostic ability for SLE by the area under the curve (AUC) in receiver operating characteristic (ROC) curve analysis. Taken together, our study indicates that the serum level of HMGB-1 is a promising biomarker for the diagnosis and monitoring of SLE.

Kidney-brain axis in the pathogenesis of cognitive impairment.

The kidney-brain axis is a bidirectional communication network connecting the kidneys and the brain, potentially affected by inflammation, uremic toxin, vascular injury, neuronal degeneration, and so on, leading to a range of diseases. Numerous studies emphasize the disruptions of the kidney-brain axis may contribute to the high morbidity of neurological disorders, such as cognitive impairment (CI) in the natural course of chronic kidney disease (CKD). Although the pathophysiology of the kidney-brain axis has not been fully elucidated, epidemiological data indicate that patients at all stages of CKD have a higher risk of developing CI compared with the general population. In contrast to other reviews, we mentioned some commonly used medicines in CKD that may play a pivotal role in the pathogenesis of CI. Revealing the pathophysiology interactions between kidney damage and brain function can reduce the potential risk of future CI. This review will deeply explore the characteristics, indicators, and potential pathophysiological mechanisms of CKD-related CI. It will provide a theoretical basis for identifying CI that progresses during CKD and ultimately prevents and treats CKD-related CI.

Design, synthesis and antimicrobial activity of novel berberine derivatives.

BACKGROUND: The threats to the safety of humans and the environment and the resistance of agricultural chemicals to plant pathogenic fungi and bacteria highlight an urgent need to find safe and efficient alternatives to chemical fungicides and bactericides. In this study, a series of Berberine (BBR) derivatives were designed, synthesized and evaluated for in vitro and in vivo antimicrobial activity against plant pathogenic fungi and bacteria. RESULTS: Bioassay results indicated that compounds A11, A14, A20, A21, A22, A25, A26, E1, E2, E3, Z1 and Z2 showed high inhibitory activity against Sclerotinia sclerotiorum and Botrytis cinerea. Especially, A25 showed a broad spectrum and the highest antifungal activity among these compounds. Its EC50 value against Botrytis cinerea was 1.34 µg mL-1. Compound E6 possessed high inhibitory activity against Xanthomonas oryzae and Xanthomonas Campestris, with MIC90 values of 3.12 µg mL-1 and 1.56 µg mL-1. A Topomer CoMFA model was generated for 3D-QSAR studies based on anti-B. cinerea effects, with high predictive accuracy, showed that the addition of an appropriate substituent group at the para-position of benzyl of BBR derivatives could effectively improve the anti-B. cinerea activity. In addition, compound A25 could significantly inhibit the spore germination of Botrytis cinerea at low concentration, and compound F4 exhibited remarkable curative and protective efficiencies on rice bacterial leaf blight. CONCLUSION: This study indicates that the BBR derivatives are hopeful for further exploration as the lead compound with novel antimicrobial agents. © 2024 Society of Chemical Industry.

Neutrophil-percentage-to-albumin ratio is associated with chronic kidney disease: Evidence from NHANES 2009-2018.

INTRODUCTION: The neutrophil-percentage-to-albumin ratio (NPAR), a novel inflammatory biomarker, has been used to predict the prognosis of patients with cancer and cardiovascular disease. However, the relationship between NPAR and chronic kidney disease (CKD) remains unknown. The purpose of this study was to investigate the possible association between NPAR and CKD. METHODS: The cross-sectional study included participants with complete information on NPAR, serum creatinine (Scr), or urinary albumin-to-creatinine ratio (UACR) from the 2009-2018 National Health and Nutrition Examination Survey (NHANES). CKD was defined as the presence of either low estimated glomerular filtration rate (eGFR) or albuminuria. Univariate and multivariate logistic regression and restricted cubic spline regression were used to assess the linear and nonlinear associations between NPAR and renal function. Subgroup and interactive analyses were performed to explore potential interactive effects of covariates. Missing values were imputed using random forest. RESULTS: A total of 25,236 participants were enrolled in the study, of whom 4518 (17.9%) were diagnosed with CKD. After adjustment for covariates, the odds ratios (ORs) for prevalent CKD were 1.19 (95% CI = 1.07-1.31, p <0.05) for the Q2 group, 1.53 (95% CI = 1.39-1.69, p < 0.001) for the Q3 group, and 2.78 (95% CI = 2.53-3.05, p < 0.001) for the Q4 group. There was a significant interaction between age and diabetes mellitus on the association between NPAR and CKD (both p for interaction < 0.05). And there was a non-linear association between NPAR levels and CKD in the whole population (p for non-linear < 0.001). All sensitivity analyses supported the positive association between NPAR and CKD. CONCLUSIONS: NPAR was positively correlated with increased risk of CKD. The NPAR may serve as an available and cost-effective tool for identifying and intervening the individuals at risk of CKD.

Mechanical mechanism analysis of rockburst in deep-buried tunnel with high in-situ stress.

The Qinling water conveyance tunnel has a large buried depth and high in-situ stress level, and rockburst disasters frequently occurred during excavation. In order to find out the mechanical mechanism of rockburst, the research work in this paper is as follows: (1) In-situ three-dimensional hydraulic fracturing method was used to measure the in-situ stress of the deep buried tunnel crossing the ridge. (2) Based on the measured in-situ stress results, the stress distribution characteristics of the tunnel crossing the ridge were obtained by the multiple linear regression method, and the rockburst tendency during construction was predicted. (3) A three-dimensional numerical model of tunnel excavation was established to analyze the dynamic adjustment characteristics of the surrounding rock stress and elastic strain energy during TBM excavation, and to clarify the mechanical mechanism of rockburst. The research results show that the maximum principal stress of the deep-buried tunnel crossing the ridge of Qinling is 40-66 MPa, which belongs to extremely high in-situ stress level, and medium-strong rockburst may occur during excavation. In the process of TBM excavation, the stress of the surrounding rock in the range of 2.6 times the diameter of the tunnel before and after the working face is adjusted violently, and the concentrated zones after the stress redistribution are mainly distributed in the arch roof and arch bottom, and the stress concentration coefficient can reach 2.06. The arch roof, arch waist, and arch bottom are susceptible to immediate rockburst due to stress transient unloading at the moment of excavation. After the elastic strain energy of the surrounding rock at the arch roof and the arch bottom is released and accumulated, it is easy to cause time delayed rockburst, and the depth of the rockburst pit can reach 3.5 m, which is consistent with the rockburst phenomenon in the field.

Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

Application of Diffusion Kurtosis Imaging and Blood Oxygen Level-Dependent Magnetic Resonance Imaging in Kidney Injury Associated with ANCA-Associated Vasculitis.

OBJECTIVE: Functional magnetic resonance imaging (fMRI) has been applied to assess the microstructure of the kidney. However, it is not clear whether fMRI could be used in the field of kidney injury in patients with Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: This study included 20 patients with AAV. Diffusion kurtosis imaging (DKI) and blood oxygen level-dependent (BOLD) scanning of the kidneys were performed in AAV patients and healthy controls. The mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) parameters of DKI, the R2* parameter of BOLD, and clinical data were further analyzed. RESULTS: In AAV patients, the cortex exhibited lower MD but higher R2* values compared to the healthy controls. Medullary MK values were elevated in AAV patients. Renal medullary MK values showed a positive correlation with serum creatinine levels and negative correlations with hemoglobin levels and estimated glomerular filtration rate. To assess renal injury in AAV patients, AUC values for MK, MD, FA, and R2* in the cortex were 0.66, 0.67, 0.57, and 0.55, respectively, and those in the medulla were 0.81, 0.77, 0.61, and 0.53, respectively. CONCLUSIONS: Significant differences in DKI and BOLD MRI parameters were observed between AAV patients with kidney injuries and the healthy controls. The medullary MK value in DKI may be a noninvasive marker for assessing the severity of kidney injury in AAV patients.

Two C-terminal isoforms of Aplysia tachykinin-related peptide receptors exhibit phosphorylation-dependent and phosphorylation-independent desensitization mechanisms.

Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their posttranslational modifications were observed in extracts of central nervous system ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (apTKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.

Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications.

Acute kidney injury (AKI) is a frequent and severe complication of sepsis and is characterized by significant mortality and morbidity. However, the pathogenesis of septic acute kidney injury (S-AKI) remains elusive. Metabolic reprogramming, which was originally referred to as the Warburg effect in cancer, is strongly related to S-AKI. At the onset of sepsis, both inflammatory cells and renal parenchymal cells, such as macrophages, neutrophils and renal tubular epithelial cells, undergo metabolic shifts toward aerobic glycolysis to amplify proinflammatory responses and fortify cellular resilience to septic stimuli. As the disease progresses, these cells revert to oxidative phosphorylation, thus promoting anti-inflammatory reactions and enhancing functional restoration. Alterations in mitochondrial dynamics and metabolic reprogramming are central to the energetic changes that occur during S-AKI. In this review, we summarize the current understanding of the pathogenesis of metabolic reprogramming in S-AKI, with a focus on each cell type involved. By identifying relevant key regulatory factors, we also explored potential metabolic reprogramming-related therapeutic targets for the management of S-AKI.

SKLB023 protects against inflammation and apoptosis in sepsis-associated acute kidney injury via the inhibition of toll-like receptor 4 signaling.

Sepsis-associated acute kidney injury (SA-AKI) is one of common critical illnesses with high morbidity and mortality. At present, effective therapeutic drugs for SA-AKI are remain lacking. SKLB023 is a synthetic small-molecule compound which exerts potent anti-inflammatory effects in our previous studies. Here, this study aimed to characterize the protective effect of SKLB023 on SA-AKI and explore its underlying mechanism. The SA-AKI experimental models have been established by cecum ligation/puncture (CLP) and lipopolysaccharide (LPS) injection in male C57BL/6J mice. SKLB023 was administered by gavage (50 or 25 mg/kg in CLP model and 50 mg/kg in LPS model) daily 3 days in advance and 30 min earlier on the day of modeling. Our results confirmed SKLB023 treatment could improve the survival of SA-AKI mice and ameliorate renal pathological injury, inflammation, and apoptosis in the two types of septic AKI mice. Mechanically, SKLB023 deceased the expression of TLR4 in LPS-triggered renal tubular epithelial cells, and inhibited the activation of downstream pathways including NF-κB and MAPK pathways. Our study suggested that SKLB023 is expected to be a potential drug for the prevention and treatment of septic AKI.

The Time-Varying Impact of COVID-19 on the Acute Kidney Disorders: A Historical Matched Cohort Study and Mendelian Randomization Analysis.

Background: This study aimed to explore the time-varying impact of COVID-19 on acute kidney disorders, including acute kidney injury and other acute kidney diseases. Methods: From the UK Biobank, 10,121 participants with COVID-19 were matched with up to 3 historically unexposed controls by age, sex, Townsend deprivation index, and the status of hospitalization or receiving critical care. We investigated the association between COVID-19 and incidence of acute kidney disorders, within the first 4 weeks after infection, using conditional and time-varying Cox proportional hazard regression. In addition, one-sample Mendelian randomization, utilizing the polygenic risk score for COVID-19 as an instrumental variable, was conducted to explore the potential causality of the association. Results: In the matched cohort study, we observed a significant association between COVID-19 and acute kidney disorders predominantly within the first 3 weeks. The impact of COVID-19 was time dependent, peaking in the second week (hazard ratio, 12.77; 95% confidence interval, 5.93 to 27.70) and decreasing by the fourth week (hazard ratio, 2.28; 95% confidence interval, 0.75 to 6.93). In subgroup analyses, only moderate to severe COVID-19 cases were associated with acute worsening of renal function in a time-dependent pattern. One-sample Mendelian randomization analyses further showed that COVID-19 might exert a "short-term" causal effect on the risk of acute kidney disorders, primarily confined to the first week after infection. Conclusions: The risk of acute kidney disorders following COVID-19 demonstrates a time-varying pattern. Hazard effects were observed only in patients with moderate or severe but not mild COVID-19.

Ultrasmall magnolol/ebselen nanomicelles for preventing renal ischemia/reperfusion injury.

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Accuracy of lingual fixed retainers fabricated using a CAD/CAM bending machine.

Objective: Lingual fixed retainers, made from 0.0175-inch 3-strand twisted stainless steel wire (TW) and 0.016 × 0.022-inch straight rectangular wire (RW), are generally used in clinical practice. This study aimed to calculate their accuracy by comparing the discrepancy between computer-aided customized retainers made from these two types of wires. Methods: Eleven orthodontic patients were selected, resulting in 22 maxillary and mandibular three-dimensional printing dental models. Two types of lingual fixed retainers were bonded from canine to canine. To determine the accuracy, five points were chosen for each model, resulting in 110 selected points. The absolute values of the distances on the x-, y-, and z-axes were measured to compare the accuracy of the two types of computer-aided retainers. Results: The accuracy of the two types of retainers did not differ significantly in the x- and z-axes, but only in the y-axis (P < 0.01), where RW-fixed retainers exhibited a slightly but significantly increased distance compared to the TW. Conclusions: Both types of retainers showed high accuracy; however, RW had a slight but statistically significant difference along the y-axis compared with TW. This type of computer-aided design/computer-aided manufacturing bending machine is limited to two dimensions, and the dental arch is curved. Therefore, RW may require slight manual adjustment by the practitioner after manufacturing.

Integrin αM promotes macrophage alternative M2 polarization in hyperuricemia-related chronic kidney disease.

Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia-related CKD. In vivo, we explored dynamic characteristics of renal tissue in hyperuricemia-related CKD mice. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia-related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene, which was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p-FAK or p-AKT1 phosphorylation, and concurrent inhibiting of p-FAK while activating p-AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.

Research on coronavirus disease 2019 and the kidney: A bibliometric analysis.

Background: In addition to damage to the lungs, coronavirus disease 2019 (COVID-19) can damage multiple organs, including the kidney. Our purpose was to analyze the research hotspots and trends in COVID-19 and kidney diseases using bibliometrics to help clarify the development direction of this field. Methods: We selected and extracted all relevant publications related to COVID-19 and the kidney from the Web of Science from December 1, 2019, to July 24, 2022. VOSviewer, RStudio, CiteSpace, and other software were used to visualize keywords, publishing trends, authors and their countries, and institutions in this field and perform the statistical analysis. Results: A total of 645 articles published in 220 journals were included in this study. The United States and China contributed the most publications and were most active in international cooperation. In addition to COVID-19 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acute kidney injury (AKI), kidney transplant and mortality were the three keywords with the highest frequencies. In the initial stage of the COVID-19 outbreak, research focused on the clinical symptoms of COVID-19 and other macrocharacteristics, while in a later stage, the associations between SARS-CoV-2 infection and CKD and AKI, as well as the prognosis of patients with kidney disease or those who underwent kidney transplantation, gained more attention. The immune response and vaccines were also recent research hotspots. Conclusions: This bibliometric analysis provides a comprehensive overview of research on COVID-19 and kidney disease, which has received continuous, global attention. AKI, CKD, kidney transplantation, immune response and vaccines are among the hotspots in this field.

Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.

BACKGROUND: Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated. METHODS: Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model. RESULTS: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway. CONCLUSION: Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.

Identification of the central role of RNA polymerase mitochondrial for angiogenesis.

Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.

HSD17B1 Compensates for HSD17B3 Deficiency in Fetal Mouse Testis but Not in Adults.

Hydroxysteroid (17ß) dehydrogenase (HSD17B) enzymes convert 17-ketosteroids to 17beta-hydroxysteroids, an essential step in testosterone biosynthesis. Human XY individuals with inactivating HSD17B3 mutations are born with female-appearing external genitalia due to testosterone deficiency. However, at puberty their testosterone production reactivates, indicating HSD17B3-independent testosterone synthesis. We have recently shown that Hsd17b3 knockout (3-KO) male mice display a similar endocrine imbalance, with high serum androstenedione and testosterone in adulthood, but milder undermasculinization than humans. Here, we studied whether HSD17B1 is responsible for the remaining HSD17B activity in the 3-KO male mice by generating a Ser134Ala point mutation that disrupted the enzymatic activity of HSD17B1 (1-KO) followed by breeding Hsd17b1/Hsd17b3 double-KO (DKO) mice. In contrast to 3-KO, inactivation of both HSD17B3 and HSD17B1 in mice results in a dramatic drop in testosterone synthesis during the fetal period. This resulted in a female-like anogenital distance at birth, and adult DKO males displayed more severe undermasculinization than 3-KO, including more strongly reduced weight of seminal vesicles, levator ani, epididymis, and testis. However, qualitatively normal spermatogenesis was detected in adult DKO males. Furthermore, similar to 3-KO mice, high serum testosterone was still detected in adult DKO mice, accompanied by upregulation of various steroidogenic enzymes. The data show that HSD17B1 compensates for HSD17B3 deficiency in fetal mouse testis but is not the enzyme responsible for testosterone synthesis in adult mice with inactivated HSD17B3. Therefore, other enzymes are able to convert androstenedione to testosterone in the adult mouse testis and presumably also in the human testis.

Global burden of non-communicable diseases attributable to kidney dysfunction with projection into 2040.

BACKGROUND: Spatiotemporal disparities exist in the disease burden of non-communicable diseases (NCDs) attributable to kidney dysfunction, which has been poorly assessed. The present study aimed to evaluate the spatiotemporal trends of the global burden of NCDs attributable to kidney dysfunction and to predict future trends. METHODS: Data on NCDs attributable to kidney dysfunction, quantified using deaths and disability-adjusted life-years (DALYs), were extracted from the Global Burden of Diseases Injuries, and Risk Factors (GBD) Study in 2019. Estimated annual percentage change (EAPC) of age-standardized rate (ASR) was calculated with linear regression to assess the changing trend. Pearson's correlation analysis was used to determine the association between ASR and Sociodemographic Index (SDI) for 21 GBD regions. A Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2040. RESULTS: Between 1990 and 2019, the absolute number of deaths and DALYs from NCDs attributable to kidney dysfunction increased globally. The death cases increased from 1,571,720 (95% uncertainty interval [UI]: 1,344,420-1,805,598) in 1990 to 3,161,552 (95% UI: 2,723,363-3,623,814) in 2019 for both sexes combined. Both the ASR of death and DALYs increased in Andean Latin America, the Caribbean, Central Latin America, Southeast Asia, Oceania, and Southern Sub-Saharan Africa. In contrast, the age-standardized metrics decreased in the high-income Asia Pacific region. The relationship between SDI and ASR of death and DALYs was negatively correlated. The BAPC model indicated that there would be approximately 5,806,780 death cases and 119,013,659 DALY cases in 2040 that could be attributed to kidney dysfunction. Age-standardized death of cardiovascular diseases (CVDs) and CKD attributable to kidney dysfunction were predicted to decrease and increase from 2020 to 2040, respectively. CONCLUSION: NCDs attributable to kidney dysfunction remain a major public health concern worldwide. Efforts are required to attenuate the death and disability burden, particularly in low and low-to-middle SDI regions.