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Radix Phytolaccae (RP) has a long medicinal history and is commonly used to treat systemic edema and ascites in Asia. Although RP is known to cause nephrotoxicity, the role of its main constituent, Esculentoside A (EsA), in nephrotoxicity remains undetermined. We used kidney organoids derived from human inducible pluripotent stem cells (iPSCs) to model EsA nephrotoxicity accurately. Kidney organoids were differentiated and treated with EsA at doses of 0, 15, 30, or 60 μM for 48 h. The in vitro model was compared to a mouse model of EsA nephrotoxicity (intraperitoneally injected, 25 mg·kg−1). The mechanisms were investigated. Cell viability decreased dose-dependently after treatment with EsA. As polarity was lost, tubular cells decreased, similar to mouse EsA nephrotoxicity with upregulated vimentin expression and a stimulator of the interferon gene (STING). Furthermore, 60 μM EsA could induce endothelial inflammation, lead to mitochondrial damage and activate STING by translocating mtDNA into the cytoplasm to develop an inflammatory cascade and destroy renal endothelial cells with interstitial changes. The data suggest that kidney organoids derived from iPSCs are promising for investigating nephrotoxicity. EsA nephrotoxicity involves the epithelial-mesenchymal transition via STING signaling. [Display omitted] • EsA induced epithelial-to-mesenchymal transition (EMT) in the kidney. • EsA induced EMT possibly via the cGAS-STING signaling pathway. • EsA induced EMT via mitochondrial dysfunction [ABSTRACT FROM AUTHOR]

As the life expectancy of people living with HIV (PLWH) approaches that of the general population, the burden of comorbidities such as cardiovascular disease (CVD) is increasing. Regardless of HIV status, about 50% of CVD deaths worldwide occur in Asia, and Asian PLWH have a high prevalence of conventional CVD risk factors, such as smoking, dyslipidaemia, hypertension and insulin resistance or diabetes. As well as conventional CVD risk factors, PLWH have HIV‐specific risk factors such as chronic inflammation, immune activation and endothelial damage, as well as risk factors related to antiretroviral therapy. This review describes the current knowledge on the epidemiology and risk factors of CVD in Asian PLWH and provides an Asian perspective on the recommendations for managing CVD risk in PLWH. [ABSTRACT FROM AUTHOR]

Scrub typhus, caused by Orientia tsutsugamushi , is a common systemic infection in Asia. Delay in diagnosis and treatment can lead to vasculitis in the visceral organs and other complications. The mechanisms that drive endothelial activation and the inflammatory response in O. tsutsugamushi infection remain unknown. In addition, the interaction between monocytes and endothelial cells is still unclear. Here we demonstrate that O. tsutsugamushi -infected human dermal microvascular endothelial cells produced moderate levels of chemokines and low levels of IL-6 and IFN-β, but not TNF or IL-1β. Recombinant TNF and cytokine-rich supernatants from infected monocytes markedly enhanced chemokine production in infected endothelial cells. We also show that TNF and monocyte supernatants, but not O. tsutsugamushi infection of endothelial cells per se , upregulated the endothelial cell surface expression of ICAM-1, E-selectin, and tissue factor. This finding was consistent with the inability of O. tsutsugamushi to induce cytokine secretion from endothelial cells. The upregulation of surface molecules after stimulation with monocyte supernatants was significantly reduced by neutralizing anti-TNF antibodies. These results suggest that endothelial cell activation and response are mainly mediated by inflammatory cytokines secreted from monocytes. [ABSTRACT FROM AUTHOR]

Background: This research was conducted with the aim to determine the effect of diabetes mellitus on corneal endothelial cells.Methods: The terms: ("diabetes mellitus" or "diabetes" or "diabetic") and ("corneal endothelium" or "cornea" or "Corneas") searched in Pubmed, Embase, Cochrane, and Web of science until August 2019. The included types of studies contained observational studies. The standard mean difference (SMD) which was deemed as main size effects for continuous data was calculated by means and standard deviations. The data on corneal endothelial cell density (ECD), mean cell area (MCA), cell area variation coefficient (CV) and percentage of hexagonal cells (HEX) included in the study were collected and analyzed using stata15.1.Results: The final 16 cross-sectional studies and 2 case-control studies were included for the meta-analysis. Meta-analysis revealed that diabetes mellitus could reduce ECD (SMD = - 0.352, 95% CI -0.538, - 0.166) and the HEX (SMD = - 0.145, 95% CI -0.217, - 0.074), in addition to increasing CV (SMD = 0.195, 95% CI 0.123, 0.268). Nevertheless, there was no statistically significant differences observed when combining MCA (SMD = 0.078, 95% CI -0.022, 0.178). In subgroup analysis, Type 2 diabetes patients owned less corneal ECD (P < 0.05). Moreover the same results also found during the subgroup form Asia, Europe and American. The meta-regression revealed the type of diabetes mellitus might be contributing to heterogeneity. (P = 0.008). The results indicated a significant publication bias for studies, with combined CV (Begg's test, P = 0.006; Egger's test, P = 0.005) and merged combined HEX (Begg's test, P = 0.113; Egger's test, P = 0.024).Conclusions: As indicated by meta-analysis, diabetes mellitus could cause a detrimental effect on corneal endothelium health. Diabetes mellitus contributed to the instability of corneal endothelium during the analysis. Therefore, further research is considered necessary to confirm our research results.Trial Registration: CED 42019145858 . [ABSTRACT FROM AUTHOR]

Purpose: To investigate the factors associated with endothelial survival after Descemet's membrane endothelial keratoplasty (DMEK) in eyes of Asian patients with bullous keratopathy (BK). Methods: In this retrospective, consecutive interventional case series, 72 eyes of 72 patients who underwent DMEK were evaluated. Best corrected visual acuity (BCVA) and corneal endothelial cell density (ECD) were assessed at 12 months postoperatively. Multiple regression analysis was performed to assess parameters such as age, sex, axial length, preoperative visual acuity, re-bubbling, the ratio of graft to cornea area, iris damage scores, types of filling gases, air or SF6 volume in the anterior chamber (AC) on postoperative day 1, and ECD loss rates at 12 months postoperatively. Results: BCVA improved significantly at 12 months after DMEK (P <.001). The rate of ECD loss at 12 months after DMEK was 54.4 ± 16.1%. Multiple linear regression analysis showed that a larger ratio of graft to corneal area (P = 0.0061) and higher donor ECD (P = 0.042) were the primary factors for a lower ECD loss rate at 12 months after DMEK. Conclusion: A relatively larger graft size compared to the host cornea and more donor ECD might help endothelial survival in patients with BK. Moreover, for such patients, the surgeon should attempt to use a relatively larger graft size when performing DMEK, particularly in Asian eyes. [ABSTRACT FROM AUTHOR]

microRNAs (miRNAs) have been revealed to participate in the pathological process of atherosclerosis (AS). However, the exact role of miR‐338‐3p, a target miRNA of BMP and activin membrane‐bound inhibitor (BAMBI), and its possible molecular mechanism in AS remain unidentified. In this study, we found that BAMBI was significantly decreased, whereas miR‐338‐3p increased in patients with AS and oxidized low‐density lipoprotein (ox‐LDL)‐induced HUVEC cells. Furthermore, overexpression of miR‐338‐3p significantly decreased cell viability and elevated cell apoptosis, whereas its inhibition significantly promoted cell viability and inhibited cell apoptosis in ox‐LDL‐induced HUVEC cells. Moreover, miR‐338‐3p overexpression increased TGF‐β/Smad pathway activation in ox‐LDL‐induced HUVEC cells. A dual‐luciferase reporter assay confirmed the direct interaction between miR‐338‐3p and the 3′‐untranslated region of BAMBI messenger RNA. Furthermore, the suppression of BAMBI ameliorated the effect of miR‐338‐3p inhibition against ox‐LDL‐induced HUVEC cell injury. In conclusion, our study thus suggests that miR‐338‐3p promoted ox‐LDL‐induced HUVEC cell injury by targeting BAMBI and activating the TGF‐β/Smad pathway, which may provide a novel and promising therapeutic target for AS. microRNA‐338‐3p promotes oxidized low‐density lipoprotein‐induced endothelial cell injury through targeting BAMBI and activating the TGF‐β/Smad pathway. [ABSTRACT FROM AUTHOR]

Abstract Aim Atherosclerosis (AS) is a chronic condition of the arterial vessels and a risk factor for myocardial infarction and stroke. Euxanthone is a xanthone compound extracted from Polygala caudata , and shows vasodilatory action. The aim of this study was to determine the potential pharmacological effects of euxanthone against oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell injury. Material and methods Human umbilical vein endothelial cells (HUVECs) were exposed to ox-LDL, following pre-treatment with different concentrations of euxanthone. Viability, apoptosis and DNA fragmentation were respectively assessed by CCK-8 assay, Annexin-V/PI staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay. The cellular levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were analyzed by enzyme linked immune-sorbent assays (ELISA), and reactive oxygen species (ROS) levels using dichlorodihydrofluorescin diacetate (DCFH) staining. Quantitative RT-PCR and Western blotting were respectively used to analyze the expression levels of specific mRNAs and proteins. HUVECs were transfected with Nrf2 siRNA to induce knockdown of the latter. Key findings Euxanthone pre-treatment rescued the HUVECs from ox-LDL-induced cytotoxicity, apoptosis and DNA fragmentation in a dose-dependent manner. In addition, euxanthone also significantly reversed ox-LDL-triggered loss of mitochondrial membrane potential (MMP), cytochrome C release from mitochondria to cytosol, cleavage of caspase-3 and PARP, and increase in Bax/Bcl-2 ratio. Pre-treatment with euxanthone markedly suppressed ox-LDL-induced ROS generation and inhibition of antioxidant enzymes, as well as the up-regulation of pro-inflammatory factors like MCP-1, IL-1β and TNF-α in the HUVECs. Euxanthone up-regulated and activated Nrf2 by repressing Keap1, and increased the expression of its downstream genes HO-1 and NQO-1. Nrf2 knockdown abrogated the cyto-protective, anti-apoptotic, anti-oxidant and anti-inflammatory effects of euxanthone in ox-LDL-treated HUVECs. Finally, euxanthone activated Nrf2 via the MAPK pathway and blocking the latter likewise negated the protective effects of euxanthone against cell ox-LDL. Significance Euxanthone protected HUVECs against the oxidative and inflammatory damage induced by ox-LDL, indicating its potential as a novel therapeutic agent for AS. [ABSTRACT FROM AUTHOR]

Background: Hantaan virus (HTNV) causes a severe lethal haemorrhagic fever with renal syndrome (HFRS) in humans. Despite a limited understanding of the pathogenesis of HFRS, the importance of the abundant production of pro-inflammatory cytokines has been widely recognized. Interleukin 33 (IL-33) has been demonstrated to play an important role in physiological and pathological immune responses. After binding to its receptor ST2L, IL-33 stimulates the Th2-type immune response and promotes cytokine production. Depending on the disease model, IL-33 either protects against infection or exacerbates inflammatory disease, but it is unknown how the IL-33/ST2 axis regulates the immune response during HTNV infection. Methodology/Principal Findings: Blood samples were collected from 23 hospitalized patients and 28 healthy controls. The levels of IL-33 and soluble ST2 (sST2) in plasma were quantified by ELISA, and the relationship between IL-33, sST2 and the disease severity was analyzed. The role of IL-33/sST2 axis in the production of pro-inflammatory cytokines was studied on HTNV-infected endothelial cells. The results showed that the plasma IL-33 and sST2 were significantly higher in patients than in healthy controls. Spearman analysis showed that elevated IL-33 and sST2 levels were positively correlated with white blood cell count and viral load, while negatively correlated with platelet count. Furthermore, we found that IL-33 enhanced the production of pro-inflammatory cytokines in HTNV-infected endothelial cells through NF-κB pathway and that this process was inhibited by the recombinant sST2. Conclusion/Significance: Our results indicate that the IL-33 acts as an initiator of the "cytokine storm" during HTNV infection, while sST2 can inhibit this process. Our findings could provide a promising immunotherapeutic target for the disease control. Author Summary: Hantaan virus (HTNV) causes human hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of approximately 15% in Asia. At present, the primary treatment for HFRS is limited to critical care management and the use of anti-viral drugs, such as Ribavirin. However, the cytokine storm at the acute phase of HFRS, which is thought to contribute to the development of the disease, is still lacking an effective way to prevent. An alternative way to prevent the development of cytokine storm is of priority to overcome the problem. We found that IL-33 and sST2 levels were higher in the plasma of HFRS patients, especially in their acute phase. Although both of them were positively correlated with the severity of the diseases, they acted in different roles in the regulation of the immune response during HTNV infection. In vitro study showed that IL-33 acted as an initiator of the cytokine storm in HTNV-infected endothelial cells, while sST2 acted as an inhibitor of the process. For the first time, we defined the IL-33/ST2 axis as inflammatory regulators during HTNV infection. Our results may provide a novel therapeutic target of HTNV infections. [ABSTRACT FROM AUTHOR]

Hantaan virus (HTNV), a Hantavirus serotype that is prevalent in Asia, causes hemorrhagic fever with renal syndrome (HFRS) with high mortality in human race. However, the pathogenesis of HTNV infection remains elusive. Circular RNAs (circRNAs), a new type of non-coding RNAs, play a crucial role in various pathogenic processes. Nevertheless, circRNA expression profiles and their effects on pathogenesis of HTNV infection are still completely unknown. In the present study, RNA sequencing was performed to analyze the circRNA, microRNA (miRNA), and mRNA expression profiles in HTNV-infected and mock-infected human umbilical vein endothelial cells (HUVECs). A total of 70 circRNAs, 66 miRNAs, and 788 mRNAs were differently expressed. Several differentially expressed RNAs were validated by RT-qPCR. Moreover, we verified that some differentially expressed RNAs, such as circ&#95;0000479, miR-149-5p, miR-330-5p, miR-411-3p, RIG-I, CMPK2, PARP10, and GBP1, promoted or inhibited HTNV replication. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated that the host genes of differentially expressed circRNAs were principally involved in the innate immune response, the type I interferon (IFN) signaling pathway, and the cytokine-mediated signaling pathway. Additionally, the circRNA-miRNA-mRNA regulatory network was integrally analyzed. The data showed that there were many circRNA-miRNA-mRNA interactions in HTNV infection. By dual-luciferase reporter assay, we confirmed that circ&#95;0000479 indirectly regulated RIG-I expression by sponging miR-149-5p, hampering viral replication. This study for the first time presents a comprehensive overview of circRNAs induced by HTNV and reveals that a network of enriched circRNAs and circRNA-associated competitive endogenous RNAs (ceRNAs) is involved in the regulation of HTNV infection, thus offering new insight into the mechanisms underlying HTNV-host interaction., (Copyright © 2020 Lu, Zhu, Guo, Wang, Li, Yan, Jiang, Han, Xiang, Wu, Liu, Xiong, Chen, Gong, Luo and Hou.)

Background: Diabetic nephropathy is the most common cause of end‐stage renal failure in the western world and Asia. The mechanisms are not fully elucidated, but disruption of glomerular endothelial glycocalyx and shedding of its components including syndecans has been implicated. Aims: We hypothesize that reduced glomerular filtration in diabetes is caused by disruption of endothelial glycocalyx in glomeruli, including increased shedding of syndecan‐4. The aim of this study was to determine the effects of experimental diabetic conditions by means of hyperglycemia and IL‐1β exposure on syndecan‐4 shedding in GEnC, and to investigate regulation of shedding by sheddases. Results: We found that in GEnC the expression of syndecan‐4 is higher than that of the other syndecans. In polarized GEnC, apical shedding of syndecan‐4 and syndecan‐4 gene expression was increased by 60% after IL‐1β‐stimulation, but not affected by hyperglycemic conditions. This was accompanied by a 50% increase in MMP9 gene expression in IL‐1β‐stimulated cells but not hyperglycemia. MMP9 knockdown reduced syndecan‐4 shedding by 50%. Conclusion: IL‐1β but not hyperglycemia increases the shedding of syndecan‐4 from GEnC in an MMP9‐dependent manner. This provides a potential mechanism of GEnC damage in diabetes and other inflammatory conditions. [ABSTRACT FROM AUTHOR]