EIF2α/ATF4 pathway enhances proliferation of mesangial cell via cyclin D1 during endoplasmic reticulum stress in IgA nephropathy.

IgA nephropathy (IgAN) is an essential cause of kidney failure and end-stage kidney disease worldwide. Mesangial hypercellularity is an important characteristic of IgAN, but the underlying mechanism remains unclear. Endoplasmic reticulum (ER) stress is a series of stress responses to restore the function of endoplasmic reticulum. We aimed to explore how ER stress functioned in kidneys of IgAN. We first examined ER stress in IgAN kidneys in vivo and in vitro, by testing the levels of ER stress associated proteins (BIP, p-eIF2α and ATF4). Our results showed that ER stress was activated in IgAN patients, mice and cell model. ER stress activation was related to the distribution of IgA deposition and the degree of mesangial proliferation. To determine the role of ER stress in mesangial cell (MC) proliferation of IgAN, we then tested the levels of ER stress and MC proliferation (cyclin D1, cell viability and cell cycle) through inhibiting ER stress associated proteins. After inhibiting ER stress associated proteins, ER stress was inactivated and cell proliferation was inhibited in MCs. We also explored the correlation between ER stress in the glomerulus and the clinical outcomes of IgAN patients in a prospective study. Patients with lower expression of p-eIF2α or ATF4 had higher rates of hematuria remission, proteinuria remission and clinical remission. In summary, our work outlines that in IgAN, ER stress mediated by eIF2α/ATF4 pathway promotes MC proliferation via up-regulating the expression of cyclin D1. Furthermore, p-eIF2α and ATF4 in the glomerulus negatively correlate with the clinical remission of IgAN patients.

Design and synthesis of photoaffinity-based probes for labeling ß-glucuronidase.

ß-Glucuronidase (GUSB) plays an important role in human physiological and pathological activities. The activity level of GUSB is closely related to human health and diseases. It is imperative to detect the activity of GUSB for related disease diagnosis and treatment. However, exactly evaluating the activity of GUSB in complicated biological system remains a challenge. In this study, we developed photoaffinity-based probes (AfBPs) equipped with photosensitive benzophenone group for labeling active GUSB. Through molecule docking, we predicted the binding model of the AfBPs and GUSB, and the obtained results suggested thermodynamically favorable binding. The AfBPs indicated high efficiency and showed dose-/time-dependent labeling of Escherichia coli (E. coli) GUSB. The application of AfBPs toward GUSB provides a powerful tool to study the activity of target enzymes and contributes to huge potential of enzyme inhibitor discovery and biomedical diagnostics.

Efficacy and indications of tonsillectomy in patients with IgA nephropathy: a retrospective study.

Background: The efficacy and indications of tonsillectomy in IgA nephropathy (IgAN) remain uncertain. Methods: We performed a retrospective cohort study of 452 patients with primary IgAN, including 226 patients who received tonsillectomy and 226 controls selected by propensity score matching who had never undergone tonsillectomy. Study outcomes were clinical remission defined as negative hematuria and proteinuria on three consecutive visits over a 6-month period, the endpoint defined as end-stage renal disease or an irreversible 100% increase in serum creatinine from the baseline value. In addition, we further analyzed the critical level of proteinuria in the efficacy of tonsillectomy and the correlation between MEST-C score and tonsillectomy. Results: Up to December 2019, the follow-up period lasted 46 ± 23 months (12-106 months). Kaplan-Meier and multivariate Cox regression analysis revealed that tonsillectomy was beneficial for clinical remission and renal survival. Whether proteinuria was ≤ 1 g/24h or >1 g/24h, the clinical remission and renal survival rates were greater in patients treated with tonsillectomy than without. When the pathological damage was mild or relatively severe, tonsillectomy may be beneficial to clinical remission or renal survival. Conclusions: Tonsillectomy had a favorable effect on clinical remission and delayed renal deterioration in IgAN. In addition to patients with early stage IgAN, it may also be beneficial to IgAN patients with higher levels of proteinuria and relatively severe pathological damage.

Association between albumin or prealbumin levels at different stages and prognosis in severe acute pancreatitis: a 5-year retrospective study.

Severe acute pancreatitis (SAP) is a common abdominal disorder contributing to high mortality and open laparotomy rates. The role of exogenous infused albumin in fluid resuscitation or continuous therapy has always been an unanswered question. In early stage after onset, SAP patients with higher serum albumin or prealbumin show a better prognosis. In this study, we tried to disclose the linkage between albumin/prealbumin and SAP prognosis and establish a new goal-directed therapy involving albumin and prealbumin. Pearson's chi-squared test and the Mann-Whitney U test were used to compare the descriptive data between surviving and non-surviving patients. Three days, 4-7 days, 8-14 days and 15-28 days after SAP onset were defined as stages 1-4. The average concentrations of albumin and prealbumin were calculated, and receiver operating characteristic (ROC) curves were drawn to screen out the best cutoff values associated with poor prognostic outcomes, including laparotomy and failure to survive. Kaplan-Meier survival curves and log-rank tests were used to validate the effect of the cut-off values. A total of 199 admitted patients were enrolled in this study. According to the analysis of the ROC curve, the serum albumin value should be raised to 35, 37, 40 and 42 g/L in the 1-4 stage after onset. Serum prealbumin values should be raised to 108, 180, and 181 g/L in stages 2-4 after onset. The validity of the above data was confirmed by Kaplan-Meier survival curves. Serum albumin and prealbumin levels in the early stage of SAP are significantly relevant to prognosis. Albumin should be infused from the fluid resuscitation stage to continuous therapy in order to reach the targets mentioned above. The increase in prealbumin depends on the early initiation of enteral nutrition and this also helps to ameliorate the prognosis.

Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway.

BACKGROUND: Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway. METHODS: We established a TP-treated IgAN mouse model and produced IgA1-induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3-Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p-p38 MAPK/p38 MAPK following TP treatment. RESULTS: Administering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1-induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN. CONCLUSION: TP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway.

Immunostaining of galactose-deficient IgA1 by KM55 is not specific for immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN nephropathy, IgAN) is named for the renal pathological features of IgA-dominant immunoglobulin deposition. IgA deposits, however, may also occur in other diseases, from liver disease and inflammation to chronic infections and tumors. Now increasing studies have suggested that galactose-deficient IgA1 (Gd-IgA1) plays a critical role in the pathogenesis of IgAN. This study aims to investigate whether the Gd-IgA1-specific antibody KM55 contributes to differentiating primary IgAN from other diseases with IgA deposits. METHODS: In this retrospective study, we enrolled 100 Chinese patients with IgA deposits in renal biopsies, including IgAN(n = 40), IgAN with hepatitis B virus antigen deposits(n = 14), IgA vasculitis(n = 16), lupus nephritis(n = 11), incidental IgA deposits(n = 13) and negative controls(n = 6). Double immunostaining of Gd-IgA1 and IgA was performed in all biopsies. RESULTS: There were similar patterns of Gd-IgA1 deposition in primary IgAN, IgA vasculitis, and IgAN with hepatitis B virus antigen deposits. Gd-IgA1 staining could also be seen in patients with lupus nephritis and incidental IgA deposits, but the intensity was significantly lower than IgAN, and the optimal cutoff was 2+ staining for differential diagnosis. Every increase in KM55 staining intensity of 1+ was associated with an increase in the odds of primary IgAN (OR: 4.399; 95% CI: 1.725-11.216). CONCLUSIONS: Immunostaining for Gd-IgA1 by KM55 is not specific for IgA nephropathy, but weak or negative staining may favor incidental IgA deposits.

Emerging insights into molecular mechanisms underlying pyroptosis and functions of inflammasomes in diseases.

Pyroptosis is a form of necrotic and inflammatory programmed cell death, which could be characterized by cell swelling, pore formation on plasma membranes, and release of proinflammatory cytokines (IL-1ß and IL-18). The process of pyroptosis presents as dual effects: protecting multicellular organisms from microbial infection and endogenous dangers; leading to pathological inflammation if overactivated. Two pathways have been found to trigger pyroptosis: caspase-1 mediated inflammasome pathway with the involvement of NLRP1-, NLRP3-, NLRC4-, AIM2-, pyrin-inflammasome (canonical inflammasome pathway) and caspase-4/5/11-mediated inflammasome pathway (noncanonical inflammasome pathway). Gasdermin D (GSDMD) has been proved to be a substrate of inflammatory caspases (caspase-1/4/5/11), and the cleaved N-terminal domain of GSDMD oligomerizes to form cytotoxic pores on the plasma membrane. Here, we mainly reviewed the up to date mechanisms of pyroptosis, and began with the inflammasomes as the activator of caspase-1/caspase-11, 4, and 5. We further discussed these inflammasomes functions in diseases, including infectious diseases, sepsis, inflammatory autoimmune diseases, and neuroinflammatory diseases.

Facile fabrication of hollow tubular mixed oxides for selective catalytic reduction of NOx at low temperature: a combined experimental and theoretical study.

A new versatile method was developed for the synthesis of various transition metal oxides with uniform 1D structures via electrospinning combined with heat treatment. The 1D nanowire or hollow tubular structure can be tuned by controlling heating rates. Interestingly, NOx conversion is ca. 99% at 200 °C in hollow tubular CuCo2O4.