Background:The pathophysiological importance of autophagy in renal tubules during the development of diabetic nephropathy (DN) has been implicated. Results: Autophagy was inactivated because lysosomal membrane permeabilization and lysosomal dysfunction were triggered by advanced glycation end products. Conclusion:The autophagy-lysosome pathway is disrupted in renal tubules in DN. Significance:The findings open a new field for studying the mechanisms of DN.

Lysosomal membrane permeabilization (LMP) has been shown to cause the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol and initiate a cell death pathway. Whether proteinuria triggers LMP in renal tubular epithelial cells (TECs) to accelerate the progression of renal tubulointerstitial injury remains unclear. In the present study, we evaluated TEC injury as well as changes in lysosomal number, volume, activity, and membrane integrity after urinary protein overload in vivo and in vitro. Our results revealed that neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels were significantly increased in the urine of patients with minimal change nephrotic syndrome (MCNS) and the culture supernatant of HK-2 cells treated by urinary proteins extracted from MCNS patients. Urinary protein overload also induced apoptotic cell death in HK-2 cells. Importantly, we found that lysosomal volume and number were markedly increased in TECs of patients with MCNS and HK-2 cells overloaded with urinary proteins. However, lysosome function, as assessed by proteolytic degradation of DQ-ovalbumin and cathepsin-B and cathepsin-L activities, was decreased in HK-2 cells overloaded with urinary proteins. Furthermore, urinary protein overload led to a diffuse cytoplasmic immunostaining pattern of cathepsin-B and irregular immunostaining of lysosome-associated membrane protein-1, accompanying a reduction in intracellular acidic components, which could be improved by pretreatment with antioxidant. Taken together, our results indicate that overloading of urinary proteins caused LMP and lysosomal dysfunction at least partly via oxidative stress in TECs.

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BackgroundPrimary Sjögren’s syndrome (pSS) and breast cancer are a highly prevalent autoimmune disease and malignancy, respectively, both occurring predominantly in females. Whether there is a link between these two diseases is uncertain. We conducted a systematic review and meta-analysis to investigate the risk, incidence, and mortality of breast cancer in patients with pSS.MethodsWe systematically searched Embase, PubMed, and Web of Science on January 31, 2022 to identify the study that assessed risk, incidence, or mortality of breast cancer in pSS. The fixed or random-effects models were applied to pool the effect estimates based on heterogeneity measured by Cochran’s Q-test and Higgins’ I2.ResultsTen studies involving 725,805 participants and 64,836 pSS patients were included in our analysis. The pooled result showed that, overall, pSS was not associated with the risk (SIR=0.92, 95%CI: 0.66-1.29, P=0.646) and mortality (HR = 0.78, 95%CI: 0.26-2.34, P = 0.664) of breast cancer; however, when stratified by geographic region, we found that patients with pSS in Asian countries (SIR=1.32, 95%CI: 1.10-1.58, P=0.003) and Argentina (SIR=3.76, 95%CI: 1.04-9.45, P=0.019) had an elevated risk of breast cancer, while pSS in Europe was associated with a reduced risk (SIR=0.61, 95%CI: 0.51-0.73, P<0.001). The pooled result from 28,635 female pSS patients indicated that the incidence of breast cancer was 2.15 (95% CI: 1.33-3.50) per 1000 person/years.ConclusionThis study suggests that there may be geographical differences in the association between pSS and breast cancer risk; patients with pSS in European countries are associated with a lower risk of breast cancer, while Asia and Argentina are the opposite. Future research is needed to further characterize the effect of pSS on breast cancer risk and the pathophysiological mechanisms underlying this association to unravel the complex relationship between the two.

BackgroundCalcitonin gene-related peptide (CGRP) can protect against hyperoxia-induced lung injury, making the upregulation of CGRP a potential therapeutic approach for this type of injury. However, the effects of CGRP on the Wnt7b/β-catenin signaling pathway are unclear. In this study, we investigated the roles of CGRP and the Wnt7b/β-catenin signaling pathway in hyperoxia-induced lung injury.MethodsPremature Sprague Dawley (SD) rats were exposed to 21, 40, 60 and 95% oxygen for 3, 7 and 14 days. The animals’ body weights, survival rates and endogenous CGRP levels were measured. Lung samples were harvested for histological analyses and measurements of malondialdehyde (MDA) concentration and total antioxidant capacity (TAOC). We also assessed the MDA concentration and TAOC in the lung tissues after administration of 200 nmol/kg CGRP8–37 (a CGRP antagonist). Finally, alveolar epithelial type II (AEC II) cells were isolated from premature rats, exposed to 21 or 95% oxygen for 3, 7 and 14 days, and treated with 10− 8 mol/l exogenous CGRP. The protein expressions of Wnt7b and β-catenin were assessed using western blotting, and TCF and c-myc mRNA expressions were assessed using qPCR.ResultsRats exposed to 60 and 95% oxygen had significantly lower body weights and survival rates than the 21 and 40% groups, and the decrease was time dependent. Endogenous CGRP was elevated in the lung tissues of premature rats exposed to 95% oxygen. CGRP8–37 induced apparent inflammation in the lung tissue and alveolar structural remodeling. In addition, the expression levels of Wnt7b and β-catenin were markedly increased after exposure for 3 days. They peaked at 7 days, then declined at 14 days. The levels of TCF/c-myc in AEC II cells increased significantly after CGRP treatment when compared with cells that had only undergone hyperoxia.ConclusionsCGRP protected against hyperoxia-induced lung injury in premature rats. This process involves the Wnt7b/β-catenin signaling pathway.