No abstract

Glyphosate-based herbicides have been used worldwide for decades and have been suggested to induce nephrotoxicity, but the underlying mechanism is not yet clear.In this study, we treated a human renal proximal tubule cell line (HK-2) with glyphosate for 24 hours at concentrations of 0, 20, 40 and 60 μM. Glyphosate was found to reduce cell viability and induce apoptosis and oxidative stress in a dose-dependent manner. Because the chemical structures of glyphosate and those of its metabolite AMPA are similar to glycine and glutamate, which are agonists of the N-methyl-Daspartate receptor (NMDAR), we investigated the potential role of the NMDAR pathway in mediating the proapoptotic effect of glyphosate on proximal tubule cells.We found that NMDAR1 expression, as well as intracellular Ca 2+ ([Ca 2+ ] i ) and reactive oxygen species (ROS) levels, increased after glyphosate treatment. Blocking NMDAR attenuated glyphosate-induced upregulation of [Ca 2+ ] i and ROS levels as well as apoptosis. Meanwhile, inhibition of [Ca 2+ ] i reduced glyphosate-induced ROS and apoptosis, and inhibition of ROS alleviated glyphosate-induced apoptosis. In mice exposed to 400 mg/kg glyphosate, the urine low molecular weight protein levels started to increase from day 7. Upregulation of apoptosis and NMDAR1 expression in renal proximal tubule epithelium and an imbalance of oxidant and antioxidative products were observed. These results strongly suggest that activation of the NMDAR1 pathway, together with its downstream [Ca 2+ ] i and oxidative stress, is involved in glyphosate-induced renal proximal tubule epithelium apoptosis.

Liver fibrosis is the most serious pathology caused by Schistosoma japonicum infection, which arises when schistosome eggs are deposited in the liver. Eosinophils, macrophages and hepatic stellate cells (HSCs) have been identified as major cellular contributors to the development of granulomas and fibrosis, but little is known about the effects of hepatocytes on granuloma formation. Here, we found that the levels of Wnt signalling-related molecules, transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) in hepatocytes were markedly elevated after S. japonicum infection. Liver fibrosis was exacerbated when exogenous Wnt3a was introduced, but was alleviated when Wnt signalling was suppressed by DKK1, accompanied by the reduced expression of TGF-β and CTGF in hepatocytes. These results indicate that the hepatocytic expression of TGF-β and CTGF is mediated by Wnt signalling. Additionally, the hepatocytes isolated from infected mice promoted the activation of primary HSCs in vitro, however, this effect was not observed when hepatocytes from DKK1 treated S. japonicum-infected mice was employed in the co-culture system. Our findings identify a novel pro-fibrogenic role of hepatocytes in schistosomiasis-induced liver fibrosis that is dependent on Wnt signalling, which may serve as a potential target for ameliorating hepatic fibrosis caused by helminths.

The immune system plays an essential role in the development of tumors, which has been demonstrated in multiple types of cancers. Consistent with this, immunotherapies with targets that disrupt these mechanisms and turn the immune system against developing cancers have been proven effective. In neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, the understanding of the complex interactions of the immune system is incomplete despite the discovery of the pivotal role of immune cells in the tumor microenvironment. Individuals with NF1 show a loss of the NF1 gene in nonneoplastic cells, including immune cells, and the aberrant immune system exhibits intriguing interactions with NF1. This review aims to provide an update on recent studies showing the bilateral influences of NF1 mutations on immune cells and how the abnormal immune system promotes the development of NF1 and NF1-related tumors. We then discuss the immune receptors major histocompatibility complex class I and II and the PD-L1 mechanism that shield NF1 from immunosurveillance and enable the immune escape of tumor tissues. Clarification of the latest understanding of the mechanisms underlying the effects of the abnormal immune system on promoting the development of NF1 will indicate potential future directions for further studies and new immunotherapies.