Metadherin silencing results in the inhibition of pyroptosis in lipopolysaccharide/adenosine triphosphate - stimulated renal tubular epithelial cells.

Pyroptosis is induced following inflammation via activation of the NLRP3 inflammasome. Lipopolysaccharide (LPS)-induced acute inflammation causes pyroptosis in renal tubular epithelial cells, which aggravates kidney damage and is involved in physiopathological processes in multiple renal diseases. Metadherin (Mtdh) induces inflammation by NLRP3 inflammasome activation. Specifically, it induces inflammatory injury in the kidney by activating the nuclear factor kappa B (NF-κB) signaling pathway, which is involved in NLRP3 inflammasome activation. However, the role of Mtdh in pyroptosis in renal tubular epithelial cells is unclear. Therefore, we investigated whether Mtdh participates in pyroptosis in LPS/adenosine triphosphate (ATP)-treated NRK-52E cells by activating the NLRP3 inflammasome and NF-κB signaling pathway. We induced pyroptosis in NRK-52E cells with LPS/ATP, after which Mtdh was silenced via transfection with small interfering RNA. LPS/ATP upregulated Mtdh expression and induced pyroptosis and NLRP3 inflammasome activation in NRK-52E cells. However, downregulation of Mtdh expression resulted in the alleviation of pyroptosis in LPS/ATP-treated NRK-52E cells. Additionally, activation of the NLRP3 inflammasome and NF-κB signaling pathway was inhibited. This demonstrates that downregulation of Mtdh expression results in the inhibition of pyroptosis in LPS/ATP-treated NRK-52E cells through the suppression of NLRP3 inflammasome activation, which occurs via inhibition of the NF-κB signaling pathway.

Association between VDR gene FokI polymorphism and renal function in patients with IgA nephropathy.

BACKGROUND: Studies have shown that the occurrence and development of IgA nephropathy (IgAN) are genetically susceptible, but the relationship between vitamin D receptor (VDR) gene polymorphisms and renal function in IgAN patients is unclear. METHODS: We investigated the relationship between VDR FokI (rs2228570) single nucleotide polymorphism (SNP) and renal function and related clinicopathologic parameters in IgAN patients. Clinical and pathological data of 282 IgAN patients treated at the First Affiliated Hospital of Guangxi Medical University were collected, and FokI genotypes were determined by PCR and direct sequencing. Patients were divided into the renal dysfunction group and normal renal function (control) group by estimated glomerular filtration rate (eGFR) and serum creatinine level. RESULTS: Frequencies of TT genotype and T allele in the renal dysfunction group were higher than those of the control group. Blood urea nitrogen, serum phosphorus (P), proportions of mesangial cell proliferation, interstitial fibrosis/tubular atrophy and crescents in T allele carriers were higher than those in non-T allele carriers, while eGFR and 25-Hydroxyvitamin D3 were lower in T allele carriers than non-T allele carriers. Multiple linear regression analysis showed that eGFR was affected by FokI genotypes in IgAN patients. Logistics regression analysis showed that middle and elderly age, elevated P, intact parathyroid hormone and TT genotype were independent risk factors for renal dysfunction in IgAN patients; the odds ratio of carrying the TT genotype was as high as 84.77 (P < 0.05 for all). CONCLUSIONS: IgA nephropathy patients carrying the VDR FokI TT genotype have an increased risk of renal dysfunction. VDR FokI SNP is closely related to renal function, calcium-phosphate metabolism, and related pathological damage in IgAN patients.

Matrine suppresses lipopolysaccharide-induced fibrosis in human peritoneal mesothelial cells by inhibiting the epithelial-mesenchymal transition.

BACKGROUND: Peritoneal fibrosis is the primary reason that patients with end-stage renal disease (ESRD) have to cease peritoneal dialysis. Peritonitis caused by Gram-negative bacteria such as Escherichia coli (E. coli) were on the rise. We had previously shown that matrine inhibited the formation of biofilm by E. coli. However, the role of matrine on the epithelial-mesenchymal transition (EMT) in peritoneal mesothelial cells under chronic inflammatory conditions is still unknown. METHODS: We cultured human peritoneal mesothelial cells (HPMCs) with lipopolysaccharide (LPS) to induce an environment that mimicked peritonitis and investigated whether matrine could inhibit LPS-induced EMT in these cells. In addition, we investigated the change in expression levels of the miR-29b and miR-129-5p. RESULTS: We found that 10 µg/ml of LPS induced EMT in HPMCs. Matrine inhibited LPS-induced EMT in HPMCs in a dose-dependent manner. We observed that treatment with matrine increased the expression of E-cadherin (F = 50.993, P < 0.01), and decreased the expression of alpha-smooth muscle actin (F = 32.913, P < 0.01). Furthermore, we found that LPS reduced the expression levels of miR-29b and miR-129-5P in HPMCs, while matrine promoted the expression levels of miR-29b and miR-129-5P. CONCLUSIONS: Matrine could inhibit LPS-induced EMT in HPMCs and reverse LPS inhibited expressions of miR-29 b and miR-129-5P in HPMCs, ultimately reduce peritoneal fibrosis. These findings provide a potential theoretical basis for using matrine in the prevention and treatment of peritoneal fibrosis.

Dianhydrogalactitol, a potential multitarget agent, inhibits glioblastoma migration, invasion, and angiogenesis.

The complexity of cancer has led to single-target agents exhibiting lower-than-desired clinical efficacy. Drugs with multiple targets provide a feasible option for the treatment of complex tumors. Multitarget anti-angiogenesis agents are among the new generation of anticancer drugs and have shown favorable clinical efficacy. Dianhydrogalactitol (DAG) is a chemotherapeutic agent for chronic myeloid leukemia and lung cancer. Recently, it has been tested in phase II trials of glioblastoma treatment; however, mechanisms of DAG in glioblastoma have not been elucidated. Here we show that DAG could inhibit the migration and invasion of U251 cell line by inhibiting matrix metalloproteinase-2 (MMP2) expression. Furthermore, DAG could also inhibit tumor angiogenesis in vitro as well as in the zebrafish model. Mechanistic studies reveal that DAG inhibited both VEGFR2 and FGFR1 pathways. Our results suggest that DAG may be a potential multitarget agent that can inhibit tumor migration, invasion, and angiogenesis, and the anti-angiogenic effects may be involved in dual-suppression VEGF/VEGFR2 and FGF2/FGFR1 signal pathways.

Cross-talk between Arg methylation and Ser phosphorylation modulates apoptosis signal-regulating kinase 1 activation in endothelial cells.

We describe a novel functional interaction between ASK1 and PRMT5. We show that PRMT5 interacts with and methylates ASK1 at arginine residue 89 and thereby negatively regulates its activity by promoting the interaction between ASK1 and Akt and thus phosphorylating ASK1 at serine residue 83. Furthermore, the association between ASK1 and Akt is enhanced by VEGF stimulation, and PRMT5 is required for this association. Moreover, PRMT5-mediated ASK1 methylation impaired the H2O2-induced activity of ASK1, and this inhibitory effect of PRMT5 was abolished by replacement of arginine 89 with Trp or depletion of PRMT5 expression by RNA interference. Together the results demonstrate cross-talk between arginine methylation and serine phosphorylation in ASK1.