M1 macrophages accelerate renal glomerular endothelial cell senescence through reactive oxygen species accumulation in streptozotocin-induced diabetic mice.

Cellular senescence is a fundamental aging mechanism leading to tissue dysfunction. Accumulation of senescent cells is observed in the context of diabetes, which plays an important role in the pathogenesis of diabetes and its complications. Macrophages, the most prevalent leucocytes found in diabetic kidney, have been implicated in the modulation of cellular senescence; however, their role and mechanism in cellular senescence of diabetic kidney have not been determined. In this study, we found trends of cellular senescence in the glomeruli of streptozotocin-induced diabetic mice. The onset of glomerular senescence was confirmed by increased SA-ß-gal staining, the upregulation of p16INK4a, p21, and p53 protein levels and the increased expression of SASP RNA. The senescent cells in the glomeruli were mainly endothelial cells. We next confirmed that M1 macrophages accumulated in the glomeruli, occurred just shortly before glomerular senescence. Therefore, we examined whether M1 macrophage accumulation is associated with glomerular endothelial cell senescence. Thus, an in vitro co-culture model was established using human renal glomerular endothelial cells (HRGECs) and M1-polarized THP-1 macrophages. Indeed, M1 macrophages induced senescence in HRGECs. Furthermore, intracellular ROS levels and p38 MAPK signalling activation were significantly increased in HRGECs and reducing ROS generation significantly abolished M1 macrophage-mediated endothelial senescence and p38 MAPK activation, suggesting that M1 macrophage-mediated endothelial senescence is largely dependent on ROS. Thus, our results demonstrate that kidney M1 macrophage accumulation is in connection with endothelial cell senescence and strategy to modulate M1 macrophages accumulation is promising to be a new target for immunotherapy for diabetic kidney disease and other age-related diseases.

Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats.

BACKGROUND: Long-term diabetes-associated complications are the major causes of morbidity and mortality in individuals with diabetes. These diabetic complications are closely linked to immune system activation along with chronic, non-resolving inflammation, but therapies to directly reverse these complications are still not available. Our previous study demonstrated that mesenchymal stem cells (MSCs) attenuated chronic inflammation in type 2 diabetes mellitus (T2DM), resulting in improved insulin sensitivity and islet function. Therefore, we speculated that MSCs might exert anti-inflammatory effects and promote the reversal of diabetes-induced kidney, liver, lung, heart, and lens diseases in T2DM rats. METHODS: We induced a long-term T2DM complication rat model by using a combination of a low dose of streptozotocin (STZ) with a high-fat diet (HFD) for 32 weeks. Adipose-derived mesenchymal stem cells (ADSCs) were systemically administered once a week for 24 weeks. Then, we investigated the role of ADSCs in modulating the progress of long-term diabetic complications. RESULTS: Multiple infusions of ADSCs attenuated chronic kidney disease (CKD), nonalcoholic steatohepatitis (NASH), lung fibrosis, and cataracts; improved cardiac function; and lowered serum lipid levels in T2DM rats. Moreover, the levels of inflammatory cytokines in the serum of each animal group revealed that ADSC infusions were able to not only inhibit pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α expression but also increase anti-inflammatory cytokine IL-10 systematically. Additionally, MSCs reduced the number of iNOS(+) M1 macrophages and restored the number of CD163(+) M2 macrophages. CONCLUSIONS: Multiple intravenous infusions of ADSCs produced significant protective effects against long-term T2DM complications by alleviating inflammation and promoting tissue repair. The present study suggests ADSCs may be a novel, alternative cell therapy for long-term diabetic complications.

Autophagy knocked down by high-risk HPV infection and uterine cervical carcinogenesis.

Cervical cancer is a leading cause of cancer death among women in the world. The specific etiopathogenesis of cervical cancer is indeed complex. Even so, we should make arduous efforts to have a precise understanding of the complicate cellular/molecular mechanisms underlying initiation, progression and/or prevention of the cervical cancer. The high-risk human papillomavirus (hrHPV) is considered as the major causative agent of cervical cancer. But with the existence of hrHPV only is not sufficient, autophagy plays a vital character in the development of cervical cancer. Autophagy is the endogenous, tightly regulated cellular "housekeeping" process responsible for the degradation of damaged and dysfunctional cellular organelles and protein aggregates. Our aims in this review were (1) to provide a brief synopsis of process of autophagy (including an overview of the key molecular mediators of this catabolic process and its relationship with hrHPV infection) and (2) most importantly, summarize the current evidence for autophagy-mediated cervical carcinogenesis. One of the latest opinions about the etiopathogenesis is that hrHPV leads to the occurrence of cervical cancer via inhibiting the host's autophagy. The infection of hrHPV will cause the autophagy of cancerous cells, resulting in autophagic cell death, which will suppress the further infection of HPV in return. But the autophagy would be knocked down by the hrHPV, which means the protecting action would end with failure. What's worse, the negative denouement will enhance the infectivity of HPV ultimately, which leads to accelerate cervical carcinogenesis.