Induction of pyroptotic cell death as a potential tool for cancer treatment

Cancer is a complex pathological disease and the existing strategies for introducing chemotherapeutic agents have restricted potential due to a lack of cancer cell targeting specificity, cytotoxicity, bioavailability, and induction of multi-drug resistance. As a prospective strategy in tackling cancer, regulating the inflammatory pyroptosis cell death pathway has been shown to successfully inhibit the proliferation and metastasis of various cancer cell types. Activation of inflammasomes such as the NLRP3 results in pyroptosis through cleavage of gasdermins, which forms pores in the cell membranes, inducing membrane breakage, cell rupture, and death. Furthermore, pyroptotic cells release pro-inflammatory cytokines such as IL-1β and IL-18 along with various DAMPs that prime an auxiliary anti-tumor immune response. Thus, regulation of pyroptosis in cancer cells is a way to enhance their immunogenicity. However, immune escape involving myeloid-derived suppressor cells has limited the efficacy of most pyroptosis-based immunotherapy strategies. In this review, we comprehensively summarize the cellular and molecular mechanisms involved in the inflammasome-mediated pyroptosis pathways in cancer cells, exploring how it could modulate the tumor microenvironment and be beneficial in anti-cancer treatments. We discuss various existing therapeutic strategies against cancer, including immunotherapy, oncolytic virus therapy, and nanoparticle-based therapies that could be guided to trigger and regulate pyroptosis cell death in cancer cells, and reduce tumor growth and spread. These pyroptosis-based cancer therapies may open up fresh avenues for targeted cancer therapy approaches in the future and their translation into the clinic

Absence of the caspases 1/11 modulates liver global lipid profile and gut microbiota in high-fat-diet-induced obese mice

Obesity is a chronic disease with rising worldwide prevalence and largely associated with several other comorbidities, such as cancer, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome. Hepatic steatosis, a hallmark of NAFLD, is strongly correlated with obesity and has been correlated with changes in the gut microbiota, which can promote its development through the production of short-chain fatty acids (SCFAs) that regulate insulin resistance, bile acid, choline metabolism, and inflammation. Recent studies have suggested a controversial role for the inflammasome/caspase-1 in the development of obesity and non-alcoholic steatohepatitis (NASH). Here, we evaluated the role of inflammasome NLRP3 and caspases 1/11 in the establishment of obesity and hepatic steatosis in diet-induced obese mice, correlating them with the global lipid profile of the liver and gut microbiota diversity. After feeding wild-type, caspases 1/11, and NLRP3 knockout mice with a standard fat diet (SFD) or a high-fat diet (HFD), we found that the caspases 1/11 knockout mice, but not NLRP3 knockout mice, were more susceptible to HFD-induced obesity, and developed enhanced hepatic steatosis even under SFD conditions. Lipidomics analysis of the liver, assessed by MALDI-MS analysis, revealed that the HFD triggered a significant change in global lipid profile in the liver of WT mice compared to those fed an SFD, and this profile was modified by the lack of caspases 1/11 and NLRP3. The absence of caspases 1/11 was also correlated with an increased presence of triacylglycerol in the liver. Gut microbial diversity analysis, using 16S rRNA gene sequencing, showed that there was also an increase of Proteobacteria and a higher Firmicutes/Bacteroidetes ratio in the gut of caspases 1/11 knockout mice fed an HFD. Overall, mice without caspases 1/11 harbored gut bacterial phyla involved with weight gain, obesity, and hepatic steatosis. Taken together, our data suggest an important role for caspases 1/11 in the lipid composition of the liver and in the modulation of the gut microbial community composition. Our results further suggest that HFD-induced obesity and the absence of caspases 1/11 may regulate both lipid metabolism and gut microbial diversity, and therefore may be associated with NAFLD and obesity10CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP312359/2016-02016/22577-6This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq -#312359/2016-0). CM was funded by the Canada Research Chair Program, the Canadian Foundation for Innovation, McGill University, and the Canadian Institutes for Health Research (PJT-149098). ME was funded by the São Paulo Research Foundation (FAPESP) (2016/22577-6)

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

The Cellular Impact of the ZIKA Virus on Male Reproductive Tract Immunology and Physiology

Zika virus (ZIKV) has been reported by several groups as an important virus causing pathological damage in the male reproductive tract. ZIKV can infect and persist in testicular somatic and germ cells, as well as spermatozoa, leading to cell death and testicular atrophy. ZIKV has also been detected in semen samples from ZIKV-infected patients. This has huge implications for human reproduction. Global scientific efforts are being applied to understand the mechanisms related to arboviruses persistency, pathogenesis, and host cellular response to suggest a potential target to develop robust antiviral therapeutics and vaccines. Here, we discuss the cellular modulation of the immunologic and physiologic properties of the male reproductive tract environment caused by arboviruses infection, focusing on ZIKV. We also present an overview of the current vaccine effects and therapeutic targets against ZIKV infection that may impact the testis and male fertility