A cysteine-triggered fluorogenic donor base on native chemical ligation for tracking H2S delivery in vivo.

A hydrogen sulfide (H2S) donor is a fundamental molecular tool used as an exogenous source in biological studies and therapies. However, finding a controllable and visual fluorescent H2S donor is difficult. We report a new H2S donor, HSD560, the H2S release of which is triggered by cysteine. Importantly, the H2S generation is accompanied with enhanced green fluorescence, which could be utilized to track H2S release in cells using microscopy. H2S release from HSD560 undergoes a non-enzymatic native chemical ligation (NCL) process, which provides an accurate match with activated fluorescence and localization of H2S in zebrafish.

Machine learning identifies two autophagy-related genes as markers of recurrence in colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) is the most common cancer worldwide. Patient outcomes following recurrence of CRC are very poor. Therefore, identifying the risk of CRC recurrence at an early stage would improve patient care. Accumulating evidence shows that autophagy plays an active role in tumorigenesis, recurrence, and metastasis. METHODS: We used machine learning algorithms and two regression models, univariable Cox proportion and least absolute shrinkage and selection operator (LASSO), to identify 26 autophagy-related genes (ARGs) related to CRC recurrence. RESULTS: By functional annotation, these ARGs were shown to be enriched in necroptosis and apoptosis pathways. Protein-protein interactions identified SQSTM1, CASP8, HSP80AB1, FADD, and MAPK9 as core genes in CRC autophagy. Of 26 ARGs, BAX and PARP1 were regarded as having the most significant predictive ability of CRC recurrence, with prediction accuracy of 71.1%. CONCLUSION: These results shed light on prediction of CRC recurrence by ARGs. Stratification of patients into recurrence risk groups by testing ARGs would be a valuable tool for early detection of CRC recurrence.

MicroRNA-150 deletion in mice protects kidney from myocardial infarction-induced acute kidney injury.

Despite greater understanding of acute kidney injury (AKI) in animal models, many of the preclinical studies are not translatable. Most of the data were derived from a bilateral renal pedicle clamping model with warm ischemia. However, ischemic injury of the kidney in humans is distinctly different and does not involve clamping of renal vessel. Permanent ligation of the left anterior descending coronary artery model was used to test the role of microRNA (miR)-150 in AKI. Myocardial infarction in this model causes AKI which is similar to human cardiac bypass surgery. Moreover, the time course of serum creatinine and biomarker elevation were also similar to human ischemic injury. Deletion of miR-150 suppressed AKI which was associated with suppression of inflammation and interstitial cell apoptosis. Immunofluorescence staining with endothelial marker and marker of apoptosis suggested that dying cells are mostly endothelial cells with minimal epithelial cell apoptosis in this model. Interestingly, deletion of miR-150 also suppressed interstitial fibrosis. Consistent with protection, miR-150 deletion causes induction of its target gene insulin-like growth factor-1 receptor (IGF-1R) and overexpression of miR-150 in endothelial cells downregulated IGF-1R, suggesting miR-150 may mediate its detrimental effects through suppression of IGF-1R pathways.

Concentration- and stage-specific effects of nitrite on colon cancer cell lines.

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Nitrite in cured meats is thought to contribute to increased incidence of colon cancer. We sought to determine the effect of nitrite on human colon cancer cell lines at different stages. Our results indicate nitrite has no effect on proliferation of stage 1 SW116 colon cancer cells, while nitrite inhibits proliferation of stage 2 SW480 at 10 nM-100 µM and inhibits stage 3 HCT15 proliferation at 100 nM-1 µM, but promotes a significant increase in proliferation on stage 4 COLO205 cells at 100 µM. Furthermore, nitrite inhibited invasion into Matrigel® of stage 3 SW480 colon cancer cells in a concentration-dependent manner. However, it significantly promotes the invasion of stage 4 cells at 100 µM. Our FACS data demonstrated that nitrite decreased cell cycle progression in SW480 and HCT15 with arrested G2/M transition and delayed G1 phase entry in a concentration-dependent manner. However, 100 µM nitrite promoted cell cycle progression in COLO205 cells with increased S-phase entry. Taken together, our data indicate nitrite inhibits cancer cell progression at low concentrations and early stage but promotes cancer cell progression at higher concentrations in cells representing stage 4 colon carcinomas.

Nitrite and nitrate: cardiovascular risk-benefit and metabolic effect.

PURPOSE OF REVIEW: To review the most recent published literature on the biological effects of nitrite and nitrate in order to establish the context for potential health benefits vs. potential risks or adverse effects. Nitrite and nitrate are indigenous to our diet and are formed naturally within our body from the oxidation of nitric oxide. Emerging health benefits from dietary sources of nitrite and nitrate contradict decades of epidemiological research that have suggested an association of nitrite and nitrate in foods, primarily cured and processed meat, with certain cancers. RECENT FINDINGS: The major source of exposure of nitrite and nitrate comes from the consumption of nitrate-enriched vegetables. The preponderance of epidemiological studies shows a very weak association with consumption of meats and certain cancers, which contain very little nitrite and nitrate. Nitrite and nitrate in certain foods and diets can be metabolized to nitric oxide and promote cardiovascular benefits and cytoprotection. SUMMARY: The cardiovascular benefits of nitrite and nitrate are beginning to be translated in humans by the increasing number of clinical trials using nitrite and nitrate. The collective body of evidence suggests that foods enriched in nitrite and nitrate provide significant health benefits with very little risk.

Food sources of nitrates and nitrites: the physiologic context for potential health benefits.

The presence of nitrates and nitrites in food is associated with an increased risk of gastrointestinal cancer and, in infants, methemoglobinemia. Despite the physiologic roles for nitrate and nitrite in vascular and immune function, consideration of food sources of nitrates and nitrites as healthful dietary components has received little attention. Approximately 80% of dietary nitrates are derived from vegetable consumption; sources of nitrites include vegetables, fruit, and processed meats. Nitrites are produced endogenously through the oxidation of nitric oxide and through a reduction of nitrate by commensal bacteria in the mouth and gastrointestinal tract. As such, the dietary provision of nitrates and nitrites from vegetables and fruit may contribute to the blood pressure-lowering effects of the Dietary Approaches to Stop Hypertension (DASH) diet. We quantified nitrate and nitrite concentrations by HPLC in a convenience sample of foods. Incorporating these values into 2 hypothetical dietary patterns that emphasize high-nitrate or low-nitrate vegetable and fruit choices based on the DASH diet, we found that nitrate concentrations in these 2 patterns vary from 174 to 1222 mg. The hypothetical high-nitrate DASH diet pattern exceeds the World Health Organization's Acceptable Daily Intake for nitrate by 550% for a 60-kg adult. These data call into question the rationale for recommendations to limit nitrate and nitrite consumption from plant foods; a comprehensive reevaluation of the health effects of food sources of nitrates and nitrites is appropriate. The strength of the evidence linking the consumption of nitrate- and nitrite-containing plant foods to beneficial health effects supports the consideration of these compounds as nutrients.