Development and validation of postoperative and preoperative platelets ratio (PPR) to predict the prognosis of patients undergoing surgery for colorectal cancer: A dual-center retrospective cohort study.

BACKGROUND: Platelets occupy a prominent place in tumor proliferation and metastasis, and platelet count is relevant to the prognosis of tumor patients. But preoperative platelet counts cannot be standardized and individualized due to the variability among individuals, instruments, and regions, and the connection between postoperative platelet count and prognosis remains unknown. A standardized indicator of platelet count was designed to forecast the prognosis of colorectal cancer (CRC). METHODS: Five hundred and eighty six patients who suffered radical resection of CRC between 2013 and 2019 were collected. A development-validation cohort of standardized and individualized platelet counts for prognostic assessment of CRC was designed. We first determined the ability of PPR and other peripheral blood count-related indicators to predict the mortality of patients with CRC and validated them in a separate cohort. Kaplan-Meier analysis was executed to evaluate the survival and univariate and multivariate analyses were executed to explore the relevance. Time-dependent ROC was measured to estimate the predictive usefulness. Decision curve analysis was used to verify the clinical net benefit. RESULTS: Important baseline variables showed a similar distribution in two independent queues. In the development cohort, postoperative platelet count and postoperative/preoperative platelets ratio (PPR) were independent predictors of prognosis in CRC patients. PPR showed the largest area under the curve (AUC) in evaluating 1-year and 5-year OS (AUC: 0.702 and 0.620) compared to others. In the validation cohort, platelet/lymphocyte ratio and PPR were validated to be independently concerned about OS of CRC patients and PPR showed the largest AUC in evaluating 1-year and 3-year OS (AUC: 0.663 and 0.673). PPR and joint index of platelet count and PPR showed better predictive value and clinical net benefit. CONCLUSIONS: PPR has been identified and validated to be independently concerned about OS of patients with CRC and was a reliable and economic indicator to evaluate the prognosis.

Hydrogen sulfide attenuates uranium-induced kidney cells pyroptosis via upregulation of PI3K/AKT/mTOR signaling.

We have identified that hydrogen sulfide (H2 S), a gaseous mediator, plays a crucial role in antioxidative, anti-inflammatory, and cytoprotective effects on uranium (U)-triggered rat nephrotoxicity. Pyroptosis is a special mode of inflammation and programmed cell death involved in the activation of inflammasome and Caspase-1 and the release of inflammatory cytokines. This study aims to confirm whether H2 S can alleviate U-induced rat NRK-52E cell pyroptosis and to investigate the H2 S underlying regulatory mechanism. Our results indicate that pretreatment with NaHS (an H2 S donor) significantly inhibited U-increased reactive oxygen species level, NLRP3, apoptosis-related speck-like protein consisting of a caspase recruitment domain (ASC), and cleaved Caspase-1 proteins expression, gasdermin D messenger RNA (GSDMD mRNA) expression, interleukin (IL)-1ß and IL-18 contents, lactate dehydrogenase leakage, and numbers of double-positive dying kidney cells. NaHS application evidently augmented phosphorylated PI3K, AKT, and mTOR expression as well as ratios of their respective phosphorylation to the corresponding total proteins which were downregulated by U treatment. But, LY294002 (a PI3K inhibitor) administration effectively abrogated the consequences of NaHS on the levels of p-PI3K, cleaved Caspase-1, ASC and NLRP3 proteins, GSDMD mRNA expression, and (IL)-1ß and IL-18 contents. Simultaneously, LY294002 significantly reversed the effects of NaHS on U-induced pyroptosis rate and cytotoxicity. Taken together, these results indicate that H2 S ameliorated U-triggered NRK-52E cells pyroptosis via upregulation of PI3K/AKT/mTOR pathway, suggesting a novel role for H2 S in the management of nephrotoxicity caused by U exposure.

Melatonin alleviates diet-induced steatohepatitis by targeting multiple cell types in the liver to suppress inflammation and fibrosis.

The pathogenesis of nonalcoholic steatohepatitis (NASH), a severe stage of nonalcoholic fatty liver disease, is complex and implicates multiple cell interactions. However, therapies for NASH that target multiple cell interactions are still lacking. Melatonin (MEL) alleviates NASH with mechanisms not yet fully understood. Thus, we herein investigate the effects of MEL on key cell types involved in NASH, including hepatocytes, macrophages, and stellate cells. In a mouse NASH model with feeding of a methionine and choline-deficient (MCD) diet, MEL administration suppressed lipid accumulation and peroxidation, improved insulin sensitivity, and attenuated inflammation and fibrogenesis in the liver. Specifically, MEL reduced proinflammatory cytokine expression and inflammatory signal activation and attenuated CD11C+CD206- M1-like macrophage polarization in the liver of NASH mice. The reduction of proinflammatory response by MEL was also observed in the lipopolysaccharide-stimulated Raw264.7 cells. Additionally, MEL increased liver fatty acid ß-oxidation, leading to reduced lipid accumulation, and restored the oleate-loaded primary hepatocytes. Finally, MEL attenuated hepatic stellate cell (HSC) activation and fibrogenesis in the liver of MCD-fed mice and in LX-2 human HSCs. In conclusion, MEL acts on multiple cell types in the liver to mitigate NASH-associated phenotypes, supporting MEL or its analog as potential treatment for NASH.

Direct adenylation from 5'-OH-terminated oligonucleotides by a fusion enzyme containing Pfu RNA ligase and T4 polynucleotide kinase.

5'-Adenylated oligonucleotides (AppOligos) are widely used for single-stranded DNA/RNA ligation in next-generation sequencing (NGS) applications such as microRNA (miRNA) profiling. The ligation between an AppOligo adapter and target molecules (such as miRNA) no longer requires ATP, thereby minimizing potential self-ligations and simplifying library preparation procedures. AppOligos can be produced by chemical synthesis or enzymatic modification. However, adenylation via chemical synthesis is inefficient and expensive, while enzymatic modification requires pre-phosphorylated substrate and additional purification. Here we cloned and characterized the Pfu RNA ligase encoded by the PF0353 gene in the hyperthermophilic archaea Pyrococcus furiosus. We further engineered fusion enzymes containing both Pfu RNA ligase and T4 polynucleotide kinase. One fusion enzyme, 8H-AP, was thermostable and can directly catalyze 5'-OH-terminated DNA substrates to adenylated products. The newly discovered Pfu RNA ligase and the engineered fusion enzyme may be useful tools for applications using AppOligos.

Deuterium-Reinforced Polyunsaturated Fatty Acids Prevent Diet-Induced Nonalcoholic Steatohepatitis by Reducing Oxidative Stress.

Background and Objectives: Oxidative stress is implicated in the progression of nonalcoholic steatohepatitis (NASH) through the triggering of inflammation. Deuterium-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to the reactive oxygen species (ROS)-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-) PUFAs. Here, we aimed to investigate the impacts of D-PUFAs on oxidative stress and its protective effect on NASH. Materials and Methods: C57BL/6 mice were randomly divided into three groups and were fed a normal chow diet, a methionine-choline-deficient (MCD) diet, and an MCD with 0.6% D-PUFAs for 5 weeks. The phenotypes of NASH in mice were determined. The levels of oxidative stress were examined both in vivo and in vitro. Results: The treatment with D-PUFAs attenuated the ROS production and enhanced the cell viability in tert-butyl hydroperoxide (TBHP)-loaded hepatocytes. Concurrently, D-PUFAs decreased the TBHP-induced oxidative stress in Raw 264.7 macrophages. Accordingly, D-PUFAs increased the cell viability and attenuated the lipopolysaccharide-stimulated proinflammatory cytokine expression of macrophages. In vivo, the administration of D-PUFAs reduced the phenotypes of NASH in MCD-fed mice. Specifically, D-PUFAs decreased the liver transaminase activity and attenuated the steatosis, inflammation, and fibrosis in the livers of NASH mice. Conclusion: D-PUFAs may be potential therapeutic agents to prevent NASH by broadly reducing oxidative stress.

Chemoselective Oxyfunctionalization of Functionalized Benzylic Compounds with a Manganese Catalyst.

Whilst allowing for easy access to synthetically versatile motifs and for modification of bioactive molecules, the chemoselective benzylic oxidation reactions of functionalized alkyl arenes remain challenging. Reported in this study is a new non-heme Mn catalyst stabilized by a bipiperidine-based tetradentate ligand, which enables methylene oxidation of benzylic compounds by H2 O2 , showing high activity and excellent chemoselectivity under mild conditions. The protocol tolerates an unprecedentedly wide range of functional groups, including carboxylic acid and derivatives, ketone, cyano, azide, acetate, sulfonate, alkyne, amino acid, and amine units, thus providing a low-cost, more sustainable and robust pathway for the facile synthesis of ketones, increase of complexity of organic molecules, and late-stage modification of drugs.

Visible-Light-Promoted Diboron-Mediated Transfer Hydrogenation of Azobenzenes to Hydrazobenzenes.

A visible-light-promoted transfer hydrogenation of azobenzenes has been developed. In the presence of B2pin2 and upon visible-light irradiation, the reactions proceeded smoothly in methanol at ambient temperature. The azobenzenes with diverse functional groups have been reduced to the corresponding hydrazobenzenes with a yield of up to 96%. Preliminary mechanistic studies indicated that the hydrogen atom comes from the solvent and the transformation is achieved through a radical pathway.

Visible-light-promoted selective O-alkylation of 2-pyridones with α-aryldiazoacetates.

A visible-light-promoted O-H insertion reaction between 2-pyridones and α-aryldiazoacetates has been developed. Upon visible light irradiation, the reaction proceeds smoothly under mild and catalyst-free conditions. A wide scope of 2-pyridones and α-aryldiazoacetates are well tolerated, and various O-alkylated 2-pyridones are obtained with perfect selectivity and good functional group tolerance. A photoinduced radical process is probably responsible for the excellent selectivity.

Catalyst-free, visible-light-promoted S-H insertion reaction between thiols and α-diazoesters.

A visible-light-promoted S-H insertion reaction between thiols and α-diazoesters was developed. The reaction proceeded smoothly at room temperature with a broad substrate scope, affording various thioethers in moderate to excellent yields. The catalyst- and additive-free nature, sustainable energy source and mild reaction conditions make this strategy more eco-friendly.

Visible-Light-Mediated Hydroacylation of Azobenzenes with α-Keto Acids.

A visible-light-mediated protocol for the hydroacylation of azobenzenes with α-keto acids has been developed. In the absence of any catalyst or additive, decarboxylative hydroacylation proceeded smoothly under visible-light irradiation at room temperature. A wide range of azobenzenes and α-keto acids were well-tolerated and afforded hydroacylation products in high to excellent yields. Preliminary investigations indicated that photoactive azobenzenes absorb visible light to enable the transformation.