Ferroptosis inhibitor alleviates sorafenib-induced cardiotoxicity by attenuating KLF11-mediated FSP1-dependent ferroptosis.

Sorafenib is a standard first-line drug for advanced hepatocellular carcinoma, but the serious cardiotoxic effects restrict its therapeutic applicability. Here, we show that iron-dependent ferroptosis plays a vital role in sorafenib-induced cardiotoxicity. Remarkably, our in vivo and in vitro experiments demonstrated that ferroptosis inhibitor application neutralized sorafenib-induced heart injury. By analyzing transcriptome profiles of adult human sorafenib-treated cardiomyocytes, we found that Krüppel-like transcription factor 11 (KLF11) expression significantly increased after sorafenib stimulation. Mechanistically, KLF11 promoted ferroptosis by suppressing transcription of ferroptosis suppressor protein 1 (FSP1), a seminal breakthrough due to its ferroptosis-repressing properties. Moreover, FSP1 knockdown showed equivalent results to glutathione peroxidase 4 (GPX4) knockdown, and FSP1 overexpression counteracted GPX4 inhibition-induced ferroptosis to a substantial extent. Cardiac-specific overexpression of FSP1 and silencing KLF11 by an adeno-associated virus serotype 9 markedly improved cardiac dysfunction in sorafenib-treated mice. In summary, FSP1-mediated ferroptosis is a crucial mechanism for sorafenib-provoked cardiotoxicity, and targeting ferroptosis may be a promising therapeutic strategy for alleviating sorafenib-induced cardiac damage.

A Hydrogen Evolution Catalyst [Co2O2] Metallacycle Enables Regioselective Allene C(sp2)-H Functionalization.

Selective functionalization of allenic C(sp2)-H is an ideal approach to upgrading simple allenes to synthetically useful allenes, albeit suffering from challenges associated with inert reactivity and inferior selectivity. Inspired by energy chemistry, a catalytic hydrogen evolution reaction (HER) strategy was leveraged to selectively activate weakly acidic allene C(sp2)-H bonds in a reductive mode. An array of [Co2O2] metallacycle complexes were readily devised starting from amino acids, and they were demonstrated as robust HER catalysts, which would selectively break allenic C(sp2)-H bonds to release hydrogen. With the newly developed HER catalyst, regioselective electrochemical functionalization of allenic C(sp2)-H with alcoholic α C(sp3)-H was unprecedentedly achieved. This strategy features excellent regioselectivity, unconventional chemoselectivity, good functional-group tolerance (62 examples), and mild conditions. Mechanism experiments revealed a reactive hydroxy-coordinated cobalt(II) species in the reaction. Density functional theory (DFT) calculations were also conducted to rationalize the regioselectivity observed in the reaction.

The regulation of simulated artificial oro-gastrointestinal transit stress on the adhesion of Lactobacillus plantarum S7.

BACKGROUND: Oro-gastrointestinal stress in the digestive tract is the main stress to which orally administered probiotics are exposed. The regulation of oro-gastrointestinal transit (OGT) stress on the adhesion and survival of probiotics under continuous exposure to simulated salivary-gastric juice-intestinal juice was researched in this study. RESULTS: Lactobacillus plantarum S7 had a higher survival rate after exposure to simulated OGT1 (containing 0.15% bile salt) stress and OGT2 (containing 0.30% bile salt) stress. The adhesion ability of L. plantarum S7 was significantly increased by OGT1 stress (P < 0.05) but was not changed significantly by OGT2 stress (P > 0.05), and this trend was also observed in terms of the thickness of the surface material of L. plantarum S7 cells. The expression of surface proteins of L. plantarum S7, such as the 30 S ribosomal proteins, mucus-binding protein and S-layer protein, was significantly downregulated by OGT stress (P < 0.05); meanwhile, the expression of moonlight proteins, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycorate kinase (PGK), beta-phosphoglucomutase (PGM1), GroEL and glucose-6-phosphate isomerase (PGI), was significantly upregulated (P < 0.05). However, the upregulation of GAPDH, PGK, PGM1 and PGI mediated by OGT1 stress was greater than those mediated by OGT2 stress. The quorum sensing pathway of L. plantarum S7 was changed significantly by OGT stress compared with no OGT stress cells (P < 0.05), and the expression of Luxs in the pathway was significantly upregulated by OGT1 stress (P < 0.05). The ABC transportation pathway was significantly altered by OGT1 stress (P < 0.05), of which the expression of the peptide ABC transporter substrate-binding protein and energy-coupling factor transporter ATP-binding protein EcfA was significantly upregulated by OGT stress (P < 0.05). The glycolide metabolism pathway was significantly altered by OGT1 stress compared with that in response to OGT2 stress (P < 0.05). CONCLUSION: L. plantarum S7 had a strong ability to resist OGT stress, which was regulated by the proteins and pathways related to OGT stress. The adhesion ability of L. plantarum S7 was enhanced after continuous exposure to OGT1 stress, making it a potential probiotic with a promising future for application.

Electrochemically Generated Carbanions Enable Isomerizing Allylation and Allenylation of Aldehydes with Alkenes and Alkynes.

The direct coupling of aldehydes with petrochemical feedstock alkenes and alkynes would represent a practical and streamlined approach for allylation and allenylation chemistry. However, conventional approaches commonly require preactivated substrates or strong bases to generate allylic or propargylic carbanions and only afford branched allylation or propargylation products. Developing a mild and selective approach to access synthetically useful linear allylation and allenylation products is highly desirable, albeit with formidable challenges. We report a strategy using hydrogen evolution reaction (HER) to generate a carbanion from weakly acidic sp3 C-H bonds (pKa ∼ 35-40) under mild reaction conditions, obviating the use of strong bases, Schlenk techniques, and multistep procedures. The cathodically generated carbanion reverses the typical reaction selectivity to afford unconventional isomerizing allylation and allenylation products (125 examples). The generation of carbanions was monitored and identified by in situ ultraviolet-visible (UV-vis) spectroelectrochemistry. Furthermore, we extended this protocol to the generation of other carbanions and their application in coupling reactions between alcohols with carbanions. The appealing features of this approach include mild reaction conditions, excellent functional group tolerance, unconventional chemo- and regioselectivity, and the diverse utility of products, which includes offering direct access to diene luminophores and bioactive scaffolds. We also performed cyclic voltammetry, control experiments, and density functional theory (DFT) calculations to rationalize the observed reaction selectivity and mechanism.

Effectiveness and Safety of Bu Shen Kai Qiao Fang in the Treatment of Alzheimer's Disease: Study Protocol for a Multicenter, Prospective, Real-World Clinical Trial.

Background: Alzheimer's disease (AD) is a common degenerative disease of the nervous system with serious impact on quality of life of patients and their families. With an aging population, AD has become a major public health problem in China and worldwide. However, the physiological and pathological mechanisms of AD have not been fully elucidated, and there is a lack of effective prevention and clinical treatment methods. Many studies have found that traditional Chinese medicine (TCM) has a good therapeutic effect on cognitive function in AD patients. Bu Shen Kai Qiao Fang (BSKQF) is one such Chinese herbal preparation used in the treatment of AD. We designed a protocol for a real-world clinical study of BSKQF combined with Donepezil hydrochloride (DH) to evaluate the efficacy and safety of this approach in the treatment of AD patients. Methods: This is a protocol for a real-world, multicenter, prospective, observational cohort study. The study will recruit 860 AD patients from four hospitals across China. Equal numbers of patients will be treated with BSKQF and DH or with DH only. The criteria for grouping are based primarily on patient preference. Outcome measures include scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MOCA) and will be recorded at baseline, and at one, two and three months after enrollment. The plasma Aß42 and plasma Tau levels of participating patients will also be measured by ELISA at baseline and after 3 months of treatment. Safety metrics and adverse events (AEs) of participating patients will be monitored and recorded. Discussion: This study will evaluate the clinical efficacy and safety of BSKQF in the treatment of AD. The results will provide reliable evidence for the clinical application of BSKQF in the treatment of AD. Study Registration: Trial registration: Chinese Clinical Trial Registry, NO. ChiCTR2000039670, Registered 5 November 2020 https://www.chictr.org.cn/showprojEN.html?proj=63800.

Tree-Based Risk Factor Identification and Stroke Level Prediction in Stroke Cohort Study.

Objective. This study focuses on the identification of risk factors, classification of stroke level, and evaluation of the importance and interactions of various patient characteristics using cohort data from the Second Hospital of Lanzhou University. Methodology. Risk factors are identified by evaluation of the relationships between factors and response, as well as by ranking the importance of characteristics. Then, after discarding negligible factors, some well-known multicategorical classification algorithms are used to predict the level of stroke. In addition, using the Shapley additive explanation method (SHAP), factors with positive and negative effects are identified, and some important interactions for classifying the level of stroke are proposed. A waterfall plot for a specific patient is presented and used to determine the risk degree of that patient. Results and Conclusion. The results show that (1) the most important risk factors for stroke are hypertension, history of transient ischemia, and history of stroke; age and gender have a negligible impact. (2) The XGBoost model shows the best performance in predicting stroke risk; it also gives a ranking of risk factors based on their impact. (3) A combination of SHAP and XGBoost can be used to identify positive and negative factors and their interactions in stroke prediction, thereby providing helpful guidance for diagnosis.

Beneficial effects of Lactobacillus rhamnosus hsryfm 1301 fermented milk on rats with nonalcoholic fatty liver disease.

A growing stream of research suggests that probiotic fermented milk has a good effect on nonalcoholic fatty liver disease. This work aimed to study the beneficial effects of Lactobacillus rhamnosus hsryfm 1301 fermented milk (fermented milk) on rats with nonalcoholic fatty liver disease induced by a high-fat diet. The results showed that the body weight and the serum levels of total cholesterol, total glyceride, low-density lipoprotein, alanine transaminase, aspartate aminotransferase, free fatty acid, and reactive oxygen species were significantly increased in rats fed a high-fat diet (M) for 8 wk, whereas high-density lipoprotein cholesterol and superoxide dismutase were significantly decreased. However, the body weight and the serum levels of total cholesterol, total glyceride, alanine transaminase, aspartate aminotransferase, free fatty acid, reactive oxygen species, interleukin-8, tumor necrosis factor-α, and interleukin-6 were significantly decreased with fermented milk (T) for 8 wk, and the number of fat vacuoles in hepatocytes was lower than that in the M group. There were significant differences in 19 metabolites in serum between the M group and the C group (administration of nonfermented milk) and in 17 metabolites between the T group and the M group. The contents of 7 different metabolites, glycine, glycerophosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, thioetheramide-PC, d-aspartic acid, oleic acid, and l-glutamate, were significantly increased in the M group rat serum, and l-palmitoyl carnitine, N6-methyl-l-lysine, thymine, and 2-oxadipic acid were significantly decreased. In the T group rat serum, the contents of 8 different metabolites-1-O-(cis-9-octadecenyl)-2-O-acetyl-sn-glycero-3-phosphocholine, acetylcarnitine, glycine, glycerophosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, d-aspartic acid, oleic acid, and l-glutamate were significantly decreased, whereas creatinine and thymine were significantly increased. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that 50 metabolic pathways were enriched in the M/C group and T/M group rat serum, of which 12 metabolic pathways were significantly different, mainly distributed in lipid metabolism, amino acid, and endocrine system metabolic pathways. Fermented milk ameliorated inflammation, oxygenation, and hepatocyte injury by regulating lipid metabolism, amino acid metabolic pathways, and related metabolites in the serum of rats with nonalcoholic fatty liver disease.

Autoxidated linolenic acid inhibits aflatoxin biosynthesis in Aspergillus flavus via oxylipin species.

Aflatoxins produced by Aspergillus species are among the most toxic and carcinogenic compounds in nature. Although it has been known for a long time that seeds with high oil content are more susceptible to aflatoxin contamination, the role of fatty acids in aflatoxin biosynthesis remains controversial. Here we demonstrate in A. flavus that both the saturated stearic acid (C18:0) and the polyunsaturated linolenic acid (C18:3) promoted aflatoxin production, while C18:3, but not C18:0, inhibited aflatoxin biosynthesis after exposure to air for several hours. Further experiments showed that autoxidated C18:3 promoted mycelial growth, sporulation, and kojic acid production, but inhibited the expression of genes in the AF biosynthetic gene cluster. Mass spectrometry analyses of autoxidated C18:3 fractions that were able to inhibit aflatoxin biosynthesis led to the identification of multiple oxylipin species. These results may help to clarify the role of fatty acids in aflatoxin biosynthesis, and may explain why controversial results have been obtained for fatty acids in the past.

Aspergillus flavus grown in peptone as the carbon source exhibits spore density- and peptone concentration-dependent aflatoxin biosynthesis.

BACKGROUND: Aflatoxins (AFs) are highly carcinogenic compounds produced by Aspergillus species in seeds with high lipid and protein contents. It has been known for over 30 years that peptone is not conducive for AF productions, although reasons for this remain unknown. RESULTS: In this study, we showed that when Aspergillus flavus was grown in peptone-containing media, higher initial spore densities inhibited AF biosynthesis, but promoted mycelial growth; while in glucose-containing media, more AFs were produced when initial spore densities were increased. This phenomenon was also observed in other AF-producing strains including A. parasiticus and A. nomius. Higher peptone concentrations led to inhibited AF production, even in culture with a low spore density. High peptone concentrations did however promote mycelial growth. Spent medium experiments showed that the inhibited AF production in peptone media was regulated in a cell-autonomous manner. mRNA expression analyses showed that both regulatory and AF biosynthesis genes were repressed in mycelia cultured with high initial spore densities. Metabolomic studies revealed that, in addition to inhibited AF biosynthesis, mycelia grown in peptone media with a high initial spore density showed suppressed fatty acid biosynthesis, reduced tricarboxylic acid (TCA) cycle intermediates, and increased pentose phosphate pathway products. Additions of TCA cycle intermediates had no effect on AF biosynthesis, suggesting the inhibited AF biosynthesis was not caused by depleted TCA cycle intermediates. CONCLUSIONS: We here demonstrate that Aspergillus species grown in media with peptone as the sole carbon source are able to sense their own population densities and peptone concentrations to switch between rapid growth and AF production. This switching ability may offer Aspergillus species a competition advantage in natural ecosystems, producing AFs only when self-population is low and food is scarce.