Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels.

Taxol (paclitaxel) is the first approved microtubule-stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first-line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer-associated missence mutations in ß-tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol-resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol-resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug-susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6-fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 µM.

Foliar spraying of Zn/Si affects Cd accumulation in paddy grains by regulating the remobilization and transport of Cd in vegetative organs.

The reduction of cadmium (Cd) accumulation in rice grains through biofortification of essential nutrients like zinc (Zn) and silicon (Si) is an area of study that has gained significant attention. However, there is limited understanding of the mechanism of Zn/Si interaction on Cd accumulation and remobilization in rice plants. This work used a pot experiment to examine the effects of Zn and Si applied singly or in combination on the physiological metabolism of Cd in different rice organs under Cd stress. The results revealed that: Zn/Si application led to a significant decrease in root Cd concentration and reduce the value of Tf Soil-Root in filling stage. The content of phytochelatin (PCs, particularly PC2) and glutathione (GSH) in roots, top and basal nodes were increased with Zn/Si treatment application. Furthermore, Zn/Si treatment promoted the distribution of Cd in cell wall during Cd stress. These findings suggest that Zn/Si application facilitates the compartmentalization of Cd within subcellular structures and enhances PCs production in vegetative organs, thereby reducing Cd remobilization. Zn/Si treatment upregulated the metabolism of amino acid components involved in osmotic regulation, secondary metabolite synthesis, and plant chelating peptide synthesis in vegetative organs. Additionally, it significantly decreased the accumulation of Cd in globulin, albumin, and glutelin, resulting in an average reduction of 50.87% in Cd concentration in milled rice. These results indicate that Zn/Si nutrition plays a crucial role in mitigating heavy metal stress and improving the nutritional quality of rice by regulating protein composition and coordinating amino acid metabolism balance.

Graphical education and appropriate time before elective colonoscopy make better bowel preparation.

Background: Inadequate bowel preparation leads to lower polyp detection rates, longer procedure times and lower cecal intubation rates. However, there is no consensus about high-quality bowel preparation, so our study evaluated graphical education and appropriate time before elective colonoscopy. Patients and Methods: We performed a secondary analysis of a national colorectal cancer screening programme of 738 patients. The patients were divided into a group given a graphical information manual (n = 242) or a word-only one (n = 496). They were also divided into groups according to the interval between bowel preparation and colonoscopy: 6-8 h (Group 1, n = 106), 9-12 h (Group 2, n = 228) and 13-17 h (Group 3, n = 402). All patients were scored according to the Boston Bowel Preparation Scale (BBPS) during the examination. Results: The bowel preparation of the graphical group was significantly better than the text group (P < 0.001). After adjustment, the bowel preparation score of Group 1 and Group 2 were both significantly higher than that of Group 3 (P = 0.012 and P = 0.032). Maximum BBPS was 6.31 when the interval time was 6.52 h (95% confidence interval: 5.95-6.66), and when the interval was <10 h, the BBPS was ≥6. Conclusion: High-quality bowel preparation was linked to graphical education and appropriate time before colonoscopy. We suggest that the interval between taking the first laxative and colonoscopy should be <10 h, preferably 6.5 h. Prospective multicentre research is needed to give more evidence of high-quality bowel preparation methods.

Post-traumatic Stress Disorder and Risk Factors in Patients With Acute Myocardial Infarction After Emergency Percutaneous Coronary Intervention: A Longitudinal Study.

This study aimed to investigate the status and risk factors of post-traumatic stress disorder (PTSD) in patients with acute myocardial infarction (AMI) after emergency percutaneous coronary intervention (PCI) in acute and convalescence phases. A longitudinal study design was used. Two questionnaire surveys were conducted in the acute stage of hospitalization, and 3 months after onset in patients. Logistic regression was used to analyze the risk factors for PTSD in AMI patients. The incidence of PTSD was 33.1 and 20.4% in acute and convalescent patients, respectively. The risk factors related to PTSD were door-to-balloon time (DTB) (≥92.6 min), left ventricular ejection fraction (LVEF) (<50%), smoking, anxiety, and depression. AMI patients after PCI had PTSD in the acute and convalescent stage. The findings indicate that tailored measures should be developed and carried out to prevent PTSD and improve the mental health of patients with AMI after undergoing PCI.

Curcumin functions as an anti-inflammatory and antioxidant agent on arsenic-induced hepatic and kidney injury by inhibiting MAPKs/NF-κB and activating Nrf2 pathways.

Chronic arsenic exposure has been associated with various toxic effects, especially to the organs of liver and kidney. As a plant polyphenol, curcumin is the most vital bioactive ingredient of turmeric and has a wide range of pharmacological activities. In the present study, we investigated the potential roles of curcumin against arsenic-induced liver and kidney dysfunctions in mice. Curcumin treatment (200 mg/kg) not only decreased the deposition of arsenic in liver and kidney, but also relieved the hepatic and nephritic biochemical indexes (Glutamic oxaloacetic transaminase [AST], Alanine aminotransferase [ALT], albumin, and creatinine) altered by arsenic at doses of 10 and 25 mg/L via drinking water. What's more, curcumin exerted influences on the activities of myeloperoxidase and on the secretion of inflammatory cytokines in liver and kidney tissues. In addition, the levels of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) phosphorylation were declining while NRF2-signaling targets were increasing in mice liver and kidney by curcumin administration. In conclusion, our results here suggest that curcumin could exert both anti-inflammatory and antioxidant functions on arsenic-induced hepatic and kidney injury by inhibiting MAPKs/NF-κB and activating Nrf2 pathways cooperatively.

Activated production of silent metabolites from marine-derived fungus Penicillium citrinum.

As an attempt to utilize of rare earth elements as a novel method to activate the silent genes in fungus, the marine-derived fungus Penicillium citrinum was cultured under ordinary laboratory fermentation conditions in the presence of scandium chloride (ScCl3, 50 µM), and chemical investigation led to the isolation and characterization of three new peptide derivatives (1-3), along with four known pyrrolidine alkaloids (4-7). Those structures were elucidated by spectroscopic data interpretation, as well as chemical reactions. Comparative metabolic profiling of the culture extracts (with/without scandium chloride) indicated that compounds 1-3 scarcely detected in the absence of ScCl3. In addition, the antibacterial and cytotoxic activities of all isolated products were evaluated.