Efficient screening of pharmacological broad-spectrum anti-cancer peptides utilizing advanced bidirectional Encoder representation from Transformers strategy.

In the vanguard of oncological advancement, this investigation delineates the integration of deep learning paradigms to refine the screening process for Anticancer Peptides (ACPs), epitomizing a new frontier in broad-spectrum oncolytic therapeutics renowned for their targeted antitumor efficacy and specificity. Conventional methodologies for ACP identification are marred by prohibitive time and financial exigencies, representing a formidable impediment to the evolution of precision oncology. In response, our research heralds the development of a groundbreaking screening apparatus that marries Natural Language Processing (NLP) with the Pseudo Amino Acid Composition (PseAAC) technique, thereby inaugurating a comprehensive ACP compendium for the extraction of quintessential primary and secondary structural attributes. This innovative methodological approach is augmented by an optimized BERT model, meticulously calibrated for ACP detection, which conspicuously surpasses existing BERT variants and traditional machine learning algorithms in both accuracy and selectivity. Subjected to rigorous validation via five-fold cross-validation and external assessment, our model exhibited exemplary performance, boasting an average Area Under the Curve (AUC) of 0.9726 and an F1 score of 0.9385, with external validation further affirming its prowess (AUC of 0.9848 and F1 of 0.9371). These findings vividly underscore the method's unparalleled efficacy and prospective utility in the precise identification and prognostication of ACPs, significantly ameliorating the financial and temporal burdens traditionally associated with ACP research and development. Ergo, this pioneering screening paradigm promises to catalyze the discovery and clinical application of ACPs, constituting a seminal stride towards the realization of more efficacious and economically viable precision oncology interventions.

Synergistic effects and molecular mechanisms of DL-3-n-butylphthalide combined with dual antiplatelet therapy in acute ischemic stroke.

DL-3-n-butylphthalide (NBP) is isolated from the seeds of Apium graveolens L., and has been recently used as a neuroprotective agent for acute ischemic stroke. The present study aimed to determine the efficacy and safety of the combined use of dual antiplatelet therapy (DAPT) and NBP for treating of acute ischemic stroke in rats and to explore the synergistic mechanism of this treatment strategy in rat middle cerebral artery occlusion models. The efficacy of DAPT combined with NBP was evaluated by determining neurological deficits, infarction status, and histological changes. Changes in body weight, blood glucose level, blood count, and serum biochemical parameters were detected to evaluate the safety. To explore the synergistic pharmacological mechanism, the mRNA expression and protein levels of key proteins in the pyroptosis-inflammatory pathway, and the pyroptosis ratio of microglias were examined. Compared with the administration of NBP or DAPT alone, combination of them significantly improved neurological deficits, reduced infarct area, and repaired tissue injury and inflammation after cerebral ischemia. No hepatorenal toxicity was observed. The mRNA expression and protein levels of key proteins in the pyroptosis-inflammation pathway, and the pyroptosis ratio of microglias were significantly downregulated in the combined administration group than in the monotherapy group. We demonstrated that the combined use of NBP and DAPT exhibits better efficacy and high safety and plays a synergistic role by inhibiting the pyroptosis-inflammation pathway in the brain tissues, particularly in microglial cells.

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Vitro and in Vivo.

Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsA-induced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.

A pharmacokinetics interaction study of antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide in rats by liquid chromatography-tandem mass spectrometry.

A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method has been developed to determine the pharmacokinetic interactions of the antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide. For the determination of aspirin metabolite salicylic acid, clopidogrel inactive metabolite SR26334 and NBP prototype drug in rat plasma, plasma samples were prepared by precipitation of proteins using methanol containing 0.1% formic acid, followed by centrifugation. Chromatography was performed on a C18 column, eluting with a gradient of acetonitrile (with 0.1% formic acid)-water (with 0.1% formic acid). The detection adopted electrospray ion source and positive ion multiple reaction monitoring modes. The linear detection response range of salicylic acid is 80-80,000 ng/ml, and the linear detection response range of SR26334 and dl-3-n-butylphthalide is 10-10,000 ng/ml. Our study revealed that dl-3-n-butylphthalide affected the pharmacokinetics of aspirin and clopidogrel when administered to rats.

Antidepressant Shugan Jieyu Capsule Alters Gut Microbiota and Intestinal Microbiome Function in Rats With Chronic Unpredictable Mild Stress -Induced Depression.

Shugan Jieyu Capsule (SG) has been widely used in China to treat mild to moderate depression. Hypericum perforatum L. (St John's Wort, SJW) is the main ingredient of SG and has been used as herbal medicine to treat depression in western countries. However, it is known that SJW has low bioavailability and does not easily get through the blood-brain barrier. Therefore, how SG plays an antidepressant effect in the central nervous system (CNS) remains an urgent problem to be solved. Mounting research has described the relationship between antidepressants and intestinal microbiota to illuminate antidepressive mechanisms in the CNS. We aimed to investigate the effects of therapy with SG on the function of gut microbiota and intestinal microbiota in rats with chronic unpredictable mild stress (CUMS)-induced depression. The psychophysiological state and the hypothalamic-pituitary-adrenal axis function of rats are evaluated through behavioral experiments, corticosterone levels, serotonin levels, and adrenal index measurements. 16S rDNA amplicon sequencing is used to test the changes in gut microbiota and make functional predictions of genes. With treatment of SG, the depression-like behaviors of CUMS-induced rats were reversed; the corticosterone levels and the adrenal index decreased significantly; the level of serotonin increased significantly; and the alpha and beta diversity analysis of microbiota showed an increase in the richness and uniformity of the flora were increased. SG regulated the relative abundance of Actinobacteria, Erysipelotrichaceae, Bifidobacteriaceae, Atopobiaceae, Dubosiella, and Bifidobacterium; Linear discriminant analysis effect size analysis demonstrated that Lactobacillaceae (family level), Lactobacillus (genus level), Lactobacillales (order level), Bacilli (class level), and Lactobacillus-reuteri (species level) were biomarkers in the SG group samples, and also likely to modulate metabolic pathways, such as those involved in carbohydrate metabolism, amino acid metabolism, and signal transduction. These data clearly illustrated the effect of SG on gut microbiome, thus laying the foundation for uncovering more insights on the therapeutic function of the traditional Chinese antidepressants. The potential of SG on mechanisms of antidepression to alter gut microbiota and intestinal microbiome function exposed to CUMS can be explored.