EXCLI Journal最新文献

Fluorophore-coupled bile acids (BA) represent an important tool for intravital analysis of BA flux in animal models of cholestatic diseases. However, addition of a fluorophore to a BA may alter transport properties. We developed and validated a 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole-coupled taurocholic acid (3β-NBD-TCA) as a probe for intravital analysis of BA homeostasis. We compared transport of 3β-NBD-TCA to [3H]-TCA in HEK293 cells stably expressing the mouse hepatic or renal BA carriers mNtcp or mAsbt, respectively. We also studied distribution kinetics intravitally in livers and kidneys of anesthetized wildtype and mOatp1a/1b cluster knockout mice (OatpKO) with and without administration of the Ntcp inhibitor Myrcludex B and the ASBT inhibitor AS0369. In vitro, 3β-NBD-TCA and [3H]-TCA showed comparable concentration- and time-dependent transport via mNtcp and mAsbt as well as similar inhibition kinetics for Myrcludex B and AS0369. Intravital analysis in the livers of wildtype and OatpKO mice revealed contribution of both mNtcp and mOatp1a/1b in the 3β-NBD-TCA uptake from the sinusoidal blood into hepatocytes. Combined deletion of mOatp1a/1b and inhibition of mNtcp by Myrcludex B blocked the uptake of 3β-NBD-TCA from sinusoidal blood into hepatocytes. This led to an increase of 3β-NBD-TCA signal in the systemic circulation including renal capillaries, followed by strong enrichment in a subpopulation of proximal renal tubular epithelial cells (TEC). The enrichment of 3β-NBD-TCA in TEC was strongly reduced by the systemic ASBT inhibitor AS0369. NBD-coupled TCA has similar transport kinetics as [3H]-TCA and can be used as a tool to study hepatorenal BA transport. See also the graphical abstract(Fig. 1).

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Its treatment is complicated due to the development of resistance to conventional chemotherapy and targeted therapy. Deoxybouvardin and related cyclic hexapeptides reportedly exhibit antitumor activities, but their mechanisms of action remain unclear. This study aimed to investigate the anticancer mechanisms of deoxybouvardin glucoside (DBG), a glucosidic form of deoxybouvardin from Rubia species, in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. The effects of DBG treatment on cell proliferation were evaluated using a viability assay. The inhibitory effects of DBG treatment on the activities and phosphorylation of the protein kinases epidermal growth factor receptor (EGFR), MET, and AKTs were assessed using in vitro kinase assay and western blot, respectively. DBG treatment inhibited the growth of HCC827 cells in a concentration- and time-dependent manner. Results of in vitro kinase assay and western blotting showed that DBG treatment significantly inhibited the activities and phosphorylation of the protein kinases EGFR, MET, and AKT. Prediction using molecular docking showed that DBG is located in the ATP-binding pockets of these kinases, supporting the kinase inhibition by DBG treatment. Moreover, DBG treatment induced reactive oxygen species (ROS) generation and cell cycle arrest in the cells. The induction of apoptosis by DBG through caspase activation was confirmed by Z-VAD-FMK treatment. In summary, DBG treatment inhibited the growth of GEF-sensitive and -resistant NSCLC cells by targeting EGFR, MET, and AKTs. Moreover, it induced apoptosis by inducing ROS generation and caspase activation. These results indicate that DBG is a potential therapeutic agent for the treatment of GEF-resistant NSCLC. See also the graphical abstract(Fig. 1).

Bloodborne pathogens (BBPs) pose formidable challenges in the realm of infectious diseases, representing significant risks to both human and animal health worldwide. The review paper provides a thorough examination of bloodborne pathogens, highlighting the serious worldwide threat they pose and the effects they have on animal and human health. It addresses the potential dangers of exposure that healthcare workers confront, which have affected 3 million people annually, and investigates the many pathways by which these viruses can spread. The limitations of traditional detection techniques like PCR and ELISA have been criticized, which has led to the investigation of new detection methods driven by advances in sensor technology. The objective is to increase the amount of knowledge that is available regarding bloodborne infections as well as effective strategies for their management and detection. This review provides a thorough overview of common bloodborne infections, including their patterns of transmission, and detection techniques.

Chronic atrophic gastritis (CAG) is considered as a significant risk factor for triggering gastric cancer incidence, if not effectively treated. Sijunzi decoction (SD) is a well-known classic formula for treating gastric disorders, and Sijunzi-similar formulae (SF) derived from SD have also been highly regarded by Chinese clinical practitioners for their effectiveness in treating chronic atrophic gastritis. Currently, there is a lack of meta-analysis for these formulae, leaving unclear which exhibits optimal efficacy. Therefore, we employed Bayesian network meta-analysis (BNMA) to evaluate the efficacy and safety of SF as an intervention for CAG and to establish a scientific foundation for the clinical utilization of SF. The result of meta-analysis demonstrated that the combination of SF and basic therapy outperformed basic therapy alone in terms of clinical efficacy rate, eradication rate of H. pylori, and incidence of adverse events. As indicated by the SUCRA value, Chaishao Liujunzi decoction (CLD) demonstrated superior efficacy in enhancing clinical effectiveness and ameliorating H. pylori infection, and it also showed remarkable effectiveness in minimizing the occurrence of adverse events. Comprehensive analysis of therapeutic efficacy suggests that CLD is most likely the optimal choice among these six formulations, holding potential value for optimizing clinical treatment strategies. See also the graphical abstract(Fig. 1).

Oral cancer retains one of the lowest survival rates worldwide, despite recent therapeutic advancements signifying a tenacious challenge in healthcare. Artificial intelligence exhibits noteworthy potential in escalating diagnostic and treatment procedures, offering promising advancements in healthcare. This review entails the traditional imaging techniques for the oral cancer treatment. The role of artificial intelligence in prognosis of oral cancer including predictive modeling, identification of prognostic factors and risk stratification also discussed significantly in this review. The review also encompasses the utilization of artificial intelligence such as automated image analysis, computer-aided detection and diagnosis integration of machine learning algorithms for oral cancer diagnosis and treatment. The customizing treatment approaches for oral cancer through artificial intelligence based personalized medicine is also part of this review. See also the graphical abstract(Fig. 1).

The shortage of treatment options for leishmaniasis, especially those easy to administer and viable for deployment in the world's poorest regions, highlights the importance of employing these strategies to cost-effectively investigate repurposing candidates. This scoping review aims to map the studies using in silico methodologies for drug repurposing against leishmaniasis. This study followed JBI recommendations for scoping reviews. Articles were searched on PubMed, Scopus, and Web of Science databases using keywords related to leishmaniasis and in silico methods for drug discovery, without publication date restrictions. The selection was based on primary studies involving computational methods for antileishmanial drug repurposing. Information about methodologies, obtained data, and outcomes were extracted. After the full-text appraisal, 34 studies were included in this review. Molecular docking was the preferred method for evaluating repurposing candidates (n=25). Studies reported 154 unique ligands and 72 different targets, sterol 14-alpha demethylase and trypanothione reductase being the most frequently reported. In silico screening was able to correctly pinpoint some known active pharmaceutical classes and propose previously untested drugs. Fifteen drugs investigated in silico exhibited low micromolar inhibition (IC₅₀ < 10 µM) of Leishmania spp. in vitro. In conclusion, several in silico repurposing candidates are yet to be investigated in vitro and in vivo. Future research could expand the number of targets screened and employ advanced methods to optimize drug selection, offering new starting points for treatment development. See also the graphical abstract(Fig. 1).

Cartilage tissue, characterized by its limited regenerative capacity, presents significant challenges in clinical therapy. Recent advancements in cartilage regeneration have focused on integrating stem cell therapies, tissue engineering strategies, and advanced modeling techniques to overcome existing limitations. Stem cells, particularly Mesenchymal Stem Cells (MSCs) and induced pluripotent stem cells (iPSCs), hold promise for cartilage repair due to their ability to differentiate into chondrocytes, the key cells responsible for cartilage formation. Tissue engineering approaches, including 3D models, organ-on-a-chip systems, and organoids, offer innovative methods to mimic natural tissue microenvironments and evaluate potential treatments. MSC-based techniques, such as cell sheet tissue engineering, address challenges associated with traditional therapies, including cell availability and culture difficulties. Furthermore, advancements in 3D bioprinting enable the fabrication of complex tissue structures, while organ-on-a-chip systems provide microfluidic platforms for disease modeling and physiological mimicry. Organoids serve as simplified models of organs, capturing some complexity and enabling the monitoring of pathophysiological aspects of cartilage diseases. This comprehensive review underscores the transformative potential of integrating stem cell therapies, tissue engineering strategies, and advanced modeling techniques to improve cartilage regeneration and pave the way for more effective clinical treatments.