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Low-molecular-weight protein tyrosine phosphatases (LMW-PTPs) are involved in promoting the intracellular survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis. These PTPs directly alter host signalling pathways to evade the hostile environment of macrophages and avoid host clearance. Among these, protein tyrosine phosphatase A (Mt-PTPa) is implicated in phagosome acidification failure, thereby inhibiting phagosome maturation to promote Mycobacterium tuberculosis (Mtb) survival. In this study, we explored Mt-PTPa as a potential drug target for treating Mtb. We started by screening a library of 502 pure natural compounds against the activities of Mt-PTPa in vitro, with a threshold of 50% inhibition of activity via a <500 µM concentration of the candidate drugs. The initial screen identified epigallocatechin, myricetin, rosmarinic acid, and shikonin as hits. Among these, the naphthoquinone, shikonin (5, 8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-1,4-naphthoquinone), showed the strongest inhibition (IC₅₀ 33 µM). Further tests showed that juglone (5-hydroxy-1,4-naphthalenedione), another naphthoquinone, displayed similar potent inhibition of Mt-PTPa to shikonin. Kinetic analysis of the inhibition patterns suggests a non-competitive inhibition mechanism for both compounds, with inhibitor constants (Ki) of 8.5 µM and 12.5 µM for shikonin and juglone, respectively. Our findings are consistent with earlier studies suggesting that Mt-PTPa is susceptible to specific allosteric modulation via a non-competitive or mixed inhibition mechanism.

While normal levels of reactive oxygen and nitrogen species (RONS) are required for proper organismal function, increased levels result in oxidative stress. Oxidative stress may be managed via the scavenging activities of antioxidants (e.g., curcumin) and the action of enzymes, including superoxide dismutase (SOD). In this work, the uptake and clearance of dietary curcuminoids (consisting of curcumin, demethoxycurcumin, and bisdemethoxycurcumin) was assessed in Drosophila melanogaster larvae following chronic or acute exposure. High levels of curcuminoid uptake and loss were observed within a few hours and leveled off within eight hours post treatment onset. The addition or removal of curcuminoids from media resulted in corresponding changes in SOD activity, and the involvement of each of the three SOD genes was assessed for their contribution to total SOD activity. Taken together, these data provide insight into the uptake and clearance dynamics of curcuminoids and indicate that, while SOD activity generally increases following curcuminoid treatment, the individual SOD genes appear to contribute differently to this response.

Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of the small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiquitin-proteasome system in the cytoplasm or the autophagy-lysosomal system during endocytosis. In this review, we describe and compare technologies for the targeted inhibition and targeted degradation of the epidermal growth factor receptor (EGFR), one of the major proteins responsible for the onset and progression of many types of cancer. In addition, we develop an alternative strategy, called alloAUTO, based on the binding of new heterocyclic compounds to an allosteric site located in close proximity to the EGFR catalytic site. These compounds cause the targeted degradation of the transmembrane receptor, simultaneously activating both systems of protein degradation in cells. Damage to the EGFR signaling pathways promotes the inactivation of Bim sensor protein phosphorylation, which leads to the disintegration of the cytoskeleton, followed by the detachment of cancer cells from the extracellular matrix, and, ultimately, to cancer cell death. This hallmark of targeted cancer cell death suggests an advantage over other targeted protein degradation strategies, namely, the fewer cancer cells that survive mean fewer chemotherapy-resistant mutants appear.

RNA, like DNA and proteins, can undergo modifications. To date, over 170 RNA modifications have been identified, leading to the emergence of a new research area known as epitranscriptomics. RNA editing is the most frequent RNA modification in mammalian transcriptomes, and two types have been identified: (1) the most frequent, adenosine to inosine (A-to-I); and (2) the less frequent, cysteine to uracil (C-to-U) RNA editing. Unlike other epitranscriptomic marks, RNA editing can be readily detected from RNA sequencing (RNA-seq) data without any chemical conversions of RNA before sequencing library preparation. Furthermore, analyzing RNA editing patterns from transcriptomic data provides an additional layer of information about the epitranscriptome. As the significance of epitranscriptomics, particularly RNA editing, gains recognition in various fields of biology and medicine, there is a growing interest in detecting RNA editing sites (RES) by analyzing RNA-seq data. To cope with this increased interest, several bioinformatic tools are available. However, each tool has its advantages and disadvantages, which makes the choice of the most appropriate tool for bench scientists and clinicians difficult. Here, we have benchmarked bioinformatic tools to detect RES from RNA-seq data. We provide a comprehensive view of each tool and its performance using previously published RNA-seq data to suggest recommendations on the most appropriate for utilization in future studies.