The development of drug-resistant pathogenic bacteria poses challenges to global health for their treatment and control. In this context, stress response enables bacterial populations to survive extreme perturbations in the environment but remains poorly understood. Specific modules are activated for unique stressors with few recognized global regulators. The phenomenon of cross-stress protection strongly suggests the presence of central proteins that control the diverse stress responses. In this work, Escherichia coli was used to model the bacterial stress response. A Protein-Protein Interaction Network was generated by integrating differentially expressed genes in eight stress conditions of pH, temperature, and antibiotics with relevant gene ontology terms. Topological analysis identified 24 central proteins. The well-documented role of 16 central proteins in stress indicates central control of the response, while the remaining eight proteins may have a novel role in stress response. Cluster analysis of the generated network implicated RNA binding, flagellar assembly, ABC transporters, and DNA repair as important processes during response to stress. Pathway analysis showed crosstalk of Two Component Systems with metabolic processes, oxidative phosphorylation, and ABC transporters. The results were further validated by analysis of an independent cross-stress protection dataset. This study also reports on the ways in which bacterial stress response can progress to biofilm formation. In conclusion, we suggest that drug targets or pathways disrupting bacterial stress responses can potentially be exploited to combat antibiotic tolerance and multidrug resistance in the future.
Prostate cancer is the most common type of cancer among men and the second most frequent cause of cancer-related mortality around the world. The progression of advanced prostate cancer to castration-resistant prostate cancer (CRPC) plays a major role in disease-associated morbidity and mortality, posing a significant therapeutic challenge. Resistance has been associated with the activation of androgen receptors via several mechanisms, including alternative dehydroepiandrosterone biosynthetic pathways, other androgen receptor activator molecules, oncogenes, and carcinogenic signaling pathways. Tumor microenvironment plays a critical role not only in the cancer progression but also in the drug resistance. Numerous natural products have shown major potential against particular or multiple resistance pathways as shown by in vitro and in vivo studies. However, their efficacy in clinical trials has been undermined by their unfavorable pharmacological properties (hydrophobic molecules, instability, low pharmacokinetic profile, poor water solubility, and high excretion rate). Nanoparticle formulations can provide a way out of the stalemate, employing targeted drug delivery, improved pharmacokinetic drug profile, and transportation of diagnostic and therapeutic agents via otherwise impermeable biological barriers. This review compiles the available evidence regarding the use of natural products for the management of CRPC with a focus on nanoparticle formulations. PubMed and Google Scholar search engines were used for preclinical studies, while ClinicalTrials.gov and PubMed were searched for clinical studies. The results of our study suggest the efficacy of natural compounds such as curcumin, resveratrol, apigenin, quercetin, fisetin, luteolin, kaempferol, genistein, berberine, ursolic acid, eugenol, gingerol, and ellagic acid against several mechanisms leading to castration resistance in preclinical studies, but fail to set the disease under control in clinical studies. Nanoparticle formulations of curcumin and quercetin seem to increase their potential in clinical settings. Using nanoparticles based on betulinic acid, capsaicin, sintokamide A, niphatenones A and B, as well as atraric acid seems promising but needs to be verified with preclinical and clinical studies.
Background: With prostate cancer being the fifth-greatest cause of cancer mortality in 2020, there is a dire need to expand the available treatment options. Castration-resistant prostate cancer (CRPC) progresses despite androgen depletion therapy. The mechanisms of resistance are yet to be fully discovered. However, it is hypothesized that androgens depletion enables androgen-independent cells to proliferate and recolonize the tumor.Objectives: Natural bioactive compounds from edible plants and herbal remedies might potentially address this need. This review compiles the available cheminformatics-based studies and the translational studies regarding the use of natural products to manage CRPC.Methods: PubMed and Google Scholar searches for preclinical studies were performed, while ClinicalTrials.gov and PubMed were searched for clinical updates. Studies that were not in English and not available as full text were excluded. The period of literature covered was from 1985 to the present.Results and Conclusion: Our analysis suggested that natural compounds exert beneficial effects due to their broad-spectrum molecular disease-associated targets. In vitro and in vivo studies revealed several bioactive compounds, including rutaecarpine, berberine, curcumin, other flavonoids, pentacyclic triterpenoids, and steroid-based phytochemicals. Molecular modeling tools, including machine and deep learning, have made the analysis more comprehensive. Preclinical and clinical studies on resveratrol, soy isoflavone, lycopene, quercetin, and gossypol have further validated the translational potential of the natural products in the management of prostate cancer.
: Glioma predominantly targets glial cells in the brain and spinal cord. There are grade I, II, III, and IV gliomas with anaplastic astrocytoma and glioblastoma multiforme as the most severe forms of the disease. Current diagnostic methods are limited in their data acquisition and interpretation, markedly affecting treatment modalities and patient outcomes. Circulating extracellular vesicles (EVs) or “magic bullets” contain bioactive signature molecules such as DNA, RNA, proteins, lipids, and metabolites. These secretory “smart probes” participate in myriad cellular activities, including glioma progression. EVs are released by all cell populations and may serve as novel diagnostic biomarkers and efficient nanovehicles in the targeted delivery of encapsulated therapeutics. The present review describes the potential of EVbased biomarkers for glioma management.
Background: The plant Acacia leucophloea (Roxb.) Wild. Family Fabaceae is of paramount importance in Indian medicine. Objectives: We sought to evaluate the in vitro antimicrobial activity of A. leucophloea stem bark extract together with its phytochemical characterization and exploration of drug-likeness attributes. Methods: In vitro Kirby-Bauer disc-diffusion and Tube-dilution assays were exploited for determining the antimicrobial activity of the methanolic bark extracts against several bacterial test strains. Spectral characterization of the isolated phytoconstituents was performed using spectroscopy techniques viz., UV, IR, 1H NMR, and mass spectroscopy followed by the in silico studies like docking and ADME-T studies. Results: The crude methanolic extracts were active against all the bacterial test strains, albeit weakly or moderately, as indicated by the zone of inhibition and minimum inhibitory concentration in the antimicrobial assays. The isolated phytoconstituent was identified to be 3-(3,4-dihydro-5-methoxy-2H-chromen-6-yl)-2,5-dimethoxy-2H-chromen-7-ol (hereby coined as acacianol), a novel isoflavone analog. Acacianol demonstrated a strong binding affinity towards the bacterial DNA gyrase over clorobiocin, especially in case of cavity 4 with no predicted toxicities in silico, except skin sensitization and chromosome damage. Conclusion: Acacianol is a pharmacologically important novel phytocompound with alluring antimicrobial and ADME-T properties prompting further exploration.
Objective The prevalence of Mycoplasma hominis and Ureaplasma urealyticum (genital mycoplasma) amongst Indonesian women is poorly understood because of limited availability of diagnostic techniques. We sought to compare the diagnostic parameters of the AF Genital System® with those of culture methods and PCR as the gold standard for identification of M. hominis and U. urealyticum in vaginal swab specimens. Methods This was an observational diagnostic study. Eighty-eight specimens were collected from patients with abnormal vaginal discharge. Detection of M. hominis and U. urealyticum was performed using the AF Genital System®, culture methods, and PCR. Results Compared with PCR and culture methods, respectively, the AF Genital System® had sensitivities of 66.6% and 57% ( M. hominis) and 55.5% and 77.8% ( U. urealyticum). Compared with PCR and culture methods, respectively, the AF Genital System® had specificities of 82.9% and 86.5% ( M. hominis) and 82.3% and 84.8% ( U. urealyticum). Conclusion The sensitivity of the AF Genital System® for detection of M. hominis and U. urealyticum from vaginal swab samples was lower than that of PCR, but specificity was reasonably good (82% to 83%).
Background: 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones are promising antitumor agents with enormous data on their profound cytotoxic effects on the human cancer cell lines. Objectives: We sought to perform a Quantitative structure cytotoxicity relationship (QSCR) analysis of a series of previously reported fluoroquinolone analogues using computer-assisted multiple regression analysis and investigate the cytotoxicity-inducing structural parameters among these congeners. Methods: The dataset was segregated into training and test sets of 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones by using a random selection method embedded in Vlife MDS 4.6 software and subjected to QSCR analysis. Next, cross-validation of the generated QSCR models was performed along with the external test set prediction. Finally, the data was analyzed, and contour plots were developed to deduce the cytotoxicity-inducing structural parameters among these congeners using Minitab® software. Results: The validated QSCR model exhibited a statistically significant predictive value of 92.27 percent. Our QSCR model revealed a direct proportionality between hydrogen counts and cytotoxicity and exclusion of sulphur and nitrogen with lesser crowding of cyclopropyl rings in future potential 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-one analogues. Based on the QSCR model predictions and contour plot analysis, the de novo REPUBLIC1986 molecule provided the best hit with predicted IC50 (µM) of 0.45 against CHO cell line and is amenable to salt formation crucial for anti-ovarian cancer activity. Conclusion: These findings suggest the relevancy of the developed QSCR model in designing novel, potent, and safer anti-cancer drugs with 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones as seed compounds.
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