Exploring MTH1 inhibitory potential of Thymoquinone and Baicalin for therapeutic targeting of breast cancer.

Cancers frequently have increased ROS levels due to disrupted redox balance, leading to oxidative DNA and protein damage, mutations, and apoptosis. The MTH1 protein plays a crucial role by sanitizing the oxidized dNTP pools. Hence, cancer cells rely on MTH1 to prevent the integration of oxidized dNTPs into DNA, preventing DNA damage and allowing cancer cell proliferation. We have discovered Thymoquinone (TQ) and Baicalin (BC) as inhibitors of MTH1 using combined docking and MD simulation approaches complemented by experimental validations via assessing binding affinity and enzyme inhibition. Docking and MD simulations studies revealed an efficient binding of TQ and BC to the active site pocket of the MTH1, and the resultant complexes are appreciably stable. Fluorescence measurements estimated a strong binding affinity of TQ and BC with Ka 3.4 ×106 and 1.0 ×105, respectively. Treating breast cancer cells with TQ and BC significantly inhibited the growth and proliferation (IC50 values 28.3 µM and 34.8 µM) and induced apoptosis. TQ and BC increased the ROS production in MCF7 cells, imposing substantial oxidative stress on cancer cells and leading to cell death. Finally, TQ and BC are proven strong MTH1 inhibitors, offering promising prospects for anti-cancer therapy.

Breast Cancer Prognostic Hub Genes Identified by Integrated Transcriptomic and Weighted Network Analysis: A Road Toward Personalized Medicine.

Breast cancer (BC) is the second-most common type and among the leading causes of worldwide cancer-related deaths. There is marked person-to-person variability in susceptibility to, and phenotypic expression and prognosis of BC, a predicament that calls for personalized medicine and individually tailored therapeutics. In this study, we report new observations on prognostic hub genes and key pathways involved in BC. We used the data set GSE109169, comprising 25 pairs of BC and adjacent normal tissues. Using a high-throughput transcriptomic approach, we selected data on 293 differentially expressed genes to establish a weighted gene coexpression network. We identified three age-linked modules where the light-gray module strongly correlated with BC. Based on the gene significance and module membership features, peptidase inhibitor 15 (PI15) and KRT5 were identified as our hub genes from the light-gray module. These genes were further verified at transcriptional and translational levels across 25 pairs of BC and adjacent normal tissues. Their promoter methylation profiles were assessed based on various clinical parameters. In addition, these hub genes were used for Kaplan-Meier survival analysis, and their correlation with tumor-infiltrating immune cells was investigated. We found that PI15 and KRT5 may be potential biomarkers and potential drug targets. These findings call for future research in a larger sample size, which could inform diagnosis and clinical management of BC, thus paving the way toward personalized medicine.

Efficient eradication of antibiotic and dye by C-dots@zeolite nanocomposites: Performance evaluation, and degraded products analysis.

Metronidazole (MET), a recalcitrant antibiotic from the nitro-imidazole family and commercially used Rhodamine B (RhB) dye, contributes a huge to water pollution, which needs to eliminate, preferably by photocatalytic degradation technique. The Cdots@zeolite (CDZ) nanocomposites with different weight ratios (1:1, 1:3, 1:5, 5:1, 1:7) were synthesized hydrothermally to degrade MET and RhB molecules. The CDZ composites were characterized by XRD, BET, EDS, and XPS technique which verifies the crystalline nature, incorporation of C-dots into zeolite frameworks with high surface area (∼187 m2/g). The morphology, d-spacing and lattice planes were analyzed by SEM images, HR-TEM and SAED analysis. The maximum degradation (∼79%) was achieved at an optimum catalyst dose of 0.2 g/L and pH 4 for MET and that of RhB was ∼90% at a catalyst dose of 0.4 g/L. The PZC (point of zero charge) value for CDZ composite was about pH 3.4, which justifies the maximum removal of MET at pH 4. The obtained rate constants 'k' were found to be 0.0081, 0.0041, and 0.0101 min-1 in sun, UV, and visible light sources, respectively. The real industrial wastewater sample has been treated to give ∼68% of COD and ∼62% TOC removal. Moreover, the intermediates of plausible degradation pathways were identified by the m/z values obtained from GC-MS analysis.

Post-fabrication structural changes and enhanced photodegradation activity of semiconductors@zeolite composites towards noxious contaminants.

This review article provides the recent progress in semiconductor-based zeolite photoactive materials for the application of noxious contaminants removal. The rapidly expanding industrialization and globalization cause serious threats to the environment or water bodies. The semiconductor@zeolite photocatalysts were implemented for water quality management/sustainment. The exclusive properties of zeolite material have been elaborated with their role in the photocatalysis process. The photoactive material's properties like single-atom catalysts (SACs), distribution of metal in the zeolite crystal were elaborated along with their role in catalytic reactions. Differently prepared semiconductor@zeolite composites such as TiO2@zeolite, binary and ternary composites, Fe/Ag/bismuth-modified/ZnO/ZnS/NiO/g-C3N4/core-shell/quantum dots modified zeolite composites, were systematically summarized. The research progress in morphologies, structural effect, degradation mechanism were recapitulated and tabulated form of % degradation with their optimal parameters such as catalyst dose, pollutant concentrations, pH, light source intensities were also provided. The significance of zeolite frameworks, the structural properties of semiconductor@zeolite photoactive materials to enhance the degradation efficiencies was explored. Analysis of the intermediate products of Norfloxacin, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), TCDF (2,3,7,8-tetrachlorodibenzofuran), diclofenac contaminants were systematically represented and structurally identified by GC-MS/HPLC-MS techniques.

Therapeutic targeting of PIM KINASE signaling in cancer therapy: Structural and clinical prospects.

BACKGROUND: PIM kinases are well-studied drug targets for cancer, belonging to Serine/Threonine kinases family. They are the downstream target of various signaling pathways, and their up/down-regulation affects various physiological processes. PIM family comprises three isoforms, namely, PIM-1, PIM-2, and PIM-3, on alternative initiation of translation and they have different levels of expression in different types of cancers. Its structure shows a unique ATP-binding site in the hinge region which makes it unique among other kinases. SCOPE OF REVIEW: PIM kinases are widely reported in hematological malignancies along with prostate and breast cancers. Currently, many drugs are used as inhibitors of PIM kinases. In this review, we highlighted the physiological significance of PIM kinases in the context of disease progression and therapeutic targeting. We comprehensively reviewed the PIM kinases in terms of their expression and regulation of different physiological roles. We further predicted functional partners of PIM kinases to elucidate their role in the cellular physiology of different cancer and mapped their interaction network. MAJOR CONCLUSIONS: A deeper mechanistic insight into the PIM signaling involved in regulating different cellular processes, including transcription, apoptosis, cell cycle regulation, cell proliferation, cell migration and senescence, is provided. Furthermore, structural features of PIM have been dissected to understand the mechanism of inhibition and subsequent implication of designed inhibitors towards therapeutic management of prostate, breast and other cancers. GENERAL SIGNIFICANCE: Being a potential drug target for cancer therapy, available drugs and PIM inhibitors at different stages of clinical trials are discussed in detail.