Current Chemical Biology - Volume 14, Issue 1, 2020

Autophagy is a well-maintained process by which the cells recycle intracellular materials to maintain homeostasis in various cellular functions. However, autophagy is a defensive mechanism that maintains cell survival under antagonistic conditions, the induction of the autophagic process may substantially lead to cell death. The conflicting roles of autophagy including allowing cell survival or promoting cell death could have a troublesome impact on the efficiency of chemotherapeutic agents. Accordingly, understanding the role of autophagy in cancer is a vital need for its optimal manipulation in therapy.

Scientific interest in mycobacteria has been sparked by the medical importance of Mycobacterium tuberculosis (Mtb) that is known to cause severe diseases in mammals, i.e. tuberculosis and by properties that distinguish them from other microorganisms which are notoriously difficult to treat. The treatment of their infections is difficult because mycobacteria fortify themselves with a thick impermeable cell envelope. Channel and transporter proteins are among the crucial adaptations of Mycobacterium that facilitate their strength to combat against host immune system and anti-tuberculosis drugs. In previous studies, it was investigated that some of the channel proteins contribute to the overall antibiotic resistance in Mtb. Moreover, in some of the cases, membrane proteins were found responsible for virulence of these pathogens. Given the ability of M. tuberculosis to survive as an intracellular pathogen and its inclination to develop resistance to the prevailing anti-tuberculosis drugs, its treatment requires new approaches and optimization of anti-TB drugs and investigation of new targets are needed for their potential in clinical usage. Therefore, it is imperative to investigate the survival of Mtb. in stressed conditions with different behavior of particular channel/ transporter proteins. Comprehensive understanding of channel proteins and their mechanism will provide us direction to find out preventive measures against the emergence of resistance and reduce the duration of the treatment, eventually leading to plausible eradication of tuberculosis.

In human cells, Heat Shock Protein-90 (HSP-90) is present in the cytosol, nucleoplasm, endoplasmic reticulum, and mitochondria. The eukaryotic HSP-90 is multifunctionary and essential for cell viability, signal transduction, cell-cycle control as well as transcriptional regulation. The intracellular environment does not restrict HSP-90. It has a vital role in all types of inflammatory disorders, including cancer, autoimmune diseases, infectious inflammatory conditions. Hence, pharmacological inhibition of HSP-90 is currently a choice of therapeutic target for the treatment of autoimmune diseases, cancer, and infectious diseases. Based on the biology of HSP-90, several COOH-terminal ATPase sites of HSP-90, NH2-terminal ATPase sites of HSP-90, and Histone deacetylase inhibitors are evaluated and classified under various groups. For the treatment of different inflammatory disorders, HSP-90 identified as a promising therapeutic target. The present review may guide researchers for evaluating the HSP-90 targeted pathway as a useful therapeutic target for inflammatory diseases, including cancers.

Background: 3'-(3,4-dimethoxyphenyl)-4'-(4-(methylsulfonyl)phenyl)-4'H-spiro [indene-2,5'-isoxazol]-1(3H)-one and 4'-(4-(methylsulfonyl)phenyl)-3'-(3,4,5-trimethoxyphenyl)- 4'H-spiro[indene-2,5'-isoxazol]-1(3H)-one compounds containing indanonic spiroisoxazoline core are widely known for their antiproliferative activities and investigation of tubulin binding modes. Objective: To evaluate the cytotoxicity effect of Dimethoxy and Trimethoxy Indanonic Spiroisoxazolines against HepG2 cancerous liver cell line and to perform a comparison with other known anti-liver cancer drugs. Methods: The evaluation of cytotoxicity of dimethoxy and trimethoxy indanonic spiroisoxazoline compounds, Oxaliplatin, Doxorubicin, 5-fluorouracil and Cisplatin against HepG2 (hepatocellular liver carcinoma) cell line has been performed using MTT assay and analyzed by GraphPad PRISM software (version 8.0.2). Results: Potent cytotoxicity effects against HepG2 cell line, comparable to Cisplatin (IC50= 0.047±0.0045 μM), Oxaliplatin (IC50= 0.0051μM), Doxorubicin (IC50= 0.0014μM) and 5- fluorouracil (IC50= 0.0089 μM), were shown by both dimethoxy (IC50= 0.059±0.012 μM) and trimethoxy (IC50= 0.086±0.019 μM) indanonic spiroisoxazoline compounds. Conclusion: In vitro biological evaluations revealed that dimethoxy and trimethoxy indanonic spiroisoxazoline compounds are good candidates for the development of new anti-liver cancer agents.

Background: The tumor microenvironment, including microbiome populations in the local niche of several types of solid tumors like mammary and colorectal cancer are distinct. The occurrence of one type of cancer over another varies from animals to human individuals. Further, clinical data suggest that specific cancer types such as mammary and colorectal cancer are rare in ruminants like goat. Methods: Fresh urine samples were collected from healthy ruminants (cow, goat, buffalo, ox), non-ruminant animals (horse, jenny) and human. Further, these urine samples were subjected to fractionation by drying, vortexing, centrifugation and sterile filtration in DMSO extraction solvent. Collected urine DMSO fraction (UDF) samples from all sources were subjected to DNA metabolizing assay with plasmid DNA pBR322 and genomic DNA of MCF-7 cells. Next, based on the discernible DNA metabolizing effects of goat UDF among other sources, goat UDF was tested for anti-proliferative effects upon HCT-116 and MCF-7 cells using Trypan blue dye exclusion assay. Results: This paper reports that goat UDF possesses very clear DNA metabolizing effects (up to 95%) upon plasmid and genomic DNA compared to other ruminants, non-ruminants and human UDF samples. Interestingly, autoclaving of goat UDF and other sample results in the significant loss of DNA metabolizing effects. In this way, data potentially indicate that the goat UDF sample contains metabolite or similar organic compounds. Further, in vitro treatment of the goat, UDF sample shows clear anti-proliferative effects upon HCT-116 (up to 75%) and MCF-7 (up to 40%). Conclusion: This study signifies the clear differences in DNA metabolizing effects of goat UDF over other selected animal sources. Furthermore, the observed DNA metabolizing effects of goat UDF well correlate with anti-proliferative effects upon HCT-116 and MCF-7 cells. This study is a first report to show the comparison of urine metabolites among various animals. Interestingly, findings propose an indirect link that may support the possible reasons behind xeno-tumor heterogeneity in the form of rare occurrences of colorectal and mammary cancer in goat over other ruminants, non-ruminants and human.

Background: The present research work is focused on the development of alternative antioxidant and anti-inflammatory agents. The review of the literature reveals that many benzofused thiazole analogues have been used as lead molecules for the design and development of therapeutic agent, including anticancer, anti-inflammatory, antioxidant and antiviral. The synthesized benzofused thiazole derivatives are evaluated for in vitro antioxidant, anti-inflammatory activities and molecular docking study. Thus, the present research work aims to synthesize benzofused thiazole derivatives and to test their antioxidant and antiinflammatory activities. Objective: To design and synthesize an alternative antioxidant and anti-inflammatory agents. Methods: The substituted benzofused thiazoles 3a-g were prepared by cyclocondensation reaction of appropriate carboxylic acid with 2-aminothiophenol in POCl3 and heated for about 2-3 h to offer benzofused thiazole derivatives 3a-g. All the newly synthesized compounds were in vitro screened for their anti-inflammatory and antioxidant activities by using a known literature method. Results: At the outset, the study of in vitro indicated that the compounds code 3c, 3d and 3e possessed distinct anti-inflammatory activity as compared to a standard reference. All the tested compounds show potential antioxidant activity against one or more reactive (H2O2, DPPH, SO and NO) radical scavenging species. Additionally, docking simulation is further performed to the position of compounds 3d & 3e into the anti-inflammatory active site to determine the probable binding model. Conclusion: New anti-inflammatory and antioxidant agents were needed; it has been proved that benzofused thiazole derivatives were 3c, 3d and 3e constituted as an interesting template for the evaluation of new anti-inflammatory agents and an antioxidant’s work also may provide an interesting template for further development.