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Autophagy is a homeostatic process that recycles damaged organelles and long-lived proteins by delivering them in double-membrane vesicles to lysosomes for degradation. Autophagy has a prominent role in survival, proliferation, and resistance of tumors in metabolic and chemotherapeutic stress conditions. Clinical trials with chloroquine—a known autophagy inhibitor—were unable to achieve complete autophagy inhibition in vivo, warranting the search for more potent autophagy inhibitors. In a process of exploring the mechanism of action of previously identified cytotoxic s-triazine analogs, we discovered that both IITZ-01 and IITZ-02 act as potent autophagy inhibitors. Treatment with these compounds resulted in the vacuolated appearance of cells due to their specific accumulation in lysosomes. In addition, these basic compounds also deacidify lysosomes as evidenced by the decrease in lysotracker red staining and inhibit maturation of lysosomal enzymes leading to lysosomal dysfunction. IITZ-01 and IITZ-02 enhance autophagosome accumulation but inhibit autophagosomal degradation by impairing lysosomal function, finally resulting in the inhibition of autophagy. Interestingly, compound IITZ-01 exhibited more than 10-fold potent autophagy inhibition along with 12- to 20-fold better cytotoxic action than CQ. IITZ-01 and IITZ-02 also abolished mitochondrial membrane potential and triggered apoptosis through the mitochondria-mediated pathway. Furthermore, IITZ-01 and IITZ-02 displayed potent antitumor action in vivo through autophagy inhibition and apoptosis induction in MDA-MB-231 breast cancer xenograft model with IITZ-01 exhibiting superior anticancer efficacy. Overall, these data demonstrate that IITZ-01 is potent autophagy inhibitor with single-agent anticancer activity and awaits further preclinical development as potential anticancer therapeutic.

Ta2O5additive borophosphate glasses having composition (40 B2O3– 20 CaO – 25 Li2O – (15-X) P2O5– X Ta2O5(mol %); where X = 0, 0.5, 1.0, 2.0, 3.0) were synthesized to investigate their bioactive behavior by immersion in SBF for 7, 14, and 21 days. The formation of hydroxyapatite confirms bioactive behavior which was confirmed using XRD (amorphous glass to crystalline hydroxyapatite diffraction line), FTIR (functional group of hydroxyapatite), and FESEM (smooth to flake-like morphology). The increase in Ta2O5(mol %) shows a decrease in the intensity of hydroxyapatite diffraction lines. Physical characteristics such as density, molar volume, glass transition temperature and crystallization temperature were also investigated, which indicates that the glass has a compact structure. The degradation study confirms that the glass having 3 mol% Ta2O5slows lowest weight loss after immersion in SBF for duration of 3, 7, 14, and 21 days. The variation in pH of simulated body fluid shows an increase for up to 3 days, then decreases until the 9th day and after that becomes stable up to 21 days. In addition, ibuprofen-loaded Ta2O5borophosphate glass cement were developed to monitor the release of drug for 21 days in phosphate based saline solution having pH 7.2 and their bioactive behavior. MTT assay indicates that Ta2O5borophosphate glasses were not toxic to MG-63 cells up to concentration of 1000 μg/mL. Ta2O5borophosphate glasses exhibit bioactive nature and have a potential application used for bone healing and drug delivery applications.

The present study was aimed to isolate novel bioactive compounds from actinomycetes species isolated from mangrove habitats. With this connection, Pseudonocardia endophytica(VUK-10) was isolated using dilution plate technique and was examined for its secondary metabolite profiling. After successive purification and spectroscopic characterization viz., FTIR, mass, NMR, DEPT, HMQC, HMBC, and COSY spectroscopy, two compounds were identified including a semi synthetic derivative N-(4-aminocyclooctyl)-3, 5-dinitrobenzamide (1), obtained from the precursor of novel natural product cyclooctane-1,4-diamine (3), along with a known compound 3-((1H-indol-6-yl) methyl) hexahydropyrrolo [1, 2-a] pyrazine-1, 4-dione (2). Anti cancer activities of the characterized compounds against in vitro cancerous cell line models, MDA-MB-231, OAW-42, HeLa, and MCF-7 reveal that HELA cells are most susceptible (IC50-10 nM compound 1and 2) followed by other studied cells. On the other hand, antibacterial and antifungal activities of the studied compounds against tested pathogens revealed that there is a significant antimicrobial activity with all the tested bacterial and fungal species. Moreover, compound 1showed the lowest MIC values against Streptococcus mutansas 4  and 16 µg/ml for Candida albicans. In conclusion, the identified novel chemical compounds in the present study may have a potential application in anticancer therapy as well as to mitigate the bacterial and fungal pathogens thus to control the infectious diseases.

Sediment samples from the mangrove ecosystem of Nizampatnam have been analyzed for actinomycetes as an elite source to screen for the formulation and production of antimicrobial and cytotoxic compounds. The actinomycetes strain VUK-10 has an interesting bioactivity profile and was isolated during our systematic study of mangrove actinomycetes. It was identified as Pseudonocardia endophyticawith the aid of polyphasic taxonomy. The ethyl acetate extract of the actinobacterial culture filtrate has been purified by gel-filtration and silica gel column chromatographic purifications led to the isolation of two diketopiperazine compounds, (3S,8aS)-3-isobutylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1) and (3R,8aS)-3-isobutylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (2). The compounds listed, alluring cytotoxic activity against MDA-MB-231, HeLa, MCF-7 and OAW-42 cancer cell lines and also exhibited antimicrobial activities against gram-positive, gram-negative bacteria and fungi. Compound 1recorded significant antibacterial activity against Xanthomonas campestrisand Escherichia coli(8μg/ml) and compound 2presented highest activity against Bacillus subtilis(4μg/ml). Compounds 1and 2were active against pathogenic fungi to plants and human beings. The activity was compared with griseofulvin and amphotericin-B, which are standard fungicides. The activity of 16μg/ml by compound 1was recorded against Epidermophyton floccosum; an anthropophilic dermatophyte responsible for tinea pedis, tinea cruris and tinea corporis. To the best of our knowledge this is the first narration on the isolation of supra said compounds from the genus Pseudonocardia.