Background Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed subtype. Acquired and intrinsic resistance to conventional endocrine therapy (ET) commonly occurs and prompts incurable metastatic disease. Hence, ET-resistant (ET-R) HR+ BCa presents a therapeutic challenge. Previous studies show elevated androgen receptor (AR) that supports resistance to ET tamoxifen and correlates with HR+ BCa metastasis. Yet surprisingly, studies with AR-blocker enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. We now report that a constitutively active, unique from canonical Enz-targeted, AR accumulates in endocrine resistant HR+ BCa cells. Methods AR protein profiles in acquired and intrinsic ET-R HR + -BCa were defined with cell-free modification tests, in-house in-vivo SUMOylation assays, and PLA imaging. Genomic activity of native AR and modified-AR mimetic was tested with reporter assays and limited transcriptome analysis. Spheroid growth and migration studies were used to evaluate inhibitory actions of Enz and combinatorial therapy. Results Sustained higher molecular weight SUMO-modified AR (SUMO-AR) persists in acquired and intrinsic ET-R BCa cell lines. Concurrently, SUMO isoforms and global SUMO-modified proteome also accumulates in the same cell lines. We identified AR as a novel substrate for the SUMO-E3 ligase HSPB1/Hsp27. Independent of ligand, SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation, enriched in the nucleus, readily chromatin-bound, and transcriptionally active. Constitutive SUMO-AR initiates a gene-expression profile that favors epithelial-mesenchymal transition. Enz combined with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa. Conclusion Targeting both unmodified and SUMO-modified AR prevents the metastatic progression of HR+ BCa with ET-R.

Niosomes, a vesicular formulation, has been explored extensively for topical application to enhance skin penetration as well as to improve skin retention of drugs. In this study, three different rifampicin (1% w/w) niosomal formulations were prepared. Span 60, propylene glycol, dimethyl sulfoxide (DMSO), methanol and distilled water were used in the formulations. Different rifampicin niosomal formulations containing 12% (RN-F1), 16% (RN-F2) and 20% (RN-F3) of Span 60 were prepared by injection method. Rifampicin content of each formulation was determined by UV spectrophotometer at 475 nm. Niosome particle size was measured by laser scattering method using Mastersizer 2000. Volume average diameter, d 50 of different formulations were found 8.488 nm (RN-F1), 12.533 nm (RN-F2) and 12.375 (RN-F3). Niosome preparations were also characterized by entrapment efficiency and in vitro drug release and pH stability test. Results of entrapment efficiency were found to be 55.11%, 57.66% and 60.17% for RN-F1, RN-F2 and RN-F3, respectively. Drug release pattern of RN-F2 and RN-3 formulations showed sustained release at controlled rate. All formulations were more stable at pH 5.8 to 7.0. Antibacterial effect of rifampicin niosomes was evaluated against S. epidermidis and S. aureus isolated from acne by antibiotic sensitivity and time kill study. The results of time kill study revealed that up to 96% of bacteria were killed within 4 hours. In this experiment, rifampicin niosomes were successfully prepared for the intention of targeting antibacterial effect in acne

In this study, twenty five samples were collected from acne, ranging from 20 to 25 years old patients. The specimens were cultured on trypticase soy agar (TSA) plate. 25 suspected single colonies were isolated using mannitol salt agar. Isolates were identified by short biochemical tests such as catalase, coagulase, oxidase and Gram staining test. Five Staphylococcus aureus and eleven Staphylococcus epidermidis strains were identified. Antibiotic sensitivity of all strains was tested according to the Kirby-Bauer method using commercially available gentamicin, erythromycin, azithromycin, oxacillin, clindamycin and rifampicin discs. 100% of the isolates were sensitive to gentamicin and rifampicin. On the other hand, 93.75% isolates were sensitive to oxacillin, erythromycin and azithromycin and 81.25% isolates were sensitive to clindamicin. Minimum inhibitory concentration (MIC) of rifampicin and gentamicin was determined by test tube serial dilution method and it was found to be 4 µg/ml for both. Our results showed that both rifampicin and gentamicin are effective antibacterial agents for acne.

Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors which regulate the expression of lipid and cholesterol metabolism genes. Moreover, LXRs and their ligands have been shown to inhibit tumor growth in a variety of cancers. We have previously identified the small molecule compound GAC0001E5 (1E5) as an LXR inverse agonist and a potent inhibitor of pancreatic cancer cells. Transcriptomic and metabolomic studies showed that 1E5 disrupts glutamine metabolism, an essential metabolic pathway commonly reprogrammed during malignant transformation, including in breast cancers. To determine the role of LXRs and potential application of 1E5 in breast cancer, we examined LXR expression in publicly available clinical samples, and found that LXR expression is elevated in breast tumors as compared to normal tissues. In luminal A, endocrine therapy-resistant, and triple-negative breast cancer cells, 1E5 exhibited LXR inverse agonist and “degrader” activity and strongly inhibited cell proliferation and colony formation. Treatments with 1E5 downregulated the transcription of key glutaminolysis genes, and, correspondingly, biochemical assays indicated that 1E5 lowered intracellular glutamate and glutathione levels and increased reactive oxygen species. These results indicate that novel LXR ligand 1E5 is an inhibitor of glutamine metabolism and redox homeostasis in breast cancers and suggest that modulating LXR activity and expression in tumor cells is a promising strategy for targeting metabolic reprogramming in breast cancer therapeutics.

Acanthus ilicifolius Linn. (Acanthaceae) is a popular mangrove ethnomedicinal plant that cures several ailments, including asthma, diabetes, cancer, and many others. Our experiment was aimed at evaluating the anti-atherogenic effect of A. ilicifolius (leaf and stem) on a high-fat diet-induced atherogenic rat model. Atherosclerosis was developed in 12 weeks. Treatment with the standard drug (3 mg/kg b.w./day, p.o. of Simvastatin), separate doses of methanolic and ethanolic extracts of A. ilicifolius leaf (250 and 500 mg/kg b.w./day, p.o.), and stem (200 and 400 mg/kg b.w./day, p.o.) was subsequently conducted for additional 15 days. The anti-atherogenic effect was evaluated by estimating the change in body weight, systolic blood pressure, and lipid profile. Histopathology of aorta, liver, and kidney of atherogenic models was done for further evaluation. The antioxidant effect of different extracts was performed via DPPH (2,2-diphenyl-1-picrylhydrazyl) assay using ascorbic acid as standard. The anticoagulant effect was determined after 15 days of treatment with the same doses of the plant extracts and the standard Warfarin (2 mg/kg b.w./day, p.o.). When compared with atherogenic control, treatment with A. ilicifolius significantly reduced ( p  < 0.01) body weight, systolic blood pressure, and serum lipid levels while it elevated HDL (high-density lipoprotein) level in a dose-dependent manner. Moreover, bleeding and clotting time was significantly decreased ( p  < 0.01) under the treatment of plant extracts. The histopathological data showed considerable improvement in tissue morphology after treatment. Our study evidenced that the alcoholic extracts of A. ilicifolius leaf and stem have anti-atherogenic properties and may be recommended as a potential herbal remedy for preventing cardiovascular diseases.