No abstract

Glutathione S‐transferase omega 1 (GSTO1) contributes to the inactivation of a wide range of drug compounds via conjugation to glutathione during phase reactions. Chemotherapy‐induced GSTO1 expression in breast cancer cells leads to chemoresistance and promotes metastasis. In search of novel GSTO1 inhibitors, we identified S2E, a thia‐Michael adduct of sulfonamide chalcone with low LC50 (3.75 ± 0.73 μm) that binds to the active site of GSTO1, as revealed by molecular docking (glide score: −8.1), cellular thermal shift assay and fluorescence quenching assay (Kb ≈ 10 × 105 mol·L−1). Docking studies confirmed molecular interactions between GSTO1 and S2E, and identified the hydrogen bond donor Val‐72 (2.14 Å) and hydrogen bond acceptor Ser‐86 (2.77 Å). Best pharmacophore hypotheses could effectively map S2E and identified the 4‐methyl group of the benzene sulfonamide ring as crucial to its anti‐cancer activity. Lack of a thiophenyl group in another analog, 2e, reduced its efficacy as observed by cytotoxicity and pharmacophore matching. Furthermore, GSTO1 inhibition by S2E, along with tamoxifen, led to a significant increase in apoptosis and decreased migration of aggressive MDA‐MB‐231 cells, as well as significantly decreased migration, invasion and mammosphere formation in sorted breast cancer stem cells (CSCs, CD24−/CD44+). GSTO1 silencing in breast CSCs also significantly increased apoptosis and decreased migration. Mechanistically, GSTO1 inhibition activated the c‐Jun N‐terminal kinase stress kinase, inducing a mitochondrial apoptosis signaling pathway in breast CSCs via the pro‐apoptotic proteins BAX, cytochrome c and cleaved caspase 3. Our study elucidated the role of the GSTO1 inhibitor S2E as a potential therapeutic strategy for preventing chemotherapy‐induced breast CSC‐mediated cancer metastasis and recurrence.

Human lymphatic filariae have evolved numerous immune evasion strategies to secure their long-term survival in a host. These strategies include regulation of pattern recognition receptors, mimicry with host glycans and immune molecules, manipulation of innate and adaptive immune cells, induction of apoptosis in effector immune cells, and neutralization of free radicals. This creates an anti-inflammatory and immunoregulatory milieu in the host: a modified Th2 immune response. Therefore, targeting filarial immunomodulators and manipulating the filariae-driven immune system against the filariae can be a potential therapeutic and prophylactic strategy. Filariae-derived immunosuppression can also be exploited to treat other inflammatory diseases and immunopathologic states of parasitic diseases, such as cerebral malaria, and to prevent leishmaniasis. This paper reviews immunomodulatory mechanisms acquired by these filariae for their own survival and their potential application in the development of novel therapeutic approaches against parasitic and inflammatory diseases. Insight into the intricate network of host immune-parasite interactions would aid in the development of effective immune-therapeutic options for both infectious and immune-pathological diseases.

Encouraged by our earlier results of promising therapeutic effect of filarial recombinant proteins BmALT2, BmCys and WbL2 individually in the mouse model of acute ulcerative colitis, in this study, these proteins have been explored individually and in different combinations for their therapeutic potential in dextran sulphate sodium (DSS)-induced chronic colitis mice. These mice, treated with filarial proteins, showed reduced disease parameters including body weight loss, disease activity index, macroscopic and histopathological scores of colon and myeloperoxidase activity in colonic mucosa. Among various treatment schemes, rBmALT2 + rBmCys which showed most pronounced therapeutic implication was found to downregulate the mRNA expressions of IFN-γ and TNF-α and upregulate IL-10 and TGF-β expression in the splenocytes. Also, increase in level of IgG1 and IgG2a isotypes in the sera of rBmALT2 + rBmCys-treated colitis mice was noted. Activated NF-κB level was found to be reduced in the colon of treated colitis mice compared to untreated one. In conclusion, filarial proteins in combination have been shown to improve the clinicopathologic status of chronic colitis through suppression of pro-inflammatory immune response most possibly in NF-κB-dependent manner. We propose this therapeutic strategy to be tested further to be considered as an effective option in chronic colitis.

Helminthic infections lead to the release of various molecules which play an important role in modulation of the host immune system. Such filarial proteins with immunomodulatory potential can be used for therapeutic purpose in inflammatory and immune mediated diseases. In the present study, we have explored the prophylactic effect of filarial SXP-RAL family protein of i.e. rWbL2 protein in DSS induced inflammatory ulcerative colitis in a mouse model. Prior treatment of rWbL2, followed by induction of colitis, showed significantly reduced disease severity as indicated by the decreased disease manifestations and improved macroscopic and microscopic inflammation. This preventive effect was found to be associated with increased release of anti-inflammatory cytokine IL-10 and decreased release of proinflammatory cytokines IFN-γ, TNF-α, IL-6 and IL-17 by the splenocytes of treated mice. From this study, it can be envisaged that pretreatment with filarial protein, rWbL2, can prevent the establishment of ulcerative colitis in BALB/c mice. The underlying immunological mechanism may involve the up-regulation of Th2 immune response with down-regulation of Th1 response.