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Curcumin, the bioactive component of turmeric also known as “Indian Yellow Gold,” exhibits therapeutic efficacy against several chronic inflammatory and infectious diseases. Even though considered as a wonder drug pertaining to a myriad of reported benefits, the translational potential of curcumin is limited by its low systemic bioavailability due to its poor intestinal absorption, rapid metabolism, and rapid systemic elimination. Therefore, the translational potential of this compound is specifically challenged by bioavailability issues, and several laboratories are making efforts to improve its bioavailability. We developed a simple one-step process to generate curcumin nanoparticles of ~200 nm in size, which yielded a fivefold enhanced bioavailability in mice over regular curcumin. Curcumin nanoparticles drastically reduced hepatotoxicity induced by antitubercular antibiotics during treatment in mice. Most interestingly, co-treatment of nanoparticle-formulated curcumin along with antitubercular antibiotics dramatically reduced the risk for disease reactivation and reinfection, which is the major shortfall of current antibiotic treatment adopted by Directly Observed Treatment Short-course. Furthermore, nanoparticle-formulated curcumin significantly reduced the time needed for antibiotic therapy to obtain sterile immunity, thereby reducing the possibility of generating drug-resistant variants of the organisms. Therefore, adjunct therapy of nano-formulated curcumin with enhanced bioavailability may be beneficial to treatment of tuberculosis and possibly other diseases.

SummaryTumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4 + CD25 + FoxP3 + T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-b (TGF-b) production in tumour cells that essentially blocked TGF-b-SMAD3/SMAD4-mediated induction of CD25/ interleukin-2 receptor a on CD4 + T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-b-induced Treg cell augmentation.

Dysregulation of the cytokine network in severe malaria owing to variations in factors like parasite load, strains and host factors is well documented but the key cytokines that are dysregulated remain poorly elucidated. Longitudinal changes in cytokine levels in an individual with parasitemia and disease resolution is likely to identify the key cytokines. We have analyzed the mRNA expression of cytokines over a 7-d period in severe (SM) and uncomplicated (UM) Plasmodium falciparum malaria. We found up-regulated expression of TNF-α, IL-1β, IFN-γ and TGF-β in SM, with decreased expression of IL-10 on d 0. Further, we observed a negative correlation of IL-10 expression with parasitemia and pro-inflammatory cytokines, suggesting IL-10 to be the key cytokine in tilting the balance to an inflammatory response. Longitudinal analysis revealed that the key cytokines associated with disease were TNF-α, IL-1β, IFN-γ, IL-12α, RANTES and TGF-β, while TNF-α, IL-10 and TGF-β discriminated between SM and UM. A higher neutrophil count in SM and its positive association with parasite density and IL-1β and IL-8 provides support for neutrophils in inflammation in malaria. Our findings suggest subversion of anti-inflammatory response in SM by parasite factors towards an exaggerated pro-inflammatory response with involvement of neutrophils, the classical inflammatory cells.

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Antigen-specific hyporesponsiveness to filarial antigens is a phenomenon observed in patent infection with lymph-dwelling filarial parasites of humans. This phenomenon has been attributed to a multitude of factors, one of which is altered monocyte function. To examine the role played by monocytes in filarial infection, we assessed the responses of monocytes obtained from normal and filarial parasite-infected individuals to both crude filarial antigen and purified recombinant filarial antigen WbSXP-1 and attempted to relate these to the altered lymphoproliferative responses seen in filarial infection. Monocytes from microfilaremic (MF) patients demonstrated an inability to respond to lipopolysaccharide compared to monocytes from endemic normal persons or from lymphedema patients. Indeed, interleukin 1␤ (IL-1␤) production was severely limited, a finding that did not extend to monocyte responses to filarial antigens. Serum from MF patients reduced adherence and spreading of normal monocytes, a finding not seen with serum from the other clinical groups. Interestingly, there was a significant correlation between the production of IL-1␤ and adherence. Moreover, the levels of spontaneous production of IL-1␤ correlated with high levels of spontaneous secretion of IL-10. The effects observed were not a result of diminished viability or alteration in the expression of the cell surface markers CD14 and HLA-DR. These data suggest that monocyte function is dampened in MF patients, a finding which could alter lymphoproliferative responses during patent infection.Understanding the induction of differentiated T-cell responses in helminth infections has been a major goal for parasite immunologists. The source of cytokines involved in the skewing of T-cell responses in helminth infections has been of particular interest, as the cytokine microenvironment is considered to be the most important factor influencing the differentiation of naive T cells and the generation of immunoregulatory cells (1,30,31,36,37). Among individuals with human lymphatic filariasis, those with patent infection (microfilaremic or antigenemic) exhibit parasite antigen-specific down-regulation of T-cell proliferation and gamma interferon production. These responses are different from those in patients with lymphedema/elephantiasis (mixed Th1/Th2 response) and infection-free endemic normal (EN) persons (predominant Th1 response to parasite antigen). The occurrence of filarial parasite-associated modulation of the immune response in microfilaremic patients is supported by extensive clinical (35,38,41) and animal (27) data. To date, however, no single mechanism can explain the modulatory effects of filarial infection in patients with patent infection.The induction and maintenance of Th2-type immune responses are based largely on studies with murine models showing that antigen affinity for the T-cell receptor (6), the dose or route by which antigen is administered (11,14), costimulatory molecule interactions (32, 49), the prevailing in vivo cytokine milieu (45),...

Background:The therapeutic potential of EcA is limited due to immunogenicity and short half-life in patients. Results: Several EcA variants were constructed that showed markedly reduced immunogenicity and cytotoxicity against leukemic lymphoblasts. Conclusion: Small changes in subunit interface and B-cell epitope significantly reduced immunogenicity and enhanced cytotoxicity. Significance: These variants have promising potential in the advanced asparaginase therapy of leukemia.

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