Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.

/pdf/obesity-fat-mass-and-immune-system-role-for-leptin-1qa0lnvban.pdf

Obesity, Fat Mass and Immune System: Role for Leptin

Withania somnifera, also called 'Indian ginseng', is an important medicinal plant of the Indian subcontinent. It is widely used, singly or in combination, with other herbs against many ailments in Indian Systems of Medicine since time immemorial. Withania somnifera contains a spectrum of diverse phytochemicals enabling it to have a broad range of biological implications. In preclinical studies, it has shown anti-microbial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective, and anti-diabetic properties. Additionally, it has demonstrated the ability to reduce reactive oxygen species, modulate mitochondrial function, regulate apoptosis, and reduce inflammation and enhance endothelial function. In view of these pharmacologic properties, W. somnifera is a potential drug candidate to treat various clinical conditions, particularly related to the nervous system. In this review, we summarize the pharmacologic characteristics and discuss the mechanisms of action and potential therapeutic applications of the plant and its active constituents.

Pharmacologic overview of Withania somnifera, the Indian Ginseng

Leishmaniasis is a parasitic disease of humans, highly prevalent in parts of the tropics, subtropics, and southern Europe. The disease mainly occurs in three different clinical forms namely cutaneous, mucocutaneous, and visceral leishmaniasis (VL). The VL affects several internal organs and is the deadliest form of the disease. Epidemiology and clinical manifestations of VL are variable based on the vector, parasite (e.g., species, strains, and antigen diversity), host (e.g., genetic background, nutrition, diversity in antigen presentation and immunity) and the environment (e.g., temperature, humidity, and hygiene). Chemotherapy of VL is limited to a few drugs which is expensive and associated with profound toxicity, and could become ineffective due to the parasites developing resistance. Till date, there are no licensed vaccines for humans against leishmaniasis. Recently, immunotherapy has become an attractive strategy as it is cost-effective, causes limited side-effects and do not suffer from the downside of pathogens developing resistance. Among various immunotherapeutic approaches, cytokines (produced by helper T-lymphocytes) based immunotherapy has received great attention especially for drug refractive cases of human VL. Therefore, a comprehensive knowledge on the molecular interactions of immune cells or components and on cytokines interplay in the host defense or pathogenesis is important to determine appropriate immunotherapies for leishmaniasis. Here, we summarized the current understanding of a wide-spectrum of cytokines and their interaction with immune cells that determine the clinical outcome of leishmaniasis. We have also highlighted opportunities for the development of novel diagnostics and intervention therapies for VL.

/pdf/cytokines-key-determinants-of-resistance-or-disease-49u4huekgl.pdf

Cytokines: Key determinants of resistance or disease progression in visceral leishmaniasis: Opportunities for novel diagnostics and immunotherapy

Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases.

Inflammation is an essential immune response for the maintenance of tissue homeostasis. In a general sense, acute and chronic inflammation are different types of adaptive response that are called into action when other homeostatic mechanisms are insufficient. Although considerable progress has been made in understanding the cellular and molecular events that are involved in the acute inflammatory response to infection and tissue injury, the causes and mechanisms of systemic chronic inflammation are much less known. The pathogenic capacity of this type of inflammation is puzzling and represents a common link of the multifactorial diseases, such as cardiovascular diseases and type 2 diabetes. In recent years, interest has been raised by the discovery of novel mediators of inflammation, such as microRNAs and adipokines, with different effects on target tissues. In the present review, we discuss the data emerged from research of leptin in obesity as an inflammatory mediator sustaining multifactorial diseases and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses. On the other direction, chronic inflammation, either from autoimmune or infectious diseases, or impaired microbiota (dysbiosis) may impair the leptin response inducing resistance to the weight control, and therefore it may be a cause of obesity. Thus, we are reviewing the published data regarding the role of leptin in inflammation, and the other way around, the role of inflammation on the development of leptin resistance and obesity.

https://www.mdpi.com/1422-0067/21/16/5887/pdf

Role of Leptin in Inflammation and Vice Versa.

An in vitro study of apoptotic like death in Leishmania donovani promastigotes by withanolides

Leptin induces the phagocytosis and protective immune response in Leishmania donovani infected THP-1 cell line and human PBMCs.

In vitro and in vivo evaluation of anti-leishmanial and immunomodulatory activity of Neem leaf extract in Leishmania donovani infection.

The emergence of drug-resistant Leishmania is the major challenge to management of visceral leishmaniasis (VL) in areas in which this parasite is endemic. Miltefosine has been widely used against VL, but the emergence of resistant strains could impose a significant threat in the near future. The present study used high-throughput proteomics to determine whether proteins are differentially expressed in miltefosine-resistant (BHU875) and -sensitive (DD8) Leishmania donovani strains. Comparative proteomic analysis revealed up-regulation of iron superoxide dismutase (FeSODA) in the resistant BHU875 strain compared to the drug-sensitive DD8 strain. In accordance with the proteomic data, BHU875 showed higher FeSODA enzymatic activity relative to the sensitive strain. Molecular characterization of BHU875 parasites in which the gene encoding FeSODA was silenced demonstrated that drug sensitivity was restored and the intracellular survival of the parasite was lowered. This suggests that FeSODA activity plays a part in miltefosine resistance. Our study provides a drug target that could be used to overcome miltefosine resistance or help in rational redesigning of miltefosine-based therapy to combat Leishmania infection.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.14923

Iron superoxide dismutase contributes to miltefosine resistance in Leishmania donovani.

Visceral leishmaniasis (VL) is responsible for several deaths in malnourished children accompanied by diminished circulating leptin and impaired cell-mediated immunity. Typically, leptin deficiency is associated with the Th2 polarization that markedly coincides with the pathogenesis of VL. The aim of the present study was to unravel the prophylactic role of leptin in malnutrition-coupled VL mice. Interestingly, we observed that L. donovani infection itself reduces the serum leptin levels in malnutrition. Exogenous leptin restored severe body weight loss and parasite load in the spleen and liver of malnourished infected mice compared to controls. Leptin increases functional CD8+ T-cell population, Granzyme-A expression down-regulates anergic T-cell markers such as PD-1 and CTLA-4. It was also noticed that, leptin suppresses GM-CSF mRNA expression in parasite favored monocytes and reduced arginase activity in bone marrow derived macrophage indicate macrophages dependent T-cell activation and proliferation. Leptin-induced IFN-γ, IL-2, and TNF-α cytokines in the culture supernatant of splenocytes upon soluble leishmanial antigen (SLA) stimulation and significantly up-regulates serum IgG2a titers, which help to generate Th1 immune response in VL. Furthermore, leptin induced a granulomatous response and restored L. donovani induced tissue degeneration in the liver. Altogether, our findings suggest the exogenous leptin can restore T cell mediated immunity in malnourished VL mice.

/pdf/leptin-regulates-granzyme-a-pd-1-and-ctla-4-expression-in-t-4jwbbzvfez.pdf

Jalaja Veronica

Papers

An in vitro study of apoptotic like death in Leishmania donovani promastigotes by withanolides

Leptin induces the phagocytosis and protective immune response in Leishmania donovani infected THP-1 cell line and human PBMCs.

In vitro and in vivo evaluation of anti-leishmanial and immunomodulatory activity of Neem leaf extract in Leishmania donovani infection.

Iron superoxide dismutase contributes to miltefosine resistance in Leishmania donovani.

Leptin regulates Granzyme-A, PD-1 and CTLA-4 expression in T cell to control visceral leishmaniasis in BALB/c Mice