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.

Deficiency of leptin (ob/ob) and/or desensitization of leptin signaling (db/db) and elevated expression of suppressor of cytokine signaling-3 (SOCS3) reported in obesity are also reported in a variety of pathologies including hypertriglyceridemia, insulin resistance, and malnutrition as the risk factors in host defense system. Viral infections cause the elevated SOCS3 expression, which inhibits leptin signaling. It results in immunosuppression by T-regulatory cells (Tregs). The host immunity becomes incompetent to manage pathogens' attack and invasion, which results in the accelerated infections and diminished vaccine-specific antibody response. Leptin was successfully used as mucosal vaccine adjuvant against Rhodococcus equi. Leptin induced the antibody response to Helicobacter pylori vaccination in mice. An integral leptin signaling in mucosal gut epithelial cells offered resistance against Clostridium difficile and Entameoba histolytica infections. We present in this review, the intervention of leptin in lethal diseases caused by microbial infections and propose the possible scope and challenges of leptin as an adjuvant tool in the development of effective vaccines.

Asiatic acid (AsA), a naturally occurring pentacyclictriterpenoid found in Centella asiatica, plays a major role in neuroprotection, anticancer, antioxidant, and hepatoprotective activities. Human serum albumin (HSA), a blood plasma protein, participates in the regulation of plasma osmotic pressure and transports endogenous and exogenous substances. The study undertaken to analyze the drug-binding mechanisms of HSA is crucial in understanding the bioavailability of drugs. In this study, we analyzed the cytotoxic activity of AsA on HepG2 (human hepatocellular carcinoma) cell lines and its binding, conformational, docking, molecular simulation studies with HSA under physiological pH 7.2. These studies revealed a clear decrease in the viability of HepG2 cells upon exposure to AsA in a dose-dependent manner with an IC50 of 45 μM. Further studies showed the quenching of intrinsic fluorescence of HSA by AsA with a binding constant of KAsA = 3.86 ± 0.01 × 10(4) M(-1), which corresponds to the free energy of (ΔG) -6.3 kcal M(-1) at 25 °C. Circular dichroism (CD) studies revealed that there is a clear decrease in the α-helical content from 57.50 ± 2.4 to 50% ± 2.3 and an increase in the β-turns from 25 ± 0.65 to 29% ± 0.91 and random coils from 17.5% ± 0.95 to 21% ± 1.2, suggesting partial unfolding of HSA. Autodock studies revealed that the AsA is bound to the subdomain IIA with hydrophobic and hydrophilic interactions. From molecular dynamics, simulation data (RMSD, Rg and RMSF) emphasized the local conformational changes and rigidity of the residues of both HSA and HSA-AsA complexes.

Resistance to antileishmanial drugs such as sodium stibogluconate (SSG), amphotericin B (Amp-B), and miltefosine is on the rise, and alternate strategies for effective treatment have gained importance in recent years. Although nanoparticle (NP)based composite drugs that have emerged recently have been found to be effective, the associated toxicity limits their usage. Bimetallic NPs produced through reduction with medicinal plant extracts are proposed to overcome the toxicity of the NPs. In the present study, three types of gold−silver bimetallic nanoparticles (Au−Ag BNPs) were synthesized through a single-step reduction process using fenugreek, coriander, and soybean leaf extracts. All of the three types of BNPs exhibited high antileishmanial effects against promastigotes with half-inhibitory concentration (IC 50 ) values in the range of 0.03−0.035 μg/mL. The IC 50 values of the BNPs are much lower compared to those of miltefosine (IC 50 = 10 μg/mL). The synthesized BNPs induced the reactive oxygen species (ROS)mediated apoptosis-like death in the promastigotes and could potentiate the antileishmanial activity of macrophages. The intracellular amastigotes were reduced by 31−46% in macrophages. The biogenic BNPs synthesized in this study and their potent antileishmanial activity provide further impetus to the ongoing quest for novel drugs to effectively manage leishmaniasis.

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