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Currently, no safe vaccine against leishmaniasis is available. So far, different control strategies against numerous reservoir hosts and biological vectors have not been environment-friendly and feasible. Hence, employing medicinal components and conventional drugs could be a promising approach to developing novel therapeutic alternatives. This study aimed to explore diallyl sulfide (DAS), a dynamic constituent of garlic, alone and in a mixture with meglumine antimoniate (MAT as standard drug) using in vitro and animal model experiments against Leishmania major stages. The binding affinity of DAS and four major defense elements of the immune system (iNOS, IFN-ɣ, IL-12, and TNF-α) was used to predict the predominant binding mode for molecular docking configurations. Herein, we conducted a broad range of experiments to monitor and assess DAS and MAT potential treatment outcomes. DAS, combined with MAT, displayed no cytotoxicity and employed a powerful anti-leishmanial activity, notably against the clinical stage. The function mechanism involved immunomodulation through the induction of Th1 cytokine phenotypes, triggering a high apoptotic profile, reactive oxygen species (ROS) production, and antioxidant enzymes. This combination significantly decreased cutaneous lesion diameter and parasite load in BALB/c mice. The histopathological findings performed the infiltration of inflammatory cells associated with T-lymphocytes, particularly CD4+ phenotypes, as determined by biochemical markers in alleviating the amastigote stage and improving the pathological changes in L. major infected BALB/c mice. Therefore, DAS and MAT deserve further advanced therapeutic development and should be considered as possible candidates for treating volunteer cases with cutaneous leishmaniasis in designing an upcoming clinical trial. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the in vitro and in silico antileishmanial activity of azacitidine (AZA) on Leishmania major promastigotes and amastigotes. The in silico method was used to evaluate the possibility of the interaction of AZA into the binding pocket of inducible nitric oxide synthase (iNOS), a leading defensive oxidative metabolite. Following that, in vitro anti-promastigote, and anti-amastigote activity of AZA was determined using an MTT assay and a macrophage model, respectively. Cytotoxic effects of AZA and meglumine antimoniate (MA) were also assessed by MTT assay on murine macrophages. All experiments were performed in triplicate. The results showed that AZA interacted with Ser133, Gln134, and Lys13 amino acids of iNOS, and the molecular docking score was obtained at -241.053 kcal/mol. AZA in combination with MA significantly (P<0.001) inhibited the growth rate of nonclinical promastigote (IC50 247.6±7.3 μM) and 8.5-fold higher of clinical intramacrophage amastigote stage (29.8±5.3 μM), compared to the untreated group. A significant upsurge of Th1 subsets and transcription genes and a meaningful decline in Th2 cytokines subclasses at the equivalent concentrations of AZA and MA was observed (P<0.001). The apoptosis effect of AZA along with MA was significantly induced on L. major in a dose-dependent manner (P<0.001). The present study demonstrated that AZA possesses antileishmanial activity in in vitro and in silico models. However, AZA combined with MA was more effective than AZA alone in inhibiting the growth rate of promastigotes and amastigotes of L. major. This study indicates that AZA in combination with MA demonstrated a potent antileishmanial mechanism, promoting immune response and enhancing an immunomodulatory role toward the Th1 pathway. This experimental study is a basic study for applying more knowledge about the mechanisms of AZA along with MA in animal models in the future. [ABSTRACT FROM AUTHOR]

Toll‐like receptors (TLRs) and inflammasomes belong to the pattern recognition receptors (PRRs) of innate immunity identifying conserved compounds produced by pathogens or discharged by injured cells. Different cell subsets in the human urogenital system, such as epithelial cells and infiltrating leukocytes, express different kinds of TLRs (such as TLR2, TLR3, TLR4, TLR5 and TLR9) as well as inflammasomes (such as NLRP3, NLRC4 and AIM2). Various types of the Trichomonas vaginalis‐derived components such as glycosyl‐phosphatidylinositol (GPI), T. vaginalis virus (TVV), Lipophosphoglycan (LPG) and flagellin can be recognized by TLR2, TLR3, TLR4 and TLR5, respectively, leading to the production of proinflammatory cytokines and chemokines in the cervicovaginal mucosa. The T. vaginalis‐induced inflammasomes can lead to pyroptosis as well as the release of IL‐1β and IL‐18 promoting innate and adaptive immune responses. The PRR‐mediated responses to T. vaginalis may contribute to the induction of protective immune responses, local inflammation, promotion of co‐infections, or even the development of malignancies, for example, prostate cancer. The protective or pathogenic roles of the TLRs and inflammasomes during trichomoniasis are highlighted in this review. A better understanding of PRR‐mediated responses provides invaluable insights to develop effective immunotherapeutic strategies against T. vaginalis infection. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine (METH) is a widely addictive and abused psychostimulant drug that affects organs of body. In this study, the effects of METH administration for 7, 14, and 28 days on the histological and functional changes of the liver and pancreas of adult male rats were investigated. Methods: In this experimental study, 58 adult male Wistar rats were randomly divided into seven groups including control (received no treatment), vehicle (received saline for 7, 14, and 28 days), and METH (received METH with a dose of 5 ml/kg, IP for 7, 14 or 28 days). Sampling from the liver and pancreas tissues was done after the above-mentioned times for each group, then, tissue samples were stained by H&E technique and evaluated for structural changes, as well as the evaluation of biochemical factors including SGPT, SGOT, and amylase enzymes. Data were analyzed by one-way ANOVA, using SPSS software version 20. Statistical significant level was considered at P<0.05. Results: In this study, METH caused a significant structural change in the liver and pancreas in the METH-treated groups compared with the control group. Functional changes depended on the length of treatment, with the 7-day treatment group having less damage than the 14- and 28-day periods. Conclusion: According to the results of the present study, methamphetamine administration for 7, 14, and 28 days had adverse effects on the rats liver and pancreas structure and their enzymes (SGPT, SGOT, and amylase). Therefore, underlying mechanism need further investigation. [ABSTRACT FROM AUTHOR]