Platelets are chief cells in hemostasis. Apart from their hemostatic roles, platelets are major inflammatory effector cells that can influence both innate and adaptive immune responses. Activated platelets have thromboinflammatory functions linking hemostatic and immune responses in several physiological and pathological conditions. Among many ways in which platelets exert these functions, platelet expression of pattern recognition receptors (PRRs), including TLR, Nod-like receptor, and C-type lectin receptor families, plays major roles in sensing and responding to pathogen-associated or damage-associated molecular patterns (PAMPs and DAMPs, respectively). In this review, an increasing body of evidence is compiled showing the participation of platelet innate immune receptors, including PRRs, in infectious diseases, sterile inflammation, and cancer. How platelet recognition of endogenous DAMPs participates in sterile inflammatory diseases and thrombosis is discussed. In addition, platelet recognition of both PAMPs and DAMPs initiates platelet-mediated inflammation and vascular thrombosis in infectious diseases, including viral, bacterial, and parasite infections. The study also focuses on the involvement of innate immune receptors in platelet activation during cancer, and their contribution to tumor microenvironment development and metastasis. Finally, how innate immune receptors participate in platelet communication with leukocytes, modulating leukocyte-mediated inflammation and immune functions, is highlighted. These cell communication processes, including platelet-induced release of neutrophil extracellular traps, platelet Ag presentation to T-cells and platelet modulation of monocyte cytokine secretion are discussed in the context of infectious and sterile diseases of major concern in human health, including cardiovascular diseases, dengue, HIV infection, sepsis, and cancer.

Leptin is a pleiotropic adipokine that regulates immunometabolism centrally and peripherally.Obese individuals present increased levels of leptin in the blood and develop hypothalamic resistance to this adipokine. Here we investigated whether leptin effects on the periphery are maintained despite the hypothalamic resistance. We previously reported that leptin injection induces in vivo neutrophil migration and peritoneal macrophage activation in lean mice through TNF-and CXCL1-dependent mechanisms. However, leptin effects on leukocyte biology during obesity remain unclear. In this study, we investigated the in vivo responsiveness of leukocytes to i.p. injected leptin in mice with diet-induced obesity (DIO). After 14-16 wk, high-sucrose, high-fat diet (HFD)-fed mice showed hyperglycemia, hyperleptinemia, and dyslipidemia compared to normalsucrose, normal-fat diet (ND). Exogenous leptin did not reduce food intake in DIO mice in contrast to control mice, indicating that DIO mice were centrally resistant to leptin. Regardless of the diet, we found increased levels of TNF-and CXCL1 in the animals injected with leptin, alongside a pronounced neutrophil migration to the peritoneal cavity and enhanced biogenesis of lipid droplets in peritoneal macrophages. Supporting our in vivo results, data from ex vivo leptin stimulation experiments confirmed hypothalamic resistance in DIO mice, whereas bone marrow cells responded to leptin stimulation through mTOR signaling despite obesity. Altogether, our results show that leukocytes responded equally to leptin in ND-or HFD-fed mice. These results support a role for leptin in the innate immune response also in obesity, contributing to the inflammatory status that leads to the development of metabolic disease. K E Y W O R D Sadipose tissue, high-fat diet, leptin signaling, leukocytes, macrophages, neutrophils INTRODUCTIONObesity has become a major health problem worldwide. It is associated with various comorbidities including cancer, type 2 diabetes, Abbreviations: DIO, diet-induced obesity or diet-induced obese; EP, epididymal; HFD, high-sucrose, high-fat diet; ND, normal-sucrose, normal-fat diet; RP, retroperitoneal; SC, subcutaneous; TAG, triacylglycerol; WAT, white adipose tissue.cardiovascular diseases, among many others. 1 Several factors, that is, genetics, epigenetics, environment, habits, and diets influence the development of obesity. Regardless of the etiology, one common aspect of obesity is the central resistance to leptin signaling. 2,3 Leptin is an adipokine that functions as a sensor of the energetic status of the organism. It acts centrally on hypothalamic neurons to induce lipolysis, energy expenditure, satiety, and inhibit food intake. 4,5 There is also evidence that leptin can regulate peripheral immune function through

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In recent years, natural products with biological activities have been increasingly researched. The elucidation of phytoconstituents is necessary for the development of drugs as a natural alternative for the treatment of various diseases. The work aimed to evaluate in vitro and in silico bioactivities of hexane (CCHE) and methanol (CCME) fractions of ethanolic extract from Centrosema coriaceum Benth (Fabaceae) leaves and elucidate their phytoconstituents. CCHE and CCME showed antifungal activity for Candida glabrata (MIC of 1000 μg/mL) with fungistatic effect and action in cell envelope by sorbitol and ergosterol assays. CCHE and CCME presented promising antioxidant activity against the DPPH radical with IC 50 of 13.61 � 0.50 and 6.31 � 0.40 μg/mL, respectively, and relative antioxidant activity (RAA%) of 45.77 � 3.61/ 28.53 � 2.25 % for CCHE and 82.18 � 2.25/ 51.99 � 3.23 % for CCME when compared to rutin and quercetin, respectively. Moreover, these fractions demonstrated promising results for the inhibition of lipid peroxidation by β-carotene/linoleic acid assay. For antiinflammatory and cytotoxicity activities, CCHE and CCME significantly inhibited the production of nitric oxide and TNF-α, without toxicity on murine intraperitoneal macrophages, respectively. Esters, alkanes, steroids, tocopherols, and terpenes were identified in CCHE by GC/MS. Flavonoids, phenolic acids, and disaccharides were detected in CCME by UFLC-QTOF-MS and FACE. Furthermore, rutin was purified from CCME. In silico predictions evidenced that compounds present in both fractions have high affinity to the fungal membrane besides antioxidant and anti-inflammatory activities. Based on these observations, CCHE and CCME have a noteworthy potential for the design of novel antifungal and anti-inflammatory agents that should be explored in future studies.

Objectives Evaluation of the anti-Leishmanial activity of imidazoquinoline-based TLR7/8 agonists. Methods TLR7/8-active imidazoquinolines (2 and 3) were synthesized and assessed for activity against Leishmania amazonensis-intracellular amastigotes using mouse peritoneal macrophages. The production of reactive oxygen species (ROS), nitric oxide (NO) and cytokines was determined in infected and non-infected macrophages. Key findings The imidazoquinolines, 2 and 3, were primarily agonists of TLR7 with compound 3 also showing modest TLR8 activity. Docking studies showed them to occupy the same binding pocket on TLR7 and 8 as the known agonists, imiquimod and resiquimod. Compounds 2 and 3 inhibited the growth of L. amazonensis-intracellular amastigotes with the most potent compound (3, IC50 = 5.93 µM) having an IC50 value close to miltefosine (IC50 = 4.05 µM), a known anti-Leishmanial drug. Compound 3 induced macrophages to produce ROS, NO and inflammatory cytokines that likely explain the anti-Leishmanial effects. Conclusions This study shows that activating TLR7 using compounds 2 or 3 induces anti-Leishmanial activity associated with induction of free radicals and inflammatory cytokines able to kill the parasites. While 2 and 3 had a very narrow cytotoxicity window for macrophages, this identifies the possibility to further develop this chemical scaffold to less cytotoxic TLR7/8 agonist for potential use as anti-Leishmanial drug.