Current Medicinal Chemistry - Volume 29, Issue 33, 2022

Inflammation is a physiological, beneficial, and auto-limiting response of the host to alarming stimuli. Conversely, a chronic systemic low-grade inflammation (CSLGI), known as a long-time persisting condition, causes damage to the organs and host tissues, representing a major risk for chronic diseases. Currently, a high global incidence of chronic inflammatory diseases is observed, often linked to the lifestyle-related changes that occurred in the last decade. The main lifestyle-related factors are proinflammatory diet, psychological stress, tobacco smoking, alcohol abuse, physical inactivity, and indoor living and working with its related consequences such as indoor pollution, artificial light exposure, and low vitamin D production. Recent scientific evidence found that gut microbiota (GM) has a main role in shaping the host’s health, particularly as CSLGI mediator. Based on the lastest discoveries regarding the remarkable GM activity, in this manuscript we focus on the elements of actual lifestyle that influence the composition and function of the intestinal microbial community in order to elicit the CSLGI and its correlated pathologies. In this scenario, we provide a broad review of the interplay between modern lifestyle, GM, and CSLGI with a special focus on the COVID symptoms and emerging long-COVID syndrome.

Inflammation is a natural reaction to external stimuli to protect the organism. However, if it is exaggerated, it can cause severe physiopathological damage, linked to diseases like rheumatoid arthritis, cancer, diabetes, allergies, and infections. Inflammation is mainly characterized by pain, increased temperature, flushing, and edema, which can be controlled using anti-inflammatory drugs. In this context, prostaglandin E2 (PGE2) inhibition has been targeted for designing new compounds with anti-inflammatory properties. It is a bioactive lipid overproduced during an inflammatory process, in which its increased production is carried out mainly by COX-1, COX-2, and microsomal prostaglandin E2 synthase-1 (mPGES-1). Recently, studies have demonstrated that mPGES-1 inhibition is a safe strategy for developing anti-inflammatory agents, which could protect against pain, acute inflammation, arthritis, autoimmune diseases, and different types of cancers. Thus, in recent years, computer-aided drug design (CADD) approaches have been increasingly used to design new inhibitors, decreasing costs and increasing the probability of discovering active substances. Finally, this review will cover all aspects involving high-throughput virtual screening, molecular docking, dynamics, fragment-based drug design, and quantitative structure-activity relationship in seeking new promising mPGES-1 inhibitors.

Background: Breast cancer (BRCA) has become the most common cancer worldwide. The tumor microenvironment (TME) in the breast exerts a crucial role in promoting BRCA initiation, progression, and metastasis. Tumor-associated macrophages (TAMs) are the primary component of tumor-infiltrating immune cells through biological mediators that convert TME into malignant tumors. Combinations of these biological mediators can promote tumor growth, metastasis, angiogenesis, and immune suppression and limit the anti-tumor activity of conventional chemotherapy and radiotherapy. Objectives: The present study aimed to highlight the functions of several biological mediators in the breast thatgenerate TME into malignant tumors. Furthermore, this review offers a rationale for TAM-targeted therapy as a novel treatment strategy for BRCA. Results: This review emphasizes TAM-associated biological mediators of TME, viz., cancer- associated fibroblasts, endothelial cells, adipocytes, tumor-derived exosomes, extracellular matrix, and other immune cells, which facilitate TME in malignant tumors. Evidence suggests that the increased infiltration of TAMs and elevated expression of TAMrelated genes are associated with a poor prognosis of BRCA. Based on these findings, TAM-targeted therapeutic strategies, including inhibitors of CSF-1/CSF-1R, CCL2/CCR2, CCL5-CCR5, bisphosphonate, nanoparticle, and exosomal-targeted delivery have been developed, and are currently being employed in intervention trials. Conclusion: This review concludes the roles of biological mediators of TME that interact with TAMs in BRCA, providing a rationale for TAM-targeted therapy as a novel treatment approach for BRCA.

Visceral leishmaniasis (VL; also known as kala-azar), caused by the protozoan parasite Leishmania donovani, is characterized by the inability of the host to generate an effective immune response. The manifestations of the disease depend on the involvement of various immune components such as activation of macrophages, cell mediated immunity, secretion of cytokines and chemokines, etc. Macrophages are the final host cells for Leishmania parasites to multiply, and they are the key to a controlled or aggravated response that leads to clinical symptoms. The two most common macrophage phenotypes are M1 and M2. The pro-inflammatory microenvironment (mainly by IL-1β, IL-6, IL-12, IL-23, and TNF-α cytokines) and tissue injury driven by classically activated macrophages (M1-like) and wound healing driven by alternatively activated macrophages (M2-like) in an anti-inflammatory environment (mainly by IL-10, TGF-β, chemokine ligand (CCL)1, CCL2, CCL17, CCL18, and CCL22). Moreover, on polarized Th cells, chemokine receptors are expressed differently. Typically, CXCR3 and CCR5 are preferentially expressed on polarized Th1 cells, whereas CCR3, CCR4, and CCR8 have been associated with the Th2 phenotype. Further, the ability of the host to produce a cell-mediated immune response capable of regulating and/or eliminating the parasite is critical in the fight against the disease. Here, we review the interactions between parasites and chemokines and chemokine receptors in the pathogenesis of VL.

Background: To date, many investigations have employed pro-/synbiotic to examine their effects on chemotherapy-related side effects; nevertheless, their findings are inconclusive. To address this issue, we carried out a systematic review to explore the effect of pro- /synbiotic consumption on chemotherapy-related side effects, including nausea, vomiting, mucositis, diarrhea, and constipation in adults using randomized controlled trials (RCTs). Methods: The electronic databases, including PubMed, Scopus, and ISI Web of Sciences, were searched systematically from the earliest available date to March 2021 to identify eligible studies. The quality of the enrolled studies was assessed based on the Cochrane Collaboration Risk of Bias tool. Results: A total of 10 studies involving 788 individuals were included in the current systematic review, with the sample size ranging from 25 to 200 and the mean age ranging from 51.04 to 66.91 years. The findings of this study imply that probiotic consumption may be more effective in terms of mucositis compared to other complications. Conclusion: Further good-quality RCTs with better methodology are required to determine whether and how pro-/synbiotics can prevent or treat chemotherapy-induced side effects. The current systematic review findings may help investigators of future studies in selecting the study population and probiotic strains.