Trimethylamine N-oxide (TMAO) is a metabolite produced by the gut microbiota and has been mainly associated with an increased incidence of cardiovascular diseases (CVDs) in humans. There are factors that affect one’s TMAO level, such as diet, drugs, age, and hormones, among others. Gut dysbiosis in the host has been studied recently as a new approach to understanding chronic inflammatory and degenerative diseases, including cardiovascular diseases, metabolic diseases, and Alzheimer’s disease. These disease types as well as COVID-19 are known to modulate host immunity. Diabetic and obese patients have been observed to have an increase in their level of TMAO, which has a direct correlation with CVDs. This metabolite is attributed to enhancing the inflammatory pathways through cholesterol and bile acid dysregulation, promoting foam cell formation. Additionally, TMAO activates the transcription factor NF-κB, which, in turn, triggers cytokine production. The result can be an exaggerated inflammatory response capable of inducing endoplasmic reticulum stress, which is responsible for various diseases. Due to the deleterious effects that this metabolite causes in its host, it is important to search for new therapeutic agents that allow a reduction in the TMAO levels of patients and that, thus, allow patients to be able to avoid a severe cardiovascular event. The present review discussed the synthesis of TMAO and its contribution to the pathogenesis of various inflammatory diseases.

Depression is the leading cause of disability worldwide, contributing to the global disease burden. From above, it is a priority to investigate models that fully explain its physiopathology to develop new treatments. In the last decade, many studies have shown that gut microbiota (GM) dysbiosis influences brain functions and participate, in association with immunity, in the pathogenesis of depression. Thereby, GM modulation could be a novel therapeutic target for depression. This review aims to evidence how the GM and the immune system influence mental illness, particularly depression. Here, we focus on the communication mechanisms between the intestine and the brain and the impact on the development of neuroinflammation contributing to the development of Major Depressive Disorder (MDD). However, most of the current findings are in animal models, suggesting the need for studies in humans. In addition, more analysis of metabolites and cytokines are needed to identify new pathophysiological mechanisms improving anti-depression treatments.

SUMMARY: Protozoan parasites of genusLeishmaniaare the causative agents of leishmaniasis.Leishmaniapromastigotes primarily infect macrophages in the host, where they transform into amastigotes and multiply. Lipophosphoglycan (LPG), the most abundant surface molecule of the parasite, is a virulence determinant that regulates the host immune response. Promastigotes are able to modulate this effect through LPG, creating a favourable environment for parasite survival, although the mechanisms underlying this modulation remain unknown. We analysed the participation of TLR2 and TLR4 in the production of cytokines and explored the possible phosphorylation of ERK and/or p38 MAP kinase signalling cascades in human macrophages stimulated withLeishmania mexicanaLPG. The results show that LPG induced the production of TNF-α, IL-1β, IL-12p40, IL-12p70 and IL-10 and led to phosphorylation of ERK and p38 MAP kinase. Specific inhibitors of ERK or p38 MAP kinases and mAbs against TLR2 and TLR4 reduced cytokine production and phosphorylation of both kinases. Our results suggest thatL. mexicanaLPG binds TLR2 and TLR4 receptors in human macrophages, leading to ERK and MAP kinase phosphorylation and production of pro-inflammatory cytokines.

Exosomes are extracellular microvesicles of endosomal origin (multivesicular bodies, MVBs) constitutively released by eukaryotic cells by fusion of MVBs to the plasma membrane. The exosomes from Leishmania parasites contain an array of parasite molecules such as virulence factors and survival messengers, capable of modulating the host immune response and thereby favoring the infection of the host. We here show that exosomes of L. mexicana amastigotes (aExo) contain the virulence proteins gp63 and PP2C. The incubation of aExo with bone marrow‐derived macrophages (BMMs) infected with L. mexicana led to their internalization and were found to colocalize with the cellular tetraspanin CD63. Furthermore, aExo inhibited nitric oxide production of infected BMMs, permitting enhanced intracellular parasite survival. Expressions of antigen‐presenting (major histocompatibility complex class I, MHC‐I, and CD1d) and costimulatory (CD86 and PD‐L1) molecules were modulated in a dose‐dependent fashion. Whereas MHC‐I, CD86 and PD‐L1 expressions were diminished by exosomes, CD1d was enhanced. We conclude that aExo of L. mexicana are capable of decreasing microbicidal mechanisms of infected macrophages by inhibiting nitric oxide production, thereby enabling parasite survival. They also hamper the cellular immune response by diminishing MHC‐I and CD86 on an important antigen‐presenting cell, which potentially interferes with CD8 T cell activation. The enhanced CD1d expression in combination with reduction of PD‐L1 on BMMs point to a potential shift of the activation route towards lipid presentations, yet the effectivity of this immune activation is not evident, since in the absence of costimulatory molecules, cellular anergy and tolerance would be expected.

The pandemic SARS coronavirus 2 utilizes efficient mechanisms to establish infection and evade the immune system. Established infection leads to severe inflammation in susceptible patients, the mai...

The prevalence of dental caries in the Mexican adult population aged 20 to 85 years is around 93.3%, and 50% in Mexican children and adolescents. Worldwide, it is the most common non-communicable disease. One of the main etiological factors for dental caries is the oral microbiome and changes in its structure and function, with an expansion of pathogenic bacteria like Streptococcus mutans. The exposed dental pulp tissue triggers an innate immune response to counteract this bacterial invasion. The relation between oral dysbiosis and innate immune responses remains unclear. We aimed to understand the relationship between innate immune response and the oral microbiota by quantifying the expression of Toll-like receptors (TLRs) and proinflammatory markers (cytokines and a chemokine) in dental pulp tissue, either exposed or not to carious dentin, and to correlate this information with the oral microbiome found in healthy teeth and those with moderate caries. RNA was purified from pulp tissue, subjected to RT-qPCR and analysed with the ^ΔΔCt method. Supragingival dental plaque of non-carious teeth and dentin of carious teeth were subjected to 16S targeted sequencing. Principal coordinate analysis, permutational multivariate ANOVA, and linear discriminant analysis were used to assess differences between non-carious and carious teeth. Correlations were assessed with Spearman´s test and corrected for multiple comparisons using the FDR method. The relative abundance (RA) of Lactobacillus, Actinomyces, Prevotella, and Mitsuokella was increased in carious teeth; while the RA of Haemophilus and Porphyromonas decreased. Olsenella and Parascardovia were only detected in carious teeth. Significant overexpression of interleukin 1 beta (IL1 β), IL6, and CXCL8 was detected in pulp tissue exposed to carious dentin. IL1β correlated positively with TLR2 and Actinomyces; yet negatively with Porphyromonas. These findings suggest that immune response of pulp tissue chronically exposed to cariogenic microbiome is triggered by proinflammatory cytokines IL1β and IL6 and the chemokine CXCL8.