Jan Martel

Effects of obesity on depression: A role for inflammation and the gut microbiota

Depression is a mental disorder associated with environmental, genetic and psychological factors. Recent studies indicate that chronic neuro-inflammation may affect brain physiology and alter mood and behavior. Consumption of a high-fat diet leads to obesity and chronic systemic inflammation. The gut microbiota mediates many effects of a high-fat diet on human physiology and may also influence the mood and behavior of the host. We review here recent studies suggesting the existence of a link between obesity, the gut microbiota and depression, focusing on the mechanisms underlying the effects of a high-fat diet on chronic inflammation and brain physiology. This body of research suggests that modulating the composition of the gut microbiota using prebiotics and probiotics may produce beneficial effects on anxiety and depression.

Mineral particles stimulate innate immunity through neutrophil extracellular traps containing HMGB1

Calcium phosphate-based mineralo-organic particles form spontaneously in the body and may represent precursors of ectopic calcification. We have shown earlier that these particles induce activation of caspase-1 and secretion of IL-1β by macrophages. However, whether the particles may produce other effects on immune cells is unclear. Here, we show that these particles induce the release of neutrophil extracellular traps (NETs) in a size-dependent manner by human neutrophils. Intracellular production ofxa0reactive oxygen species is required for particle-induced NET release by neutrophils. NETs contain the high-mobility group protein B1 (HMGB1), a DNA-binding protein capable of inducing secretion of TNF-α by a monocyte/macrophage cell line and primary macrophages. HMGB1 functions as a ligand of Toll-like receptors 2 and 4 on macrophages, leading to activation of the MyD88 pathway and TNF-α production. Furthermore, HMGB1 is critical to activate the particle-induced pro-inflammatory cascade in the peritoneum of mice. These results indicate that mineral particles promote pro-inflammatory responses by engaging neutrophils and macrophages via signaling of danger signals through NETs.

Immunomodulatory Properties of Plants and Mushrooms

Plants and mushrooms are used for medicinal purposes and the screening of molecules possessing biological activities. A single plant or mushroom may produce both stimulatory and inhibitory effects on immune cells, depending on experimental conditions, but the reason behind this dichotomy remains obscure. We present here a large body of experimental data showing that water extracts of plants and mushrooms usually activate immune cells, whereas ethanol extracts inhibit immune cells. The mode of extraction of plants and mushrooms may thus determine the effects produced on immune cells, possibly due to differential solubility and potency of stimulatory and inhibitory compounds. We also examine the possibility of using such plant and mushroom extracts to treat immune system disorders.

Myths and Realities Surrounding the Mysterious Caterpillar Fungus

The caterpillar fungus Ophiocordyceps sinensis is a medicinal mushroom increasingly used as a dietary supplement for various health conditions, including fatigue, chronic inflammation, and male impotence. Here, we propose strategies to address the existing challenges related to the study and commercial production of this mysterious fungus.The caterpillar fungus Ophiocordyceps sinensis is a medicinal mushroom increasingly used as a dietary supplement for various health conditions, including fatigue, chronic inflammation, and male impotence. Here, we propose strategies to address the existing challenges related to the study and commercial production of this mysterious fungus.

Antrodia cinnamomea produces anti-angiogenic effects by inhibiting the VEGFR2 signaling pathway

ETHNOPHARMACOLOGICAL RELEVANCEnThe medicinal mushroom Antrodia cinnamomea has been used to treat cancer but its anti-angiogenic effects have not been studied in detail.nnnAIM OF THE STUDYnThe main objective of this study was to determine the molecular mechanism of activity underlying the anti-angiogenic effects of A. cinnamomea.nnnMATERIALS AND METHODSnThe effects of an A. cinnamomea ethanol extract (ACEE) on cell migration and microvessel formation were investigated in endothelial cells in vitro and Matrigel plugs implanted into mice in vivo. Activation of intracellular signaling pathways was examined using Western blotting. Protein expression was assessed using immunohistochemistry in a mouse model of lung metastasis.nnnRESULTSnWe show that treatment with ACEE inhibits cell migration and tube formation in human umbilical vein endothelial cells (HUVECs). ACEE suppresses phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and expression of pro-angiogenic kinases in vascular endothelial growth factor (VEGF)-treated HUVECs, in addition to reducing expression of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3). ACEE treatment inhibits VEGF-induced microvessel formation in Matrigel plugs in vivo. In addition, ACEE significantly reduces VEGFR2 expression in Lewis lung carcinoma cells and downregulates the expression of cluster of differentiation 31 (CD31) and VEGFR2 in murine lung metastases.nnnCONCLUSIONnThese results indicate that A. cinnamomea produces anti-angiogenic effects by inhibiting the VEGFR2 signaling pathway.

Comprehensive organic profiling of biological particles derived from blood

Mineral nanoparticles form in physiological and pathological processes occurring in the human body. The calcium phosphate mineral phase of the particles has affinity for proteins and lipids, but the complete profiling of the organic molecules that bind to the particles has not been described in detail. We report here a comprehensive analysis of organic components found in mineralo-organic particles derived from body fluids. Based on biological staining, fluorescent tagging, proteomics and metabolomics, our results indicate that the mineral particles bind to proteins, amino acids, carbohydrates, polysaccharides, phospholipids, fatty acids, DNA and lowxa0molecular weight metabolites. These results can be used to study the formation and effects of mineralo-organic particles in biological fluids.

Mineralo-organic nanoparticles in health and disease: an overview of recent findings

We observed earlier that mineralo-organic nanoparticles form in human body fluids when the concentrations of calcium, carbonate and phosphate exceed saturation. The particles have been shown to represent mineral precursors in developing bones and teeth as well as in ectopic calcification and kidney stones. Recent studies suggest that the mineral particles may also be involved in other physiological processes, including immune tolerance against the gut microbiota and food antigens. We review here the involvement of mineralo-organic nanoparticles in physiological and pathological processes and discuss recent findings that reveal novel and unexpected roles for these particles in the human body.

NK Cell–Derived IFN-γ Protects against Nontuberculous Mycobacterial Lung Infection

In developed countries, pulmonary nontuberculous mycobacteria (NTM) infections are more prevalent than Mycobacterium tuberculosis infections. Given the differences in the pathogenesis of NTM and M. tuberculosis infections, separate studies are needed to investigate the pathological effects of NTM pathogens. Our previous study showed that anti–IFN-γ autoantibodies are detected in NTM-infected patients. However, the role of NK cells and especially NK cell–derived IFN-γ in this context has not been studied in detail. In the current study, we show that NK1.1 cell depletion increases bacterial load and mortality in a mouse model of pulmonary NTM infection. NK1.1 cell depletion exacerbates NTM-induced pathogenesis by reducing macrophage phagocytosis, dendritic cell development, cytokine production, and lung granuloma formation. Similar pathological phenomena are observed in IFN-γ–deficient (IFN-γ−/−) mice following NTM infection, and adoptive transfer of wild-type NK cells into IFN-γ−/− mice considerably reduces NTM pathogenesis. Injection of rIFN-γ also prevents NTM-induced pathogenesis in IFN-γ−/− mice. We observed that NK cells represent the main producers of IFN-γ in the lungs and production starts as soon as 1 d postinfection. Accordingly, injection of rIFN-γ into IFN-γ−/− mice 1 d (but not 2 wk) postinfection significantly improves immunity against NTM infection. NK cells also stimulate mycobacterial killing and IL-12 production by macrophages. Our results therefore indicate that IFN-γ production by NK cells plays an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary NTM infection.

Pleomorphic bacteria-like structures in human blood represent non-living membrane vesicles and protein particles

Although human blood is believed to be a sterile environment, recent studies suggest that pleomorphic bacteria exist in the blood of healthy humans. These studies have led to the development of “live-blood analysis,” a technique used by alternative medicine practitioners to diagnose various human conditions, including allergies, cancer, cardiovascular disease and septicemia. We show here that bacteria-like vesicles and refringent particles form in healthy human blood observed under dark-field microscopy. These structures gradually increase in number during incubation and show morphologies reminiscent of cells undergoing division. Based on lipid analysis and Western blotting, we show that the bacteria-like entities consist of membrane vesicles containing serum and exosome proteins, including albumin, fetuin-A, apolipoprotein-A1, alkaline phosphatase, TNFR1 and CD63. In contrast, the refringent particles represent protein aggregates that contain several blood proteins. 16S rDNA PCR analysis reveals the presence of bacterial DNA in incubated blood samples but also in negative controls, indicating that the amplified sequences represent contaminants. These results suggest that the bacteria-like vesicles and refringent particles observed in human blood represent non-living membrane vesicles and protein aggregates derived from blood. The phenomena observed during live-blood analysis are therefore consistent with time-dependent decay of cells and body fluids during incubation ex vivo.