Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by glia over-proliferation, neuro-inflammation, perturbed neural circuitry, and gastrointestinal symptoms. The role of gut dys-biosis in ASD is intriguing and should be elucidated. We investigated the effect of Propionic acid (PPA), a short-chain fatty acid (SCFA) and a product of dys-biotic ASD gut, on human neural stem cells (hNSCs) proliferation, differentiation and inflammation. hNSCs proliferated to 66 neuropsheres when exposed to PPA versus 45 in control. The neurosphere diameter also increased at day 10 post PPA treatment to (Mean: 193.47 um ± SEM: 6.673 um) versus (154.16 um ± 9.95 um) in control, p < 0.001. Pre-treatment with β-HB, SCFA receptor inhibitor, hindered neurosphere expansion (p < 0.001). While hNSCs spontaneously differentiated to (48.38% ± 6.08%) neurons (Tubulin-IIIβ positive) and (46.63% ± 2.5%) glia (GFAP positive), PPA treatment drastically shifted differentiation to 80% GFAP cells (p < 0.05). Following 2 mM PPA exposure, TNF-α transcription increased 4.98 fold and the cytokine increased 3.29 fold compared to control (P < 0.001). Likewise, GPR41 (PPA receptor) and pro-survival p-Akt protein were elevated (p < 0.001). PTEN (Akt inhibitor) level decreased to (0.42 ug/ul ± 0.04 ug/ul) at 2 mM PPA compared to (0.83 ug/ul ± 0.09 ug/ul) in control (p < 0.001). PPA at 2 mM decreased neurite outgrowth to (80.70 um ± 5.5 um) compared to (194.93 um ± 19.7 um) in control. Clearly, the data supports a significant role for PPA in modulating hNSC patterning leading to gliosis, disturbed neuro-circuitry, and inflammatory response as seen in ASD.
Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9) on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI), and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean ± SEM; MI: 2.02% ± 0.23% vs. Sham 0.75% ± 0.07%; p<0.05) and associated pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6), adverse cardiac remodeling (Mean ± SEM; MI: 33% ± 3.04% vs. Sham 2.2% ± 0.33%; p<0.05), and left ventricular dysfunction (Mean ± SEM; MI: 35.4% ± 1.25% vs. Sham 49.19% ± 1.07%; p<0.05) in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean ± SEM; MI+FGF-9: 1.39% ± 0.1% vs. MI: 2.02% ± 0.23%; p<0.05), increased M2 macrophage differentiation (Mean ± SEM; MI+FGF-9: 4.82% ± 0.86% vs. MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs. MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs. MI: 35.4% ± 1.25%; p<0.05). In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its ability to mediate monocyte to M2 differentiation and confer cardiac protection in the post-MI diabetic heart.
Recently, we proclaimed that induced pluripotent stem (iPS) cells generated from H9c2 cells, following transplantation into infarcted nondiabetic mice, can inhibit apoptosis and differentiate into cardiac myocytes. iPS cells can be an ideal candidate to expand regenerative medicine to the clinic. Therefore, examining the wide range of their potential to differentiate into neovascular cell types remains a major interest. We hypothesized that transplanted iPS cells in the infarcted diabetic db/db and nondiabetic mice can differentiate into vascular smooth muscle (VSM) and endothelial cells (ECs) as well as activate endogenous c-kit progenitor cells to enhance neovascularization along with improved cardiac function. We transplanted intramyocardially 50,000 iPS cells in the peri-infarct zone of infarcted db/db and C57BL/6 mice and hearts were examined at D14 post-MI. Cardiac function was examined using echocardiography. Our data implies that there was a significant (p < 0.001) increase in VSM and ECs in the infarcted heart following iPS cell transplantation compared with MI and sham groups in both db/db and C57BL/6 animals. Furthermore, the MI+iPS cell transplanted group also displayed a significant (p < 0.001) increase in c-kit(+ve) activated VSM and ECs confirmed with combined stainings of c-kit and cell specific markers, compared with respective controls. Next, our histology data in the MI+iPS cell group also establishes a significant (p < 0.05) increase in coronary artery vessels compared with MI, suggesting neovascularization. Furthermore, our data demonstrates significant improved cardiac function following iPS cell transplantation compared with MI. Overall increased neovascularization in the infarcted db/db and C57BL/6 mice is associated with improved cardiac function following iPS cell transplantation.
Cigarette smoke (CS) exacerbates symptoms in Crohn’s disease (CD) patients while protecting those with ulcerative colitis (UC). CD has been associated with immuno-dysregulation, mucosal dysfunction, and infection. Among the CD-debated pathogens are Mycobacterium avium subsp. paratuberculosis (MAP), adherent invasive Escherichia coli (AIEC), and Klebsiella pneumoniae. The mechanism of how CS modulates nicotinic acetylcholine receptor-α7 (α7nAChR) and elicits inflammatory response in CD-like macrophages is unknown. Here, we investigated the effect of CS/nicotine on macrophages infected with CD-associated pathogens. We measured apoptosis, bacterial viability, macrophage polarization, and gene expression/cytokine levels involved in macrophage response to nicotine/CS extracts from Havana-Leave extract (HLE-nicotine rich) and germplasm line of Maryland tobacco (LAMD-nicotine less). Nicotine (4 µg/mL) and HLE extracts (0.18%) significantly favored anti-inflammatory response in macrophages (increased CD-206 (M2) and IL-10, and decreased M1/M2 ratio; p < 0.05). While macrophages infected with MAP or treated with LPS promoted pro-inflammatory response. Further treatment of these macrophages with nicotine or HLE extracts caused higher inflammatory response (increased iNOS (M1), TNF-α, IL-6, and M1/M2 ratio, p < 0.05), increased MAP burden, and decreased apoptosis. Pre-conditioning macrophages with nicotine ahead of infection resulted in lower pro-inflammatory response. Blocking α7nAChR with an antagonist voided the effect of nicotine on macrophages. Overall, the study provides an insight toward understanding the contradictory effect of nicotine on Inflammatory Bowel Disease patients and about the mechanistic role of α7nAChR in modulation of macrophages in tobacco smokers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.