Immunoregulatory effect of mesenchymal stem cell via mitochondria signaling pathways in allergic asthma.

Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied. After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, -5, -13, -25, -33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done. BALf's eosinophils, the levels of IL-4, -5, -13, -25, -33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4. MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology.

A systematic review on the effects of Echinacea supplementation on cytokine levels: Is there a role in COVID-19?

COVID-19 is the respiratory illness caused by the novel coronavirus, SARS-CoV-2. Cytokine storm appears to be a factor in COVID-19 mortality. Echinacea species have been used historically for immune modulation. A previous rapid review suggested that Echinacea supplementation may decrease the levels of pro-inflammatory cytokines involved in cytokine storm. The objective of the present systematic review was to identify all research that has assessed changes in levels of cytokines relevant to cytokine storm in response to administration of Echinacea supplementation. The following databases were searched: Medline (Ovid), AMED (Ovid), CINAHL (EBSCO), EMBASE (Ovid). Title and abstract screening, full text screening, and data extraction were completed in duplicate using a piloted extraction template. Risk of bias assessment was completed. Qualitative analysis was used to assess for trends in cytokine level changes. The search identified 279 unique publications. After full text screening, 105 studies met criteria for inclusion including 13 human studies, 24 animal studies, and 71 in vitro or ex vivo studies. The data suggest that Echinacea supplementation may be associated with a decrease in the pro-inflammatory cytokines IL-6, IL-8, and TNF, as well as an increase in the anti-inflammatory cytokine IL-10. The risk of bias in the included studies was generally high. While there is currently no substantive research on the therapeutic effects of Echinacea in the management of either cytokine storm or COVID-19, the present evidence related to the herb's impact on cytokine levels suggests that further research may be warranted in the form of a clinical trial involving patients with COVID-19.

Subchronic toxicity evaluation of leaves from rabbiteye blueberry (Vaccinium virgatum Aiton) in rats.

Blueberry leaf may contain multiple compounds with beneficial effects. We conducted a 90-day toxicity study in rats to evaluate the safety of consuming the leaves of rabbiteye blueberry (Vaccinium virgatum Aiton; RB species). Powdered leaves were administered daily by oral gavage at doses of 500, 1000, and 2500 mg/kg body weight to male and female Sprague-Dawley rats for 90 days. Treatment did not result in death or changes in the behavior and external appearance of the animals. No alterations were observed in hematological and serum chemical parameters, urinalysis, food consumption, body weight gain, or absolute and relative organ weights at the end of the treatment period, with the exception of some leukocyte percentages in male rats treated with 500 and 1000 mg/kg blueberry leaf powder. The findings indicate that rabbiteye blueberry leaf is safe for consumption and should be investigated as a candidate functional food.

Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans.

BACKGROUND & AIMS: Systemic cellular immunity elicited by the Ty21a oral typhoid vaccine has been extensively characterized. However, very limited data are available in humans regarding mucosal immunity at the site of infection (terminal ileum [TI]). Here we investigated the host immunity elicited by Ty21a immunization on terminal ileum-lamina propria mononuclear cells (LPMC) and peripheral blood in volunteers undergoing routine colonoscopy. METHODS: We characterized LPMC-T memory (TM) subsets and assessed Salmonella enterica serovar Typhi (S Typhi)-specific responses by multichromatic flow cytometry. RESULTS: No differences were observed in cell yields and phenotypes in LPMC CD8+-TM subsets following Ty21a immunization. However, Ty21a immunization elicited LPMC CD8+ T cells exhibiting significant S Typhi-specific responses (interferon-γ, tumor necrosis factor-α, interleukin-17A, and/or CD107a) in all major TM subsets (T-effector/memory [TEM], T-central/memory, and TEM-CD45RA+), although each TM subset exhibited unique characteristics. We also investigated whether Ty21a immunization elicited S Typhi-specific multifunctional effectors in LPMC CD8+ TEM. We observed that LPMC CD8+ TEM responses were mostly multifunctional, except for those cells exhibiting the characteristics associated with cytotoxic responses. Finally, we compared mucosal with systemic responses and made the important observation that LPMC CD8+S Typhi-specific responses were unique and distinct from their systemic counterparts. CONCLUSIONS: This study provides the first demonstration of S Typhi-specific responses in the human terminal ileum mucosa and provides novel insights into the generation of mucosal immune responses following oral Ty21a immunization.

Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder.

BACKGROUND & AIMS: Emerging data on the gut microbiome in autism spectrum disorder (ASD) suggest that altered host-microbe interactions may contribute to disease symptoms. Although gut microbial communities in children with ASD are reported to differ from individuals with neurotypical development, it is not known whether these bacteria induce pathogenic neuroimmune signals. METHODS: Because commensal clostridia interactions with the intestinal mucosa can regulate disease-associated cytokine and serotonergic pathways in animal models, we evaluated whether microbiome-neuroimmune profiles (from rectal biopsy specimens and blood) differed in ASD children with functional gastrointestinal disorders (ASD-FGID, n = 14) compared with neurotypical (NT) children with FGID (NT-FGID, n = 15) and without abdominal pain (NT, n = 6). Microbial 16S ribosomal DNA community signatures, cytokines, and serotonergic metabolites were quantified and correlated with gastrointestinal symptoms. RESULTS: A significant increase in several mucosa-associated Clostridiales was observed in ASD-FGID, whereas marked decreases in Dorea and Blautia, as well as Sutterella, were evident. Stratification by abdominal pain showed multiple organisms in ASD-FGID that correlated significantly with cytokines (interleukin [IL]6, IL1, IL17A, and interferon-γ). Group comparisons showed that IL6 and tryptophan release by mucosal biopsy specimens was highest in ASD children with abdominal pain, whereas serotonergic metabolites generally were increased in children with FGIDs. Furthermore, proinflammatory cytokines correlated significantly with several Clostridiales previously reported to associate with ASD, as did tryptophan and serotonin. CONCLUSIONS: Our findings identify distinctive mucosal microbial signatures in ASD children with FGID that correlate with cytokine and tryptophan homeostasis. Future studies are needed to establish whether these disease-associated Clostridiales species confer early pathogenic signals in children with ASD and FGID.

Paraquat and psychological stressor interactions as pertains to Parkinsonian co-morbidity.

A number of epidemiological and experimental studies have implicated the non-selective herbicide, paraquat, in the development of sporadic Parkinson's disease (PD). While preclinical research has focused mainly on elucidating the nigrostriatal effects of paraquat, relatively little data are available concerning non-motor brain systems and inflammatory immune processes (which have been implicated in PD). Hence, in the present study, we sought to take a multi-system approach to characterize the influence of paraquat upon extra-nigrostriatal brain regions, as well ascertain whether the impact of the pesticide might be enhanced in the context of chronic intermittent stressor exposure. Our findings support the contention that paraquat itself acted as a systemic stressor, with the pesticide increasing plasma corticosterone, as well as altering neurochemical activity in the locus coeruleus, paraventricular nucleus of the hypothalamus, nucleus accumbens, dorsal striatum, and central amygdala. However, with the important exception striatal dopamine turnover, the stressor treatment did not further augment these effects. Additionally, paraquat altered inter-cytokine correlations and, to a lesser extent, circulating cytokine levels, and concomitant stress exposure modulated some of these effects. Finally, paraquat provoked significant (albeit modest) reductions of sucrose preference and weight gain, hinting at possible anhendonic-like or sickness responses. These data suggest that, in addition to being a well known oxidative stress generator, paraquat can act as a systemic stressor affecting hormonal and neurochemical activity, but largely not interacting with a concomitant stressor regimen.

A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma.

Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed ex-vivo using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1ß and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1ß and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23+, 25+, 25+, 29+ months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an ex-vivo T cell response and long-term overall survival. These findings warrant confirmation in a larger group of patients.