The PPAR-γ agonist pioglitazone exerts proinflammatory effects in bronchial epithelial cells during acute Pseudomonas aeruginosa pneumonia

Pseudomonas (P.) aeruginosa is a common respiratory pathogen that causes injurious airway inflammation during acute pneumonia. PPAR (peroxisome proliferator-activated receptor)-γ is involved in the regulation of metabolic and inflammatory responses in different cell types and synthetic agonists of PPAR-γ exert anti-inflammatory effects on myeloid cells in vitro and in models of inflammation in vivo. We sought to determine the effect of the PPAR-γ agonist pioglitazone on airway inflammation induced by acute P. aeruginosa pneumonia, focusing on bronchial epithelial cells. Mice pretreated with pioglitazone or vehicle (-24 and -1 hour) were infected with P. aeruginosa via the airways. Pioglitazone treatment was associated with increased expression of chemokine (Cxcl1, Cxcl2, Ccl20) and cytokine genes (Tnfa, Il6, Cfs3) in bronchial brushes obtained 6 hours after infection. This proinflammatory effect was accompanied by increased expression of Hk2 and Pfkfb3, genes encoding rate limiting enzymes of glycolysis; concurrently, the expression of Sdha, important for maintaining metabolite flux in the tricarboxylic acid cycle, was reduced in bronchial epithelial cells of pioglitazone treated-mice. Pioglitazone inhibited bronchoalveolar inflammatory responses measured in lavage fluid. These results suggest that pioglitazone exerts a selective proinflammatory effect on bronchial epithelial cells during acute P. aeruginosa pneumonia, possibly by enhancing intracellular glycolysis.

Influence of von Willebrand factor on common pathophysiological mechanisms of cerebrovascular diseases and multiple sclerosis

Endothelial dysfunction is a universal pathological mechanism underlying or contributing to the development/progression of many diseases, including cerebrovascular disease and multiple sclerosis. Von Willebrand factor is a multimeric glycoprotein synthesized by endothelial cells and megakaryocytes that participates in a range of physiological and pathological processes, including primary hemostasis and coagulation. It also regulates secretion and transport of a variety of molecules, exerts a proinflammatory effect, modulates angiogenesis and smooth muscle mitotic activity, influences atherogenesis. In this review, we discuss the synthesis, secretion, and regulation of the von Willebrand factor within the context of endothelial dysfunction and other common mechanisms that play a significant role in brain tissue damage in cerebrovascular diseases and multiple sclerosis.

A High-Fish Oil Diet Can Significantly Reshape The Gut Microbiota In Mice

Background: Gut microbiota plays an essential role for human health and recent evidence has revealed the beneficial effects of fish oil supplements on the gut microbiota. The present study was to investigate the influence of fish oil on diet-based gut microbiota changes and colitis in mice and whether pyroptosis plays a role in this process.Results: A high-fish oil diet alleviated colitis, resulted in less weight loss and improved pathological scores. Caspase-1, activated in the dextran sulphate sodium (DSS) group, was suppressed by a high-fish oil diet. AIN-93M significantly decreased the gut microbial diversity of mice, increasing the abundances of Bacteroides and Parabacteroides and decreasing the abundance of Odoribacter. In contrast, gut microbial diversity was maintained in mice fed a high-fish oil diet; the Firmicutes: Bacteroidetes ratio was increased, the abundance of Parabacteroides was increased, and that the abundance of Odoribacter was decreased.Conclusion: AIN-93M can decrease gut microbiota diversity, which may be associated with a potential proinflammatory effect. Fish oil has anti-inflammatory effects. It can also restore and maintain microbial diversity and suppress pyroptosis activation.

Influence of anticholinergic drugs on the development of an experimental periodontitis model

The endogenous microbiome of the oral cavity plays an essential role in the development of periodontal disease. It also has a significant pathogenic effect on the inner-vation of the oral cavity organs. The experimental determination of the effectiveness of various drugs is required for the effective treatment of periodontal disease, and this involves the creation of a model of experimental periodontitis. The objective of this series of studies was to determine the possibility of reproduction of the experimental model of periodontitis and the study of the effects of anticholinergic drugs on the development of an experimental periodontitis model. The reproduction of the experimental model of periodontitis was performed by injecting the gums of rats with solutions of pathogenic factors: lipopolysaccharide, hyaluronidase and trypsin. We aimed to study the effect of anticholinergic drugs (pilocarpine and atropine) on the development of an experimental model of periodontitis after the injection of a hyaluronidase solution (2 mg/ml) into the rats' gums. The study was performed on white Wistar rats. Elastase activity, malonic dialdehyde content, urease activity (bacterial contamination index), lysozyme activity (an indicator of nonspecific immunity), and catalase activity (an antioxidant enzyme) were determined in the homogenate of the studied tissues. The results of a comparative study of the effect of three pathogenic factors (lipopolysaccharide, hyaluronidase, and trypsin) on the activity of elastase in different tissues of experimental animals (gums, tooth pulp, serum, and gastric mucosa) showed that hyaluronidase has the greatest proinflammatory effect. The action of pilocarpine and atropine was determined with an underline experimental periodontitis model. It was shown that both anticholinergic drugs stimulate the inflammatory process in the periodontium and that anticholinergic drugs enhance the proinflammatory effect of hyaluronidase.

Possible therapeutic interventions in COVID-19 induced ARDS by cotinine as an ACE-2 promoter and AT-1R blocker

: In these challenging times of the pandemic, as coronavirus disease 2019 (COVID-19) has taken over the planet, its complications such as acute respiratory distress syndrome (ARDS) have the potential to wipe out a large portion of our population. Whereas a serious lack of ventilators, vaccine being months away makes the condition even worse. That's why promising drug therapy is required. One of them was suggested in this article. It is the angiotensin-converting enzyme-2 (ACE-2) to which the COVID-19 virus binds and upon downregulation of which the pulmonary permeability increases and results in the filling of alveoli by proteinaceous fluids, which finally results in ARDS. ARDS can be assisted by angiotensinII type-1 receptor (AT-1R) blocker and ACE-2 upregulator. AT-1R blocker will prevent vasoconstriction, the proinflammatory effect seen otherwise upon its activation. ACE-2 upregulation will ensure less formation of angiotensin II, vasodilatory effects due to the formation of angiotensin (1-7), increased breakdown of bradykinin at lung level. Overall, decreased vasoconstriction of vessels supplying lungs and decreased vasodilation of lung tissues will ensure decreased pulmonary permeability and eventually relieve ARDS. It should also be considered that all components of the reninangiotensin-aldosterone system (RAAS) are located in the lung tissues. A drug with the least plasma protein binding is required to ensure its distribution across these lung tissues. Cotinine appears to be a promising candidate for COVID-19- induced ARDS. It acts across the board and acts as both an AT-1R blocker, ACE-2 upregulator. It also has a weak plasma protein binding that helps to spread through the lung tissues. In this review, we summarized that cotinine, along with COVID-19 virus replication blocker anti-virals, may prove to be a promising therapy for the treatment of COVID-19 induced ARDS.

Neutrophil-Derived Semaphorin 4D Induces Inflammatory Cytokine Production of Endothelial Cells via Different Plexin Receptors in Kawasaki Disease

Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors—plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1β, IL-6, and IL-8. The disintegrin and metalloproteinase domain 17- (AMAM17-) mediated Sema4D shedding from neutrophils contributed to the elevation of sSema4D in the serum of KD patients. Furthermore, we found that Sema4D induced IL-1β production of HCAECs via plexin B2, whereas it promoted IL-6 and IL-8 production via plexin B1. Moreover, the expression of both plexin B1 and plexin B2 was upregulated in HCAECs treated with KD sera, and silencing of the two plexin receptors suppressed the overexpression of IL-1β, IL-6, and IL-8 in KD serum-treated HCAECs. Thus, our findings indicated that sSema4D released from neutrophils participates in the pathogenesis of KD-CALs by promoting inflammatory cytokine production of ECs via both plexin B1 and plexin B2, and Sema4D may be a novel predictor for KD-CALs and a candidate therapeutic target for anti-inflammatory strategies of KD.

Fish Oil Can Significantly Reshape Diet-Based Gut Microbiota in Mice

Background Studies have demonstrated the influence of diet on the gut microbiota, and recent evidence has revealed the beneficial effects of fish oil supplements on the gut microbiota. The goal of the present study was to investigate the influence of fish oil on diet-based gut microbiota changes in mice. Results AIN-93M significantly decreased the gut microbial diversity of mice, increasing the abundances of Bacteroides and Parabacteroides and decreasing the abundance of Odoribacter. In contrast, gut microbial diversity was maintained in mice fed a fish oil-intensive diet, where the Firmicutes: Bacteroidetes ratio was increased, the abundance of Parabacteroides was increased and that of Odoribacter was decreased. In contrast, the VSL#3 intervention had little influence on gut microbiota diversity, decreasing the abundance of Firmicutes. Conclusions AIN-93M can decrease gut microbiota diversity, which may be associated with a potential proinflammatory effect. Fish oil may have anti-inflammatory effects by restoring and maintaining microbial diversity.