Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, PiO2 = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly ( P < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia.NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti-inflammatory properties, also blocks astrocyte activation in respiratory centers during chronic hypoxia and ventilatory acclimatization. However, minocycline cannot reverse ventilatory acclimatization after it is established. Hence, glial cells may provide signals that initiate but do not sustain ventilatory acclimatization.

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Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

Scientific Reports ◽

10.1038/s41598-021-93918-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rhianna Jones ◽

Kyle Kroll ◽

Courtney Broedlow ◽

Luca Schifanella ◽

Scott Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Rhesus Macaques ◽

Oral Microbiome ◽

Probiotic Supplementation ◽

Siv Infection ◽

Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

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Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH

International Journal of Molecular Sciences ◽

10.3390/ijms22126332 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6332

Author(s):

Nikolaos Perakakis ◽

Pavlina Chrysafi ◽

Michael Feigh ◽

Sanne Skovgard Veidal ◽

Christos S. Mantzoros

Keyword(s):

Mouse Model ◽

Cell Activation ◽

Stellate Cell ◽

Liver Steatosis ◽

Tolerance Test ◽

The Body ◽

Oral Glucose ◽

Alcoholic Fatty Liver ◽

Metabolic Outcomes ◽

Anti Inflammatory

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.

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Perfluorocarbon attenuates response of concanavalin A-stimulated mononuclear blood cells without altering ligand-receptor interaction

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00432.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. L210-L216 ◽

Cited By ~ 7

Author(s):

Dirk Haufe ◽

Thomas Luther ◽

Matthias Kotzsch ◽

Lilla Knels ◽

Thea Koch

Keyword(s):

Cell Surface ◽

Concanavalin A ◽

Blood Cells ◽

Cell Activation ◽

Receptor Interaction ◽

Surface Binding ◽

Cellular Activation ◽

Flow Cytofluorometry ◽

Anti Inflammatory ◽

Mononuclear Blood Cells

Intrapulmonary application of perfluorocarbons (PFC) in acute lung injury is associated with anti-inflammatory effects. A direct impact on leukocytic function may be involved. To further elucidate PFC effects on cellular activation, we compared in an in vitro model the response of concanavalin A (ConA)-stimulated lymphocytes and monocytes exposed to perfluorohexane. We hypothesized that perfluorohexane attenuates the action of the lectin ConA by altering stimulant-receptor interaction on the cell surface. Mononuclear blood cells were stimulated by incubation with ConA in the presence of different amounts of perfluorohexane. The response of lymphocytes and monocytes was determined by means of IL-2 secretion and tissue factor (TF) expression, respectively. The influence of perfluorohexane on cell-surface binding of fluorescence-labeled ConA was studied using flow cytofluorometry and fluorescence microscopy. Perfluorohexane itself did not induce a cellular activation but significantly inhibited both monocytic TF expression and, to a far greater extent, IL-2 secretion of ConA-stimulated mononuclear blood cells. The effect of perfluorohexane was due neither to an alteration of cell viability nor to a binding of the stimulant. The amount of cell surface-bound ConA was not altered by perfluorohexane, and the overall pattern of ConA receptor rearrangement did not differ between controls and treated cells. In the present study, we provide further evidence for an anti-inflammatory effect of PFC that might be beneficial in states of pulmonary hyperinflammation. A PFC-induced alteration of stimulant-receptor interaction on the surface membrane does not seem to be the cause of attenuated cell activation.

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Anti-inflammatory effects of 8-hydroxydeoxyguanosine in LPS-induced microglia activation: suppression of STAT3-mediated intercellular adhesion molecule-1 expression

Experimental & Molecular Medicine ◽

10.1038/emm.2006.49 ◽

2006 ◽

Vol 38 (4) ◽

pp. 417-427 ◽

Cited By ~ 21

Author(s):

Dong Hyun Kim ◽

Ik Hyun Cho ◽

Hong Sook Kim ◽

Joo Eun Jung ◽

Ja Eun Kim ◽

...

Keyword(s):

Adhesion Molecule ◽

Intercellular Adhesion ◽

Microglia Activation ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Anti Inflammatory

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Chronic EDRF inhibition and hypoxia: effects on pulmonary circulation and systemic blood pressure

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.4.1748 ◽

1993 ◽

Vol 75 (4) ◽

pp. 1748-1757 ◽

Cited By ~ 77

Author(s):

V. Hampl ◽

S. L. Archer ◽

D. P. Nelson ◽

E. K. Weir

Keyword(s):

Pulmonary Hypertension ◽

Arterial Pressure ◽

Chronic Hypoxia ◽

Acute Hypoxia ◽

Systemic Blood Pressure ◽

Systemic Circulation ◽

Systemic Arterial Pressure ◽

Hypoxic Pulmonary Hypertension ◽

Basal Tone ◽

Isolated Lungs

It has been suggested that chronic hypoxic pulmonary hypertension results from chronic hypoxic inhibition of endothelium-derived relaxing factor (EDRF) synthesis. We tested this hypothesis by studying whether chronic EDRF inhibition by N omega-nitro-L-arginine methyl ester (L-NAME) would induce pulmonary hypertension similar to that found in chronic hypoxia. L-NAME (1.85 mM) was given for 3 wk in drinking water to rats living in normoxia or hypoxia. Unlike chronic hypoxia, chronic L-NAME treatment did not increase pulmonary arterial pressure. Cardiac output was reduced and mean systemic arterial pressure was increased by chronic L-NAME treatment. The vascular pressure-flow relationship in isolated lungs was shifted toward higher pressures by chronic hypoxia and, to a lesser degree, by L-NAME intake. In isolated lungs, vasoconstriction in response to angiotensin II and acute hypoxia and vasodilation in response to sodium nitroprusside were increased by chronic L-NAME treatment in normoxia and chronic hypoxia. Chronic hypoxia, but not L-NAME, induced hypertensive pulmonary vascular remodeling. Chronic supplementation with the EDRF precursor L-arginine did not have any significant effect on chronic hypoxic pulmonary hypertension. We conclude that the chronic EDRF deficiency state, induced by L-NAME, does not mimic chronic hypoxic pulmonary hypertension in our model. In addition, EDRF proved to be less important for basal tone regulation in the pulmonary than in the systemic circulation.

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Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.1996.270.2.c522 ◽

1996 ◽

Vol 270 (2) ◽

pp. C522-C529 ◽

Cited By ~ 142

Author(s):

M. G. Bouma ◽

F. A. van den Wildenberg ◽

W. A. Buurman

Keyword(s):

Endothelial Cells ◽

Adhesion Molecules ◽

Adhesion Molecule ◽

Vascular Endothelium ◽

Cell Activation ◽

Umbilical Vein ◽

Intercellular Adhesion Molecule ◽

Cytokine Release ◽

Adenosine Deaminase Activity ◽

Anti Inflammatory

Ischemia induces excessive ATP catabolism with subsequent local release of its metabolite adenosine, an autacoid with anti-inflammatory properties. Because activation of the vascular endothelium is critical to the inflammatory host response during ischemia and reperfusion, the effects of adenosine on two major determinants of endothelial cell activation (i.e., the release of proinflammatory cytokines and the expression of adhesion molecules) were studied. Adenosine dose dependently inhibited the release of interleukin (IL)-6 and IL-8 by stimulated human umbilical vein endothelial cells (HUVEC). Expression of E-selectin and vascular cell adhesion molecule 1 (VCAM-1), but not intercellular adhesion molecule 1 (ICAM-1), by activated HUVEC was also reduced by adenosine. Inhibition of endogenous adenosine deaminase activity by erythro-9-(2-hydroxy-3-nonyl)adenine or 2'-deoxycoformycin strongly enhanced the inhibitory effects of exogenous adenosine on cytokine release and expression of E-selectin and VCAM-1. However, a clear role for specific adenosine receptors in the described inhibitory events could not be established. Together, these data imply that the vascular endothelium constitutes an important target for the anti-inflammatory actions of adenosine.

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Anti-inflammatory role of Leptin in glial cells through p38 MAPK pathway inhibition

Pharmacological Reports ◽

10.1016/j.pharep.2016.12.005 ◽

2017 ◽

Vol 69 (3) ◽

pp. 409-418 ◽

Cited By ~ 7

Author(s):

Iván Patraca ◽

Nohora Martínez ◽

Oriol Busquets ◽

Aleix Martí ◽

Ignacio Pedrós ◽

...

Keyword(s):

P38 Mapk ◽

Glial Cells ◽

Mapk Pathway ◽

P38 Mapk Pathway ◽

Anti Inflammatory ◽

Pathway Inhibition

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Role of Harmaline as Adiponectin Modulator in Defeating Liver Cirrhosis Induced By Thioacetamide in Mice

Biomedical & Pharmacology Journal ◽

10.13005/bpj/2106 ◽

2021 ◽

Vol 14 (1) ◽

pp. 123-131

Author(s):

Doha M. Beltagy ◽

Khloud Gamal Abdelsalam ◽

Tarek M Mohamed ◽

Mai M. El-Keey

Keyword(s):

Oxidative Stress ◽

Liver Cirrhosis ◽

Transforming Growth Factor Beta ◽

Liver Tissue ◽

Cell Activation ◽

Transforming Growth Factor ◽

Stellate Cell ◽

Matrix Deposition ◽

Anti Inflammatory ◽

Tgf Β1

Liver cirrhosis is currently the 11th most common cause of death which includes inflammatory, oxidative damage, and immune response. Harmaline has antioxidant and anti-inflammatory mechanisms which can defeat against hepatic cirrhosis pathways. The present work aimed to evaluate the ameliorating effect of harmaline against liver cirrhosis induced by thioacetamide in mice. The study was carried out on sixty male mice divided into three main groups. Control and harmaline groups (GIa and GIb), thioacetamide-group (GII) and harmaline co-treated and treated groups (GIIIa and GIIIb). By the end of the experiment, adiponectin concentrations were measured in serum and liver tissue. Gene expression of adiponectin, transforming growth factor beta-1 (TGF-β1), tissue inhibitor metalloprotease-1(TIMP-1) and peroxisome proliferator activated receptor-gamma (PPAR-γ) were assessed. Some oxidative stress biomarkers as malondialdehyde, reduced glutathione, catalase, superoxide dismutase and nitric oxide were determined. The results indicated that harmaline administration cause significant suppression of oxidative stress and inflammatory response.Inhibition of hepatic stellate cell activation and extracellular matrix deposition were also noticed with a significant decrease in the expression of the profibrotic markers(TGF-β1 and TIMP-1) which have direct effects on adiponectin activation. These results were confirmed by the histological studies in liver tissue. In Conclusion,Harmaline has excellent protective role against liver cirrhosis induced by thioacetamide in mice via its antioxidant and anti-inflammatory properties.It can be therapeutically used as a safe liver support by a dose of 10 mg/kg after furtherin vivo studies.

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