The Impact of Fructo-Oligosaccharides on Gut Permeability and Inflammatory Responses in the Cecal Mucosa Quite Differs between Rats Fed Semi-Purified and Non-Purified Diets

AbstractBacteroides fragilis(BF) is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses suggesting its potential to induce pro-inflammatory responses, upon accessing the systemic compartment. Hence, we examined the impact of mucosal and systemic exposures to BF on type 1 diabetes (T1D) incidence in non-obese diabetic (NOD) mice. The impact of intestinal exposure to BF under chemically-induced enhanced gut permeability condition, which permits microbial translocation, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and suppression of autoimmunity resulting in delayed hyperglycemia, mice that received HK BF by i.v. injection showed rapid disease progression. Importantly, polysaccharide-A deficient (ΔPSA) BF failed to produce these opposing effects upon oral and systemic deliveries. Further, BF induced modulation of disease progression was observed in WT, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under enhanced gut permeability condition resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause pro-inflammatory responses upon gaining access to systemic compartment and contribute to T1D in at-risk subjects.

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AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

Scientific Reports ◽

10.1038/s41598-021-90573-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nathaniel B. Bone ◽

Eugene J. Becker ◽

Maroof Husain ◽

Shaoning Jiang ◽

Anna A. Zmijewska ◽

...

Keyword(s):

Bacterial Infections ◽

Pathogenic Bacteria ◽

Inflammatory Responses ◽

Abdominal Sepsis ◽

Immune Defense ◽

Bacterial Killing ◽

Lung Infections ◽

Sepsis Survivors ◽

The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

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Parenteral Fish-Oil Containing Lipid Emulsions Limit Initial Lipopolysaccharide-Induced Host Immune Responses in Preterm Pigs

Nutrients ◽

10.3390/nu13010205 ◽

2021 ◽

Vol 13 (1) ◽

pp. 205

Author(s):

William Yakah ◽

David Ramiro-Cortijo ◽

Pratibha Singh ◽

Joanne Brown ◽

Barbara Stoll ◽

...

Keyword(s):

Fatty Acid ◽

Fish Oil ◽

Soybean Oil ◽

Inflammatory Responses ◽

Postnatal Period ◽

Lipid Emulsions ◽

Omega 3 ◽

Oil Emulsion ◽

Mixed Oil ◽

The Impact

Multicomponent lipid emulsions are available for critical care of preterm infants. We sought to determine the impact of different lipid emulsions on early priming of the host and its response to an acute stimulus. Pigs delivered 7d preterm (n = 59) were randomized to receive different lipid emulsions for 11 days: 100% soybean oil (SO), mixed oil emulsion (SO, medium chain olive oil and fish oil) including 15% fish oil (MO15), or 100% fish oil (FO100). On day 11, pigs received an 8-h continuous intravenous infusion of either lipopolysaccharide (LPS—lyophilized Escherichia coli) or saline. Plasma was collected for fatty acid, oxylipin, metabolomic, and cytokine analyses. At day 11, plasma omega-3 fatty acid levels in the FO100 groups showed the highest increase in eicosapentaenoic acid, EPA (0.1 ± 0.0 to 9.7 ± 1.9, p < 0.001), docosahexaenoic acid, DHA (day 0 = 2.5 ± 0.7 to 13.6 ± 2.9, p < 0.001), EPA and DHA-derived oxylipins, and sphingomyelin metabolites. In the SO group, levels of cytokine IL1β increased at the first hour of LPS infusion (296.6 ± 308 pg/mL) but was undetectable in MO15, FO100, or in the animals receiving saline instead of LPS. Pigs in the SO group showed a significant increase in arachidonic acid (AA)-derived prostaglandins and thromboxanes in the first hour (p < 0.05). No significant changes in oxylipins were observed with either fish-oil containing group during LPS infusion. Host priming with soybean oil in the early postnatal period preserves a higher AA:DHA ratio and the ability to acutely respond to an external stimulus. In contrast, fish-oil containing lipid emulsions increase DHA, exacerbate a deficit in AA, and limit the initial LPS-induced inflammatory responses in preterm pigs.

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A sand fly salivary protein acts as a neutrophil chemoattractant

Nature Communications ◽

10.1038/s41467-021-23002-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anderson B. Guimaraes-Costa ◽

John P. Shannon ◽

Ingrid Waclawiak ◽

Jullyanna Oliveira ◽

Claudio Meneses ◽

...

Keyword(s):

Inflammatory Responses ◽

Calcium Influx ◽

Parasite Burden ◽

Salivary Protein ◽

Sand Fly ◽

Human Neutrophils ◽

Chemotactic Protein ◽

The Impact

AbstractApart from bacterial formyl peptides or viral chemokine mimicry, a non-vertebrate or insect protein that directly attracts mammalian innate cells such as neutrophils has not been molecularly characterized. Here, we show that members of sand fly yellow salivary proteins induce in vitro chemotaxis of mouse, canine and human neutrophils in transwell migration or EZ-TAXIScan assays. We demonstrate murine neutrophil recruitment in vivo using flow cytometry and two-photon intravital microscopy in Lysozyme-M-eGFP transgenic mice. We establish that the structure of this ~ 45 kDa neutrophil chemotactic protein does not resemble that of known chemokines. This chemoattractant acts through a G-protein-coupled receptor and is dependent on calcium influx. Of significance, this chemoattractant protein enhances lesion pathology (P < 0.0001) and increases parasite burden (P < 0.001) in mice upon co-injection with Leishmania parasites, underlining the impact of the sand fly salivary yellow proteins on disease outcome. These findings show that some arthropod vector-derived factors, such as this chemotactic salivary protein, activate rather than inhibit the host innate immune response, and that pathogens take advantage of these inflammatory responses to establish in the host.

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SARS-Coronavirus 2, A Metabolic Reprogrammer: A Review in the Context of the Possible Therapeutic Strategies

Current Drug Targets ◽

10.2174/1389450122666210917113842 ◽

2021 ◽

Vol 22 ◽

Author(s):

Poornima Gopi ◽

TR Anju ◽

Vinod Soman Pillai ◽

Mohanan Veettil

Keyword(s):

Virus Infection ◽

Host Cell ◽

Metabolic Pathways ◽

Inflammatory Responses ◽

Membrane Lipid ◽

Therapeutic Strategies ◽

Metabolic Reprogramming ◽

Multiple Organs ◽

The Cross ◽

The Impact

: Novel coronavirus, SARS-CoV-2 is advancing at a staggering pace to devastate the health care system and foster the concerns over public health. In contrast to the past outbreaks, coronaviruses aren’t clinging themselves as a strict respiratory virus. Rather, becoming a multifaceted virus, it affects multiple organs by interrupting a number of metabolic pathways leading to significant rates of morbidity and mortality. Following infection they rigorously reprogram multiple metabolic pathways of glucose, lipid, protein, nucleic acid and their metabolites to extract adequate energy and carbon skeletons required for their existence and further molecular constructions inside a host cell. Although the mechanism of these alterations are yet to be known, the impact of these reprogramming is reflected in the hyper inflammatory responses, so called cytokine storm and the hindrance of host immune defence system. The metabolic reprogramming during SARS-CoV-2 infection needs to be considered while devising therapeutic strategies to combat the disease and its further complication. The inhibitors of cholesterol and phospholipids synthesis and cell membrane lipid raft of the host cell can, to a great extent, control the viral load and further infection. Depletion of energy source by inhibiting the activation of glycolytic and hexoseamine biosynthetic pathway can also augment the antiviral therapy. The cross talk between these pathways also necessitates the inhibition of amino acid catabolism and tryptophan metabolism. A combinatorial strategy which can address the cross talks between the metabolic pathways might be more effective than a single approach and the infection stage and timing of therapy will also influence the effectiveness of the antiviral approach. We herein focus on the different metabolic alterations during the course of virus infection that help to exploit the cellular machinery and devise a therapeutic strategy which promotes resistance to viral infection and can augment body’s antivirulence mechanisms. This review may cast the light into the possibilities of targeting altered metabolic pathways to defend virus infection in a new perspective.

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The Impact of Oxidative Stress on Dental Implants

European Journal of Dental and Oral Health ◽

10.24018/ejdent.2021.2.1.37 ◽

2021 ◽

Vol 2 (1) ◽

pp. 1-8

Author(s):

César Esquivel-Chirino ◽

Juan Carlos Gómez-Landeros ◽

Erika Patricia Carabantes-Campos ◽

Daniela Carmona-Ruiz ◽

Yolanda Valero-Princet ◽

...

Keyword(s):

Oxidative Stress ◽

Dental Implants ◽

Alveolar Bone ◽

Inflammatory Responses ◽

Cell Damage ◽

Pathological Condition ◽

Periodontal Diseases ◽

Tissue Destruction ◽

Waste Products ◽

The Impact

Periodontal disease is an inflammatory condition that alters the periodontium, resulting in destruction of the alveolar bone; without treatment the condition may lead to tooth loss. Dental implants are an alternative for substitution of naturally lost teeth as they have high success rates; however, some factors are related to its failure. Peri-implantitis (PI) is a pathological condition that affects the tissues surrounding dental implants and has been reported as the major cause of implant failure; PI and periodontal diseases are characterized by tissue inflammation and bone damage. In homeostasis conditions, reactive oxygen species (ROS) have been shown to be involved in cell maintenance, signal transduction, and repair of all tissues, but ROS overaccumulation leads to oxidative stress, which generates cell damage and tissue destruction; likewise, antioxidants protect against the destructive effects of ROS by turning free radicals into waste products. The main purpose of this review was to determine some aspects of inflammatory responses and oxidative stress and analyze their relationship with the lack of osseointegration and PI.

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Comparative Study of Physiological and Haematological Parameters among Mild and Severe COVID-19 Patients Admitted in Tertiary Care Hospital of Pune District, India

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i36b31960 ◽

2021 ◽

pp. 132-139

Author(s):

Suchita Sachin Palve ◽

Pallavi Sachin Chaudhari

Keyword(s):

Inflammatory Responses ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Specific Treatment ◽

Haematological Parameters ◽

Care Hospital ◽

Physiological Variables ◽

The World ◽

High Level ◽

The Impact

Background: The COVID-19 pandemic has put global health at stake by creating havoc all over the world, due to which the world, as well as health agencies, are experiencing the greatest challenges. This disease is a health emergency due to its high level of infectiousness and the non-availability of any specific treatment [1]. Objectives: To determine and compare the significance of physiological and haematological parameters in the diagnosis of COVID 19 infection and compare the association of physiological and haematological parameters among mild and severe COVID-19 patients. Methodology: The present comparative, observational study was carried out in a designated tertiary care hospital, where admission of COVID19 patients in Pune district, India. Various parameters like age, height, weight, BMI, various physiological variables, haematological parameters, and CRP levels were assessed among 202 Mild and 50 severe COVID 19 diagnosed patients on day one of the hospital's stays. Results: Pearson’s correlation coefficient showed a significant correlation among physiological and haematological variables compared to both groups, especially physiological parameters like SBP and DBP. The results showed that TLC, CRP, NLR, PLR, among COVID 19 patients cans work as important biomarkers to understand the disease prognosis. Conclusion: Study of physiological and haematological parameters and their interrelation will help in understanding the impact of COVID 19 infection on the reactive inflammatory responses and help in understanding the prognosis of the disease among mild and severe patients.

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Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in β Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/7726058 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Hongbo Guan ◽

Yanyan Guo ◽

Liangliang Zhu ◽

Yisheng Jiao ◽

Xiaomei Liu

Keyword(s):

Fatty Acid ◽

Inflammatory Responses ◽

Cell Mass ◽

Vital Role ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Peroxisomal Biogenesis ◽

Wide Range ◽

The Impact

An adverse intrauterine environment impairs the development of pancreatic islets in the fetus and leads to insufficient β cell mass and β cell dysfunction. We previously reported that Pex14, a peroxin protein involved in the biogenesis and degradation of peroxisomes, is markedly reduced in the pancreas of an intrauterine growth restriction fetus and last into adulthood. Peroxisomes function in a wide range of metabolic processes including fatty acid oxidization, ROS detoxification, and anti-inflammatory responses. To elucidate the impact of downregulation of the Pex14 gene on β cell, Pex14 was knocked down by siRNA in INS-1 cells. Pex14 knockdown disturbed peroxisomal biogenesis and dysregulated fatty acid metabolism and lipid storage capability, thereby increased ROS level and blunted insulin secretion. Moreover, Pex14 knockdown upregulated inflammation factors and regulators of endoplasmic reticulum stress. The lipotoxicity of fatty acid (including palmitic acid and linoleic acid) in β cells was exacerbated by knockdown of Pex14, as indicated by H2O2 accumulation and increased programmed cell death. The present results demonstrate the vital role of Pex14 in maintaining normal peroxisome function and β cell viability and highlight the importance of a functional peroxisomal metabolism for the detoxification of excess FAs in β cells.

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Abstract 19409: β2-Adrenergic Receptor Regulation of Innate Immune Responses Following Acute Myocardial Injury

Circulation ◽

10.1161/circ.132.suppl_3.19409 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Laurel A Grisanti ◽

Anna Gumpert ◽

Joshua Gorsky ◽

Ashley A Repas ◽

Erhe Gao ◽

...

Keyword(s):

Immune Responses ◽

Adrenergic Receptor ◽

Inflammatory Responses ◽

Critical Role ◽

Cellular Migration ◽

Chimeric Mouse ◽

Ccr2 Expression ◽

Β2 Adrenergic Receptor ◽

The Impact

Inflammatory responses are important for cardiac remodeling and tissue repair after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune responses, in large part through the β2-adrenergic receptor (β2AR), however the influence of β2AR in regulating the inflammatory response following MI is unknown. Thus, to examine the contribution of β2AR on immune cells following MI, wild-type (WT) mice were irradiated and then received β2ARKO or WT control bone marrow (BM) transplants to create immune cell-specific knockout (KO) animals. Lack of β2AR expression in BM resulted in 100% mortality from cardiac rupture within two weeks of receiving MI, in contrast to their WT counterparts that had ∼20% death. Granulocyte populations were sequestered in the spleen of β2ARKO chimeric mice resulting in reductions in post-MI infiltration of monocyte/macrophage, neutrophil and mast cell populations into the heart. Additionally, alterations in chemokine receptor levels, particularly CCR2, on BM resulted in decreased cellular migration, and use of a CCR2 antagonist in vivo recapitulated the β2ARKO chimeric mouse phenotype following MI. Administration of β2AR agonists in vitro and in vivo increased CCR2 expression and BM migration while β2AR antagonists decreased CCR2 expression and increased splenic leukocyte retention in vivo . Use of pepducins as allosteric modulators of β2AR signaling demonstrated the importance of β-arrestin-mediated signaling in increasing CCR2 expression and responses. The impact of β2AR deletion on BM cell CCR2 expression and migration, splenic retention of leukocytes and reciprocal cardiac leukocyte infiltration following MI could be reversed via lentivirus-mediated β2AR rescue in the β2ARKO BM prior to transplantation. These results demonstrate the critical role of β2AR in the regulation of CCR2 expression on hematopoietic cells and its importance in mounting an immune response to promote healing following acute cardiac injury.

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Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

10.21203/rs.3.rs-24932/v1 ◽

2020 ◽

Author(s):

Yinquan Fang ◽

Qingling Jiang ◽

Shanshan Li ◽

Hong Zhu ◽

Xiao Ding ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Models ◽

Inflammatory Responses ◽

Microglia Activation ◽

Loss Of Function ◽

Neuron Loss ◽

Primary Mouse ◽

The Impact

Abstract Background Although β-arrestins (ARRBs) regulate diverse physiological and pathophysiological processes, their function and regulation in Parkinson’s disease (PD) remain poorly defined. Methods We measured expression of ARRB1 and ARRB2 in liposaccharide (LPS)-induced and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. ARRB1-deficient and ARRB2-deficient mouse were used to assess the impact of ARRBs on dopaminergic (DA) neuron loss and microglia activation in PD mouse models. After primary mouse DA neurons were exposed to the conditioned medium from ARRB1 knockdown or ARRB2 knockout microglia stimulated by LPS plus interferon γ (IFN-γ), the degeneration of DA neurons was quantified. Gain- and loss-of-function studies were used to study the effects of ARRBs on microglia activation in vitro. To further understand the mechanism, we measured the activation of classical inflammatory pathways and used RNA sequencing to identify the novel downstream effector of ARRBs. Result In this study, we demonstrate that expression of ARRB1 and ARRB2, particularly in microglia, is reciprocally regulated in PD mouse models. ARRB1 ablation ameliorates, whereas ARRB2 knockout aggravates, the pathological features of PD, including DA neuron loss, neuroinflammation and microglia activation in vivo, as well as microglia-mediated neuron damage and inflammation in vitro. In parallel, ARRB1 and ARRB2 produce adverse effects on the activation of inflammatory signal transducers and activators of transcription 1 (STAT1) and nuclear factor-κB (NF-κB) pathways in microglia. We also show that two ARRBs competitively interact with activated p65 in the NF-κB pathway and that nitrogen permease regulator-like 3 (Nprl3), a functionally poorly characterized protein, is a novel effector acting downstream of both ARRBs. Conclusion Collectively, these data demonstrate that two closely related ARRBs have completely opposite functions in microglia-mediated inflammatory responses, via Nprl3, and differentially affect the pathogenesis of PD, and suggest a potential therapeutic strategy.

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