Connexin 43 and Pannexin 1 hemichannels as endogenous regulators of innate immunity in sepsis.

Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infections that is initiated by the body's innate immune system. Nearly a decade ago, we discovered that bacterial lipopolysaccharide (LPS) and serum amyloid A (SAA) upregulated Connexin 43 (Cx43) and Pannexin 1 (Panx1) hemichannels in macrophages. When overexpressed, these hemichannels contribute to sepsis pathogenesis by promoting ATP efflux, which intensifies the double-stranded RNA-activated protein kinase R (PKR)-dependent inflammasome activation, pyroptosis, and the release of pathogenic damage-associated molecular pattern (DAMP) molecules, such as HMGB1.

Elevated Circulating Procathepsin L as a Potential Biomarker of Inflamm-aging.

Inflamm-aging is a condition of low-grade and chronic systemic inflammation characterized by a systemic increase in multiple inflammatory biomarkers such as tumor necrosis factor (TNF), interleukin 6 (IL-6), C-reactive protein (CRP), and CXCL9 (MIG) in experimental and clinical settings. However, despite the recent identification of extracellular procathepsin L (pCTS-L) as a novel mediator of inflammatory diseases such as sepsis, its possible role in inflamm-aging was previously not investigated. In the present study, we compared blood levels of pCTS-L and other 62 cytokines and chemokines between young and aged Balb/C mice by Western blotting and Cytokine Antibody Arrays.

Therapeutic potential of procathepsin L-inhibiting and progesterone-entrapping dimethyl-β-cyclodextrin nanoparticles in treating experimental sepsis.

The pathogenic mechanisms of bacterial infections and resultant sepsis are partly attributed to dysregulated inflammatory responses sustained by some late-acting mediators including the procathepsin-L (pCTS-L). It was entirely unknown whether any compounds of the U.S.

A two-decade journey in identifying high mobility group box 1 (HMGB1) and procathepsin L (pCTS-L) as potential therapeutic targets for sepsis.

Introduction: Microbial infections and resultant sepsis are leading causes of death in hospitals, representing approximately 20% of total deaths worldwide. Despite the difficulties in translating experimental insights into effective therapies for often heterogenous patient populations, an improved understanding of the pathogenic mechanisms underlying experimental sepsis is still urgently needed. Sepsis is partly attributable to dysregulated innate immune responses manifested by hyperinflammation and immunosuppression at different stages of microbial infections.

Development of Procathepsin L (pCTS-L)-Inhibiting Lanosterol-Carrying Liposome Nanoparticles to Treat Lethal Sepsis.

The pathogenesis of microbial infections and sepsis is partly attributable to dysregulated innate immune responses propagated by late-acting proinflammatory mediators such as procathepsin L (pCTS-L). It was previously not known whether any natural product could inhibit pCTS-L-mediated inflammation or could be strategically developed into a potential sepsis therapy. Here, we report that systemic screening of a NatProduct Collection of 800 natural products led to the identification of a lipophilic sterol, lanosterol (LAN), as a selective inhibitor of pCTS-L-induced production of cytokines [e.

Identification of procathepsin L (pCTS-L)-neutralizing monoclonal antibodies to treat potentially lethal sepsis.

Antibody-based strategies have been attempted to antagonize early cytokines of sepsis, but not yet been tried to target inducible late-acting mediators. Here, we report that the expression and secretion of procathepsin-L (pCTS-L) was induced by serum amyloid A (SAA) in innate immune cells, contributing to its late and systemic accumulation in experimental and clinical sepsis. Recombinant pCTS-L induced interleukin-6 (IL-6), IL-8, GRO-α/KC, GRO-β/MIP-2, and MCP-1 release in innate immune cells and moderately correlated with blood concentrations of these cytokines/chemokines in clinical sepsis.

Human Dermcidin Protects Mice Against Hepatic Ischemia-Reperfusion-Induced Local and Remote Inflammatory Injury.

Background: Hepatic ischemia and reperfusion (I/R) injury is commonly associated with surgical liver resection or transplantation, and represents a major cause of liver damage and graft failure. Currently, there are no effective therapies to prevent hepatic I/R injury other than ischemic preconditioning and some preventative strategies. Previously, we have revealed the anti-inflammatory activity of a sweat gland-derived peptide, dermcidin (DCD), in macrophage/monocyte cultures.

Endogenous Regulation and Pharmacological Modulation of Sepsis-Induced HMGB1 Release and Action: An Updated Review.

Sepsis remains a common cause of death in intensive care units, accounting for approximately 20% of total deaths worldwide. Its pathogenesis is partly attributable to dysregulated inflammatory responses to bacterial endotoxins (such as lipopolysaccharide, LPS), which stimulate innate immune cells to sequentially release early cytokines (such as tumor necrosis factor (TNF) and interferons (IFNs)) and late mediators (such as high-mobility group box 1, HMGB1). Despite difficulties in translating mechanistic insights into effective therapies, an improved understanding of the complex mechanisms underlying the pathogenesis of sepsis is still urgently needed.

Monoclonal antibodies capable of binding SARS-CoV-2 spike protein receptor-binding motif specifically prevent GM-CSF induction.

A severe acute respiratory syndrome (SARS)-like coronavirus 2 (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected approximately 94 million and killed more than 2,000,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibodies that can inhibit virus-ACE2 interaction to prevent viral entry.

Monoclonal Antibodies Capable of Binding SARS-CoV-2 Spike Protein Receptor Binding Motif Specifically Prevent GM-CSF Induction.

Unlabelled: A severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected more than 25.6 million and killed 852,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry.

Identification of tetranectin-targeting monoclonal antibodies to treat potentially lethal sepsis.

For the clinical management of sepsis, antibody-based strategies have only been attempted to antagonize proinflammatory cytokines but not yet been tried to target harmless proteins that may interact with these pathogenic mediators. Here, we report an antibody strategy to intervene in the harmful interaction between tetranectin (TN) and a late-acting sepsis mediator, high-mobility group box 1 (HMGB1), in preclinical settings. We found that TN could bind HMGB1 to reciprocally enhance their endocytosis, thereby inducing macrophage pyroptosis and consequent release of lactate dehydrogenase and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain.

Association between fecal microbiota and generalized anxiety disorder: Severity and early treatment response.

Background: Associations between abnormal gut microbiome compositions and anxiety-like behaviors are well established. However, it is unknown whether the gut microbiome composition is associated with the severity of generalized anxiety disorder (GAD) and relief from clinical symptoms in patients.

Methods: Stool samples from 36 patients with active GAD (A-GAD group) and 24 matched healthy control subjects (HC group) were analyzed by 16S rRNA gene sequencing.

Enhanced Macrophage Pannexin 1 Expression and Hemichannel Activation Exacerbates Lethal Experimental Sepsis.

We have recently reported an important role of Connexin 43 (Cx43) hemichannels in the pathogenesis of lethal sepsis through facilitating ATP efflux to potentiate the double-stranded RNA-activated protein kinase R (PKR)-dependent macrophage activation. Here we further elucidated the possible role of Pannexin 1 (Panx1) hemichannel in lethal sepsis by assessing its expression along with the impact of a Panx1-specific mimetic inhibitory peptide, 10Panx, on macrophage hemichannel activity in vitro and animal sepsis lethality in vivo. Both crude bacterial lipopolysaccharide (LPS) and purified serum amyloid A (SAA) effectively induced the expression and extracellular release of Panx1 by macrophages or monocytes as judged by Western blotting and immunocytochemistry assays.

Connexin 43 Hemichannel as a Novel Mediator of Sterile and Infectious Inflammatory Diseases.

Cytoplasmic membrane-bound connexin 43 (Cx43) proteins oligomerize into hexameric channels (hemichannels) that can sometimes dock with hemichannels on adjacent cells to form gap junctional (GJ) channels. However, the possible role of Cx43 hemichannels in sterile and infectious inflammatory diseases has not been adequately defined due to the lack of selective interventions. Here we report that a proinflammatory mediator, the serum amyloid A (SAA), resembled bacterial endotoxin by stimulating macrophages to up-regulate Cx43 expression and double-stranded RNA-activated protein kinase R (PKR) phosphorylation in a TLR4-dependent fashion.

New melanocortin-like peptide of can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut.

releases a 33 amino acid peptide melanocortin-like peptide of (MECO-1) that is identical to the C-terminus of the elongation factor-G (EF-G) and has interesting similarities to two prominent mammalian melanocortin hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH). Note that MECO-1 lacks HFRW, the common pharmacophore of the known mammalian melanocortin peptides. MECO-1 and the two hormones were equally effective in severely blunting release of cytokines (HMGB1 and TNF) from macrophage-like cells in response to (i) endotoxin (lipopolysaccharide) or (ii) pro-inflammatory cytokine HMGB-1.

The in Vitro Immune-Modulating Properties of a Sweat Gland-Derived Antimicrobial Peptide Dermcidin.

The epidermal barriers of the skin serve as the first layer of defense by limiting the access of many pathogens to the blood circulation. In addition, human skin also contains sweat glands that can secrete a wide array of antimicrobial peptides to restrain the growth of various microbes. In the case of microbial infection, macrophages and monocytes constitute the first line of defense by producing a wide array of proinflammatory cytokines and chemokines.

Cold-inducible RNA-binding protein mediates neuroinflammation in cerebral ischemia.

Background: Neuroinflammation is a key cascade after cerebral ischemia. Excessive production of proinflammatory mediators in ischemia exacerbates brain injury. Cold-inducible RNA-binding protein (CIRP) is a newly discovered proinflammatory mediator that can be released into the circulation during hemorrhage or septic shock.

Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis.

A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation.

Expression and characterization of recombinant human milk fat globule-EGF factor VIII.

Apoptosis plays an important role in the patho-biology of sepsis. The opsonizing protein milk fat globule-EGF factor VIII (MFG-E8) is involved in apoptotic cell clearance. Our previous studies have shown that administration of rat MFG-E8-containing exosomes or recombinant murine MFG-E8 (rmMFG-E8) is protective in a rat model of sepsis induced by cecal ligation of puncture (CLP).

Peripheral administration of human adrenomedullin and its binding protein attenuates stroke-induced apoptosis and brain injury in rats.

Stroke is a leading cause of death and the primary medical cause of acquired adult disability worldwide. The progressive brain injury after acute stroke is partly mediated by ischemia-elicited inflammatory responses. The vasoactive hormone adrenomedullin (AM), upregulated under various inflammatory conditions, counterbalances inflammatory responses.

Upregulation of Kupffer cell α2A-Adrenoceptors and downregulation of MKP-1 mediate hepatic injury in chronic alcohol exposure.

Alcohol-induced liver disease is associated with unacceptable morbidity and mortality. When activated, Kupffer cells (KCs), the resident macrophages in the liver, release proinflammatory cytokine TNF-α, a key mediator of hepatic damage. Although chronic alcohol causes increase in norepinephrine (NE) release leading to hepatic dysfunction, the mechanism of NE-induced hepatic injury in chronic alcohol exposure has not been elucidated.

Milk fat globule EGF factor 8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.

Background: Despite advances in our understanding of excessive alcohol-intake-related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor-factor VIII (MFG-E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG-E8 ameliorates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.

Antagonism of alpha2A-adrenoceptor: a novel approach to inhibit inflammatory responses in sepsis.

Sepsis is a systemic inflammatory response syndrome (SIRS) when an infection is the etiology of SIRS. Our previous studies have indicated that the release of the sympathetic neurotransmitter, norepinephrine (NE), from the gut is increased in sepsis, and that NE potentiates endotoxin-induced tumor necrosis factor (TNF)-alpha upregulation via the A subtype of alpha(2)-adrenoceptors (i.e.

Orexigenic hormone ghrelin ameliorates gut barrier dysfunction in sepsis in rats.

Objectives: We have recently shown that ghrelin, a novel orexigenic hormone, is reduced in sepsis. Ghrelin treatment, mediated through ghrelin receptors in the brain, attenuates sepsis-induced inflammation and mortality. Gut barrier dysfunction is common in sepsis.