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In recent years, research has unveiled the significant role of hydrogen sulfide (H2S) in many physiological and pathological processes. The role of endogenous H2S, H2S donors, and inhibitors has been the subject of studies that have aimed to investigate this intriguing molecule. The mechanisms by which H2S contributes to different diseases, including inflammatory conditions, cardiovascular disease, viral infections, and neurological disorders, are complex. Despite noteworthy progress, several questions remain unanswered. H2S donors and inhibitors have shown significant therapeutic potential for various diseases. This review summarizes our current understanding of H2S-based therapeutics in inflammatory conditions, cardiovascular diseases, viral infections, and neurological disorders. [ABSTRACT FROM AUTHOR]

Tightly controlled inflammation is an indispensable mechanism in the maintenance of cellular and organismal homeostasis in living organisms. However, aberrant inflammation is detrimental and has been suggested as a key contributor to organ injury with different etiologies. Substance P (SP) is a neuropeptide with a robust effect on inflammation. The proinflammatory effects of SP are achieved by activating its functional receptors, namely the neurokinin 1 receptor (NK1R) receptor and mas-related G protein-coupled receptors X member 2 (MRGPRX2) and its murine homolog MRGPRB2. Upon activation, the receptors further signal to several cellular signaling pathways involved in the onset, development, and progression of inflammation. Therefore, excessive SP–NK1R or SP–MRGPRX2/B2 signals have been implicated in the pathogenesis of inflammation-associated organ injury. In this review, we summarize our current knowledge of SP and its receptors and the emerging roles of the SP–NK1R system and the SP–MRGPRX2/B2 system in inflammation and injury in multiple organs resulting from different pathologies. We also briefly discuss the prospect of developing a therapeutic strategy for inflammatory organ injury by disrupting the proinflammatory actions of SP via pharmacological intervention. [ABSTRACT FROM AUTHOR]

The aim of this issue is to highlight novel findings or hypotheses in amino acid metabolism and regulation, especially in terms of health and disease, beyond its fundamental roles as protein constituents and nutrition (e.g., the major nitrogen sources). Therefore, slightly low protein diets with less than 4% reduced crude protein plus first four limiting amino acids (lysine (Lys), Met, threonine, and Trp) are used to improve nitrogen secretion, diarrhea, and gut health with no negative impacts of their growth performance. Four Seminal Reviews Kumar et al. 2021 overviewed the roles of hydrogen sulfide (H SB 2 sb S, a gasotransmitter with potent/diverse physiological functions that enzymatically derives from sulfur-containing amino acids), substance P (an eleven-amino-acid neuropeptide involved in vasodilation, inflammation, and pain), and adhesion molecules, including ICAM-1, VCAM-1, and selectins, in acute pancreatitis, one of the main reasons for hospitalization amongst gastrointestinal disorders [[15]]. The Special Issue "Amino Acid Metabolism and Regulation in Health and Disease 2.0", edited by us, is the successor of the previous "Amino Acid Metabolism and Regulation in Health and Disease", edited by Dr. Hieronim Jakubowski (New Jersey Medical School) and us. [Extracted from the article]

Significance: Inflammation is a normal response to injury, but uncontrolled inflammation can lead to several diseases. In recent years, research has shown endogenously synthesized hydrogen sulfide (H2S) to be a novel mediator of inflammation. This review summarizes the current understanding and recent advances of H2S role with respect to inflammation in different diseases. Recent Advances: Promising early results from clinical studies suggest an important role of H2S in human inflammatory disease. Critical Issues: Defining the precise mechanism by which H2S contributes to inflammation is a complex challenge, and there is active ongoing research that is focused on addressing this question. Most of this work has been conducted on animal models of human disease and isolated/cultured cells, and its translation to the clinic is another challenge in the area of H2S research. Future Directions: Defining the mechanism by which H2S acts as an inflammatory mediator will help us better understand different inflammatory diseases and help develop novel therapeutic approaches for these diseases. [ABSTRACT FROM AUTHOR]

Substance P (SP), encoded by the Tac1 gene, has been shown to promote leukocyte infiltration and organ impairment in mice with sepsis. Neurokinin-1 receptor (NK1R) is the major receptor that mediates the detrimental impact of SP on sepsis. This investigation studied whether SP affects the expression of adhesion molecules, including intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) on vascular endothelial cells in the liver and lungs, contributing to leukocyte infiltration in these tissues of mice with sepsis. Sepsis was induced by caecal ligation and puncture (CLP) surgery in mice. The actions of SP were inhibited by deleting the Tac1 gene, blocking NK1R, or combining these two methods. The activity of myeloperoxidase and the concentrations of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, were measured. The activity of myeloperoxidase and the concentration of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, increased in mice with CLP surgery-induced sepsis. Suppressing the biosynthesis of SP and its interactions with NK1R attenuated CLP surgery-induced alterations in the liver and lungs of mice. Our findings indicate that SP upregulates the expression of ICAM1 and VCAM1 on vascular endothelial cells in the liver and lungs, thereby increasing leukocyte infiltration in these tissues of mice with CLP surgery-induced sepsis by activating NK1R. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is a well-known toxic gas that is synthesized in the human body from the amino acids cystathionine, homocysteine, and cysteine by the action of at least two distinct enzymes: cystathionine-γ-lyase and cystathionine-β-synthase. In the past few years, H2S has emerged as a novel and increasingly important biological mediator. Imbalances in H2S have also been shown to be associated with various disease conditions. However, defining the precise pathophysiology of H2S is proving to be a complex challenge. Recent research in our laboratory has shown H2S as a novel mediator of inflammation and work in several groups worldwide is currently focused on determining the role of H2S in inflammation. H2S has been implicated in different inflammatory conditions, such as acute pancreatitis, sepsis, joint inflammation, and chronic obstructive pulmonary disease (COPD). Active research on the role of H2S in inflammation will unravel the pathophysiology of its actions in inflammatory conditions and may help develop novel therapeutic approaches for several, as yet incurable, disease conditions. [ABSTRACT FROM AUTHOR]

Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H2S), a gasotransmitter and substance P, a neuropeptide, are involved in the inflammatory process in acute pancreatitis. Cell adhesion molecules (CAM) are key players in inflammatory disease. Immunoglobulin (Ig) gene superfamily, selectins, and integrins are involved at different steps of leukocyte migration from blood to the site of injury. When the endothelial cells get activated, the CAMs are upregulated which leads to them interacting with leukocytes. This review summarizes our current understanding of the roles H2S, substance P and adhesion molecules play in acute pancreatitis. [ABSTRACT FROM AUTHOR]

Accumulating evidence has suggested that hydrogen sulfide (H2S) is endogenously generated in many types of mammalian cells. Since H2S plays an important role in cardiovascular, central nervous and gastrointestinal systems, it is currently considered to be the third gaseous mediator. Recently, more and more attention has been paid to the biological functions of H2S in inflammation. In various animal models of inflammatory diseases (such as acute pancreatitis, sepsis and endotoxemia), endogenous H2S has been shown to be overproduced and participate in regulating the severity of inflammatory response and associated organ injury. Inhibition of H2S formation is likely to protect animals against these inflammatory diseases. H2S may exert its effect on inflammation via regulating the function of leukocytes, leukocyte trafficking and immune cell survival. Furthermore, H2S has been suggested to induce the release or production of neuropeptides (substance P and calcitonin gene-related peptide), which are considered to be pro-inflammatory mediators, and therefore contribute to inflammatory response. In addition, some studies reported that low doses of sodium hydrosulfide (NaHS, an H2S donor) exhibited some anti-inflammatory effect on local inflammation (such as non-steroidal anti-inflammatory drug-induced gastric injury). Taken together, all these findings demonstrate that in addition to the vasodilation and neuromodulation activity of H2S, it may contribute to the pathogenesis of inflammatory diseases via regulating the activation of leukocytes. [ABSTRACT FROM AUTHOR]

We investigated the effect of a specific neurokinin-l receptor (NKIR) antagonist, CP-96,345, on the regulation of the expression of adhesion molecules ICAM-l, VCAM-l, E-selectin, and P-selectin as well as leukocyte recruitment during acute pancreatitis (AP). AP was induced in male Balb/C mice by 10 consecutive hourly intraperitoneal injections of caerulein. In the treatment groups, CP-96,345 was administered at 2.5 mg/kg ip either 30 mm before or I h after the first caerulein injection. Animals were killed, and the lungs and pancreas were isolated for RNA extraction and RT-PCR or for immunohistochemical staining. mRNA expression of the four adhesion molecules was upregulated in the pancreas during AP. Treatment with CP-96,345 effectively reduced the mRNA expression of P-selectin and E-selectin but not ICAM-l and VCAM-l. In the lung, ICAM-l, E-selectin, and P-selectin mRNA expression increased during AP. Antagonist treatment suppressed this elevation. Similar expression patterns were seen in the immunohistochernical stainings. Intravital microscopy of the pancreatic microcirculation revealed the effect of CP-96,345 on leukocyte recruitment. The present study provides important information on the relationship between NKIR activation and the regulation of adhesion molecules. Also, this study points to the differential regulation of inflammation in the pancreas and lung with AP. [ABSTRACT FROM AUTHOR]

Abstract: Acute pancreatitis is a common, and as yet incurable, clinical condition, the incidence of which has been increasing over recent years. Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that treatment with a neutralizing antibody against CINC, a CXC chemokine, protects rats against acute pancreatitis-associated lung injury. The hexapeptide antileukinate (Ac-RRWWCR-NH2) is a potent inhibitor of binding of CXC chemokines to the receptors (CXCR2). This study aims to evaluate the effect of treatment with antileukinate on acute pancreatitis and the associated lung injury in mice. Acute pancreatitis was induced in adult male Swiss mice by hourly intra-peritoneal injections of caerulein (50 μg/kg/h) for 10 h. Antileukinate (52.63 mg/kg, s.c.) was administered to mice either 30 min before or 1 h after starting caerulein injections. Severity of acute pancreatitis was determined by measuring plasma amylase, pancreatic water content, pancreatic myeloperoxidase (MPO) activity, pancreatic macrophage inflammatory protein-2 (MIP-2) levels and histological examination of sections of pancreas. A rise in lung MPO activity and histological evidence of lung injury in lung sections was used as criteria for pancreatitis-associated lung injury. Treatment with antileukinate protected mice against acute pancreatitis and associated lung injury, showing thereby that anti-chemokine therapy may be of value in this condition. [Copyright &y& Elsevier]

Accumulating evidence suggests the neuropeptide substance P (SP) and its receptor neurokinin-1 receptor (NK-1R) play a pivotal role in the pathogenesis of acute pancreatitis (AP). However, the mechanisms remain unclear. The present study investigated whether chemokines as proinflamatory molecules are involved in SP-NK-1R-related pathogenesis of this condition. We observed temporally and spatially selective chemokine responses in secretagogue caerulein-induced AP in mice. CC chemokines monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein-1α (MIP-1α) and CXC chemokine MIP-2 were elevated after AP induction. Time-dependent, tissue-specific analysis of their mRNA and protein expression suggested that they are early mediators in the condition and mediate local as well as systemic inflammatory responses. In contrast, another CC chemokine regulated on activation, T cells expressed and secreted (RANTES) was only involved in local pancreatic inflammation at a later stage of the disease. Either prophylactic or therapeutic treatment with a potent selective NK-1R antagonist CP-96,345 significantly suppressed caerulein-induced increase in MCP-1, MIP-1α and MIP-2 expression but had no apparent effect on RANTES expression. The suppression effect of CP-96,345 on MCP-1, MIP-1α, and MIP-2 expression was concordantly demonstrated by immunohistochemistry, which, additionally, suggested that chemokine immunoreactivity was localized to acinar cells and the infiltrating leukocytes in the pancreas and alveolar macrophages, epithelial cells, and endothelial cells in the lungs. Our data suggest that SP, probably by acting via NK-1R on various chemokine-secreting cells in the pancreas and lungs, stimulates the release of chemokines that aggravate local AP and the development of its systemic sequelae. [ABSTRACT FROM AUTHOR]

Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators, including chemokines and substance P (SP), are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly, SP levels in the pancreas and pancreatic acinar cell expression of neurokinin-1 receptor, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis. This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and to determine whether it leads to proinflammatory signaling, such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of MCP-1, macrophage inflammatory protein-1α (MIP-1α), as well as MIP-2. Furthermore, SP also increased NF-κB activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-κB pathway, since the increase in chemokine production was completely attenuated when pancreatic acini were pretreated with the selective NF-κB inhibitor NF-κB essential modulator-binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-κB dependent. [ABSTRACT FROM AUTHOR]

We have shown earlier that H2S acts as a mediator of inflammation. In this study, we have investigated the involvement of substance P and neurogenic inflammation in H2S-induced lung inflammation, lntraperitoneal administration of NariS (1–10 mg/kg), an H2S donor, to mice caused a significant increase in circulating levels of substance P in a dose-dependent manner. H2S alone could also cause lung inflammation, as evidenced by a significant increase in lung myeloperoxidase activity and histological evidence of lung injury. The maximum effect of H2S on substance P levels and on lung inflammation was observed 1 h after NaHS administration. At this time, a significant increase in lung levels of TNF-α and IL-1β was also observed. In substance P-deficient mice, the preprotachykinin-A knockout mice, H2S did not cause any lung inflammation. Furthermore, pretreatment of mice with CP-96345 (2.5 mg/kg ip), an antagonist of the neurokinin-1 (NK1) receptor, protected mice against lung inflammation caused by H2S. However, treatment with antagonists of NK2, NK3, and CGRP receptors did not have any effect on H2S-induced lung inflammation. Depleting neuropeptide from sensory neurons by capsaicin (50 mg/kg sc) significantly reduced the lung inflammation caused by H2S. In addition, pretreatment of mice with capsazepine (15 mg/kg sc), an antagonist of the transient receptor potential wmilloid-1, protected mice against H2S-induced lung inflammation. These results demonstrate a key role of substance P and neurogenic inflammation in H2S-induced lung injury in mice. [ABSTRACT FROM AUTHOR]

Hydrogen sulphide (H2S) is a naturally occurring gas synthesized from cysteine. It exhibits vasodilator activity (most probably by opening vascular smooth muscle KATP channels), influences leucocyte chemotaxis and promotes vascular smooth muscle cell apoptosis. Increased biosynthesis of H2S has been demonstrated in animal models of septic/endotoxic and haemorrhagic shock, pancreatitis and carrageenan-evoked hindpaw oedema in the rat. In each case, pharmacological inhibition of H2S biosynthesis is anti-inflammatory. [Copyright &y& Elsevier]

Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. The toxic effects of hydrogen sulphide (H 2 S) on living organisms have been recognized for nearly 300 years. In recent years, however, interest has been directed towards H 2 S as the third gaseous mediator, which has been shown to exhibit potent vasodilator activity both in vitro and in vivo most probably by opening vascular smooth muscle K ATP channels. Of the two enzymes, cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS), which utilize L-cysteine as substrate to form H 2 S, CSE is believed to be the key enzyme which forms H 2 S in the cardiovascular system. Recent studies have shown an important role of the vasodilator action of H 2 S in health and disease. IUBMB Life , 57: 603–606, 2005 [ABSTRACT FROM AUTHOR]

Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that pancreatic acinar cells produce the chemokine monocyte chemotactic protein (MCP)-1 in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Blocking chemokine production or action is a major target for pharmacological intervention in a variety of inflammatory diseases, such as acute pancreatitis. 2-Methyl-2-[[1-(phenylmethyl)-1H-indazol-3yl]methoxy] propanoic acid (bindarit) has been shown to preferentially inhibit MCP-1 production in vitro in monocytes and in vivo without affecting the production of the cytokines IL-1, IL-6, or the chemokines IL-8, protein macrophage inflammatory-1α, and RANTES. The present study aimed to define the role of MCP-1 in acute pancreatitis with the. use of bindarit. In a model of acute pancreatitis induced by caerulein hyperstimulation, prophylactic as well as therapeutic treatment with bindarit significantly reduced MCP-1 levels in the pancreas. Also, this treatment significantly protected mice against acute pancreatitis as evident by attenuated hyperamylasemia neutrophil sequestration in the pancreas (pancreatic MPO activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. [ABSTRACT FROM AUTHOR]

Hydrogen sulphide (H2S) is a naturally occurring gas, with potent vasodilator activity. In this report, we identify a role for H2S in carrageenan-induced hindpaw oedema in the rat. Intraplantar injection of carrageenan (150?µl, 2%(w?v-1)) resulted in an increase in hindpaw H2S synthesising enzyme activity and increased myeloperoxidase (MPO) activity. Pretreatment (i.p. 60?min before carrageenan) with DL-propargylglycine (PAG, 25-75?mg?kg-1), an inhibitor of the H2S synthesising enzyme cystathionine-?-lyase (CSE), significantly reduced carrageenan-induced hindpaw oedema in a dose-dependent manner (e.g. increase in hindpaw weight at 3?h, saline: 0.12±0.017?g; carrageenan, 1.39±0.037?g; PAG, 50?mg?kg-1, 1.11±0.06?g, n=10) and MPO activity (fold increase) in the hindpaw (saline: 1.0±0.12; carrageenan, 2.92±0.45?g; PAG, 50?mg?kg-1, 1.1±0.22, n=10); PAG (50?mg?kg-1) also inhibited H2S synthesising enzyme activity (nmol?µg DNA-1) in the hindpaw in a dose-dependent manner (saline, 0.46±0.05; carrageenan, 0.71±0.08?g; PAG, 50?mg?kg-1, 0.17±0.05, n=10).British Journal of Pharmacology (2005) 145, 141-144. doi:10.1038/sj.bjp.0706186 [ABSTRACT FROM AUTHOR]

Focuses on the contribution of pancreatic acinar cell death, as apoptosis or necrosis, as a determinant of the severity of acute pancreatitis and on the understanding of the mechanism of pancreatic acinar cell apoptosis. Testing of the hypothesis that apoptosis could be a favorable response to acinar cells and that interventions that favor induction of apoptotic acinar cell death might reduce the severity of an attack of acute pancreatitis; Description of modes of cell death, namely, apoptosis and necrosis.

Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Preprotachykinin-A (PPT-A) gene products substance P and neurokinin (NK)-A have been shown to play important roles in neurogenic inflammation. Substance P acts primarily (but not exclusively) via the NK1 receptor. NKA acts primarily via the NK2 receptor. Earlier work has shown that knockout mice deficient in NK1 receptors are protected against acute pancreatitis and associated lung injury. NK1 receptors, however, bind other peptides in addition to substance P, not all of which are derived from the PPT-A gene. To examine the role of PPT-A gene products in acute pancreatitis, the effect of PPT-A gene deletion on the severity of acute pancreatitis and the associated lung injury was investigated. Deletion of PPT-A almost completely protected against acute pancreatitis-associated lung injury, with a partial protection against local pancreatic damage. These results show that PPT-A gene products are critical proinflammatory mediators in acute pancreatitis and the associated lung injury. [ABSTRACT FROM AUTHOR]

Demonstrates increased production of monocyte chemotactic protein-1 (MCP-1) by a nuclear factor (NF)-κ B and Ca&sup2+;-dependent mechanism after treatment of isolated rat with supramaximal doses of cerulein. Description of chemokines; Differences in the profile of chemokines seen in different species; Effect of NF-κ B inhibitors on MCP-1 and chemokine cytokine-induced neutrophil chemoattractant production.

Evaluates the effect of complement factor C5a and C5a receptors on acute pancreatitis and associated lung injury. Recognition of the complement factor C5a; Measurement of serum amylase and neutrophil sequestration; Exacerbation of injury in the absence of C5a function.

Tests the hypothesis that complement factor C5a exerts an anti-inflammatory effect in acute pancreatitis and associated lung injury. Modulation by C5a of the severity of cerulein-induced pancreatitis and associated lung injury; Lack of effect of C5a on cerulein-induced amylase secretion.

Deals with a study which evaluated the effects of complement factor C5a and C5aR receptors in acute pancreatitis and in pancreatitis-associated lung injury. Materials and methods; Results of the study; Discussion.

Presents information pertaining to the function of the substance of P and the neurokinin 1 receptor within the acute pancreatitis and pancreatitis-associated lung injury. Important role of the neuropeptide substance P; Indication of the results.

Provides information on a study which investigated the part played by the novel gaseous mediator, hydrogen sulfide (H2S) in Escherichia coli lipopolysaccharide-induced inflammation in the mouse. Plasma concentrations of gaseous mediator in patients with septic shock; Possible inflammatory effect of H2S; Cellular targets for H2S in LPS-mediated inflammation.

Presents a study on the role of hydrogen sulfide in acute pancreatitis and associated lung injury. Effect of the induction of acute pancreatitis in mice by caerulein hyperstimulation on plasma hydrogen sulfide levels; Gene found to be expressed by mouse pancreas; Treatment that attenuated morphological changes in acute pancreatitis.

Gases such as nitric oxide and carbon monoxide play important roles both in normal physiology and in disease. In recent years, interest has been directed towards other naturally occurring gases, notably hydrogen sulfide (H2S), which is both a potent vasodilator and a mediator of long-term potentiation in the brain. This article focuses on recent work that suggests a role for H2S, and perhaps other gases, in the CNS and cardiovascular system. [Copyright &y& Elsevier]

The activation of Kupffer cells, resident macrophages in the liver, is closely associated with the inflammatory response during sepsis, which leads to multiple-organ failure. However, how Kupffer cell activation affects adhesion molecules (ICAM-1 and VCAM-1) in sepsis has not been determined. This study investigated Kupffer cell inactivation's (by gadolinium chloride; GdCl3) effects on adhesion molecule expression in CLP-induced sepsis. The induction of sepsis resulted in increased expression of liver and lung ICAM-1 and VCAM-1. GdCl3 pretreatment significantly decreased liver ICAM-1 expression but had no effect on VCAM-1 expression. In contrast, GdCl3 pretreatment had no effect on sepsis-induced increased adhesion molecule expression in the lungs. Similarly, the immunoreactivity of ICAM-1 was decreased in liver sinusoidal endothelial cells but increased in pulmonary endothelial cells in septic mice pretreated with GdCl3. Further, GdCl3 pretreatment had no effect on the immunoreactivity of VCAM-1 in endothelial cells of the liver and lungs. Hence, the findings of this study demonstrate the differential effects of Kupffer cell inactivation on liver and lung adhesion molecules and suggest the complexity of their involvement in the pathophysiology of sepsis. [ABSTRACT FROM AUTHOR]

The article focuses on the results of research conducted at National University of Singapore (NUS) on therapeutic approaches for septic shock. The condition is caused by decreased tissue perfusion and oxygen delivery due to infection and sepsis. Researchers at NUS have focused on several therapeutic targets or mediators for septic shock, including an 11-amino acid neuropeptide called Substance P.

The article presents the results of research that help define the role of biologically active gases in cardiovascular health and disease. Also known as gasotransmitters, such naturally occurring gases include nitric oxide, carbon monoxide and hydrogen sulfide, which play a major role in physiological and pathological processes such as blood pressure regulation, neurotransmission and inflammatory processes.

Hydrogen sulfide (H2S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H2S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation puncture (CLP)-induced model of sepsis, using two different and complementary approaches: Cth gene deletion and pharmacological inhibition. Our findings revealed a decreased level of H2S-synthesizing activity (via Cth) in both Cth−/− mice and PAG-treated wild-type (WT) mice following CLP-induced sepsis. Both treatment groups had reduced MPO activity and expression of chemokines (MCP-1 and MIP-2α), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-κB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth−/− mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-κB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth−/− mice following CLP-induced sepsis. The WT group with sepsis had an increased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung than the WT sham-operated control. The Cth−/−, PAG-treated WT, and Cth−/− groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H2S production via both approaches reduced adhesion molecule expression on endothelial cells and reduced liver and lung injury in mice with sepsis. In conclusion, this study demonstrates that H2S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H2S-signalling axis in sepsis. [ABSTRACT FROM AUTHOR]

The article introduces various reports on research at the National University of Singapore (NUS) focusing on the causes, prevention and treatment of cardiac and vascular diseases.

Aspergillus fumigatus is a ubiquitous airborne fungus, is the predominant cause (>90%) of invasive aspergillosis (IA) in immunosuppressed patients and has a high mortality. New approaches to prevention and treatment are needed because of the poor efficacy, toxicity and side effects of the current anti-Aspergillus drugs on patients. Thus, we aim to explore a new avenue to combat Aspergillus infection by using a novel monoclonal antibody (mAb) 1D2 against a glycoprotein on the cell wall of Aspergillus. The ability of this mAb to inhibit attachment, germination, and growth of Aspergillus conidia and hyphae in vitro were examined. A dose-dependent growth inhibition of Aspergillus conidia in the presence of mAb 1D2 was found. The mAb 1D2 inhibited attachment of Aspergillus conidia to an untreated slide surface and fibronectin-treated surface compared to an unrelated mAb 6B10. When conidia were exposed to 1D2 concomitantly with inoculation into culture media, the mAb prevented the swelling and germination of conidia. This inhibitory ability of 1D2 was less apparent if it was added two hours after inoculation. Damage to hyphae was also observed when 1D2 was added to Aspergillus hyphae that had been incubated in media overnight. These in vitro results indicate that mAb 1D2 broadly inhibits clinically important Aspergillus species and has a promising therapeutic effect both as prophylaxis to inhibit an Aspergillus infection as well as a treatment. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) and substance P (SP) are known from animal models and in vitro studies as proinflammatory mediators. In this study, peripheral blood concentrations of H2S and SP were measured in patients with Escherichia coli or Klebsiella pneumoniae bacteraemia. Fifty patients were recruited from general wards at Christchurch Hospital, during 2020–2021. Samples from age- and sex-matched healthy subjects previously recruited as controls for studies of cardiovascular disease were used as controls. The concentrations of H2S were higher than controls on day 0, day 1, and day 2, and SP was higher than controls on all 4 days. The concentrations of H2S were highest on day 0, whereas SP concentrations were higher on day 2 than other days. Interleukin-6 and C-reactive protein were significantly higher on day 0 and day 1, respectively. The concentrations of H2S and SP did not differ between 15 non-septic (SIRS 0-1) and the 35 septic subjects (SIRS ≥ 2). Substance P concentrations were higher in subjects with abdominal infection than urinary tract infections on day 0 (p = 0.0002) and day 1 (p = 0.0091). In conclusion, the peak H2S concentrations precede the SP peak in patients with Gram-negative bacteraemia, but this response varies with the site of infection. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is a life-threatening fungal disease that causes high morbidity and mortality in immunosuppressed patients. Early and accurate diagnosis and treatment of IA remain challenging. Given the broad range of non-specific clinical symptoms and the shortcomings of current diagnostic techniques, most patients are either diagnosed as "possible" or "probable" cases but not "proven". Moreover, because of the lack of sensitive and specific tests, many high-risk patients receive an empirical therapy or a prolonged treatment of high-priced antifungal agents, leading to unnecessary adverse effects and a high risk of drug resistance. More precise diagnostic techniques alongside a targeted antifungal treatment are fundamental requirements for reducing the morbidity and mortality of IA. Monoclonal antibodies (mAbs) with high specificity in targeting the corresponding antigen(s) may have the potential to improve diagnostic tests and form the basis for novel IA treatments. This review summarizes the up-to-date application of mAb-based approaches in assisting IA diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very complicated and is not yet fully understood. Worse still, the development of effective therapeutic agents is still an unmet need and a great challenge. Gases, including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), are small-molecule biological mediators that are endogenously produced, mainly by enzyme-catalyzed reactions. Accumulating evidence suggests that these gaseous mediators are widely involved in the pathophysiology of sepsis. Many sepsis-associated alterations, such as the elimination of invasive pathogens, the resolution of disorganized inflammation and the preservation of the function of multiple organs and systems, are shaped by them. Increasing attention has been paid to developing therapeutic approaches targeting these molecules for sepsis/septic shock, taking advantage of the multiple actions played by NO, CO and H2S. Several preliminary studies have identified promising therapeutic strategies for gaseous-mediator-based treatments for sepsis. In this review article, we summarize the state-of-the-art knowledge on the pathophysiology of sepsis; the metabolism and physiological function of NO, CO and H2S; the crosstalk among these gaseous mediators; and their crucial effects on the development and progression of sepsis. In addition, we also briefly discuss the prospect of developing therapeutic interventions targeting these gaseous mediators for sepsis. [ABSTRACT FROM AUTHOR]

Substance P (SP) is well known to promote inflammation in acute pancreatitis (AP) by interacting with neurokinin-1 receptor. However, mechanisms that terminate SP-mediated responses are unclear. Neutral endopeptidase (NEP) is a cell-surface enzyme that degrades SP in the extracellular fluid. In this study, we examined the expression and the role of NEP in caerulein-induced AP. Male BALB/c mice (20-25 g) subjected to 3-10 hourly injections of caerulein (50 µg/kg) exhibited reduced NEP activity and protein expression in the pancreas and lungs. Additionally, caerulein (10-7 M) also downregulated NEP activity and mRNA expression in isolated pancreatic acinar cells. The role of NEP in AP was examined in two opposite ways: inhibition of NEP (phosphoramidon [5 mg/kg] or thiorphan [10 mg/kg]) followed by 6 hourly caerulein injections) or supplementation with exogenous NEP (10 hourly caerulein injections, treatment of recombinant mouse NEP [1 mg/kg] during second caerulein injection). Inhibition of NEP raised SP levels and exacerbated inflammatory conditions in mice. Meanwhile, the severity of AP, determined by histological examination, tissue water content, myeloperoxidase activity, and plasma amylase activity, was markedly better in mice that received exogenous NEP treatment. Our results suggest that NEP is anti-inflammatory in caerulein-induced AP. Acute inhibition of NEP contributes to increased SP levels in caerulein-induced AP, which leads to augmented inflammatory responses in the pancreas and associated lung injury. [ABSTRACT FROM AUTHOR]

ute pancreatitis is an inflammatory disorder of the pancreas. Protein kinase C (PKC) δ plays an important role in mediating chemokine production in mouse pancreatic acinar cells. This study aims to investigate the role of PKC δ in the pathogenesis of acute pancreatitis and to explore the mechanisms through which PKC δ mediates pro-inflammatory signaling. Acute pancreatitis was induced in mice by ten hourly intraperitoneal injections of caerulein. PKC δ translocation inhibitor peptide (δV1-1) at a dose of 1.0 mg/kg or Tat (carrier peptide) at a dose of 1.0 mg/kg was administered to mice either 1 h before or 1 h after the first caerulein injection. One hour after the last caerulein injection, the mice were killed and pancreas, lungs, and blood were collected. Prophylactic and therapeutic treatment with δV1-1 attenuated caerulein-induced plasma amylase levels and pancreatic edema. Treatment with δV1-1 decreased myeloperoxidase activity and monocyte chemotactic protein-1 levels in both pancreas and plasma. PKC δ mediated acute pancreatitis by activating pancreatic nuclear factor κB, activator protein-1, and mitogen-activated protein kinases. Moreover, blockade of PKC δ attenuated lung myeloperoxidase activity and edema. Histological examination of pancreatic and lung sections confirmed protection against acute pancreatitis. Treatment with Tat had no protective effect on acute pancreatitis. Blockade of PKC δ represents a promising prophylactic and/or therapeutic tool for the treatment of acute pancreatitis. [ABSTRACT FROM AUTHOR]

The article presents a study on the involvement and interaction of hydrogen sulfide and transient receptor potential vanilloid type 1 in the pathologic process of sepsis. It states that male Swiss mice were treated with transient receptor potential vanilloid type 1 antagonist capsazepine 30 minutes before cecal ligation and puncture-induced sepsis. The result shows that capsazepine treatment attenuates the systemic inflammation and multiple organ damaged induced by hydrogen sulfide.

Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 µM) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SF primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-1α/CCL3. The activating effect of SF on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-1R antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SF-induced chemokine upregulation was NF-κB dependent. SP time dependently induced NF-κB p65 binding activity, IκBα degradation, and NF-κB p65 nuclear translocation in neutrophils. Inhibition of NF-κB activation with its inhibitor Bay11-7082 (10 µM) abolished SF-induced NF-κB binding activity and upregulation of MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-κB activation. [ABSTRACT FROM AUTHOR]

Abstract: Earlier studies have shown that mice deficient in NK1 receptors or its ligand, substance P, are protected against acute pancreatitis and associated lung injury. In the current study, the protective effect of NK1 receptor blockage against acute pancreatitis and associated lung injury was investigated, using a specific receptor antagonist, CP-96345. Acute pancreatitis was induced in mice by intraperitoneal (i.p.) injections of caerulein. Substance P levels in plasma, pancreas, and lungs were found to be elevated in a caerulein dose-dependent manner. Mice treated with CP-96345, either prophylactically, or therapeutically, were protected against acute pancreatitis and associated lung injury as evident by attenuation in plasma amylase, pancreatic and pulmonary myeloperoxidase activities, and histological evidence of pancreatic and pulmonary injuries. Pulmonary microvascular permeability was also reduced as a result of CP-96345 treatment. These results point to a key role of NK1 receptors in acute pancreatitis and associated lung injury. [Copyright &y& Elsevier]

A characteristic feature of all inflammatory disorders is the excessive recruitment of leukocytes to the site of inflammation. The loss of control in trafficking these cells contributes to inflammatory diseases. Leukocyte recruitment is a well-orchestrated process that includes several protein families including the large cytokine subfamily of chemotactic cytokines, the chemokines. Chemokines and their receptors are involved in the pathogenesis of several diseases. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is caused by an uncontrolled systemic inflammatory response resulting from clinical events including major surgery, trauma, multiple transfusions, severe burns, pancreatitis, and sepsis. Systemic inflammatory response syndrome involves activation of alveolar macrophages and sequestered neutrophils in the lung. The clinical hallmarks of ARDS are severe hypoxemia, diffuse bilateral pulmonary infiltrates, and normal intracardiac filling pressures. The magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ARDS. Recent evidence shows that activated leukocytes and chemokines play a key role in the pathogenesis of ARDS. The expanding number of antagonists of chemokine receptors for inflammatory disorders may hold promise for new medicines to combat ARDS. [ABSTRACT FROM AUTHOR]

Background:The prevalence of metabolic diseases continues to rise worldwide, with a growing recognition of metabolic dysregulation after acute inflammatory diseases such as acute pancreatitis (AP). Adipokines and cytokines play an important role in metabolism and the course of AP, but there is a paucity of research investigating their relationship with pancreatic hormones after AP. This study aimed to explore associations between pancreatic hormones and adipokines as well as cytokines to provide insights into the pathophysiology of altered pancreatic hormone secretion following AP. Methods:A total of 83 patients previously diagnosed with AP and no prior diabetes or pre-diabetes were recruited into this cross-sectional follow up study. Fasting venous blood samples were collected to analyse a panel of pancreatic hormones and derivatives (amylin, C-peptide, glucagon, insulin, pancreatic polypeptide, somatostatin), adipokines (adiponectin, leptin, retinol binding protein-4, and resistin), and cytokines (interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-α (TNF-α)). Linear regression analyses were used, and potential confounders were adjusted for in multivariate analyses. Results:Insulin was significantly associated with IL-6 in both unadjusted and adjusted models (p = .029 andp = .040, respectively). Amylin was significantly associated with MCP-1 in the unadjusted model (p = .046), and TNF-α in unadjusted and adjusted models (p = .025 andp = .027, respectively). Conclusions:Insulin and amylin have a strong positive association with pro-inflammatory cytokines in patients following an episode of AP. These associations have possible relevance in the development of diabetes associated with diseases of the exocrine pancreas, providing the opportunity to develop novel treatment paradigms. [ABSTRACT FROM AUTHOR]

Objective: Hydrogen sulfide (H2S) is a gaseous mediator produced in the body. In experimental models, endogenously produced H2S has been shown to have pro-inflammatory effects. The aim of this study was to investigate whether H2S is present in three common rheumatic diseases, rheumatoid arthritis (RA), gout and osteoarthritis (OA) and to determine if H2S levels correlate with disease activity. Methods: Patients with RA, gout, OA, and healthy controls (n = 30 each) were recruited. Plasma and where possible, synovial fluid (SF), were obtained. Levels of H2S and interleukin-6 (IL-6) (a known inflammatory marker as a positive control) were determined and assessed for their relationship with disease activity. Results: SF-H2S levels were significantly elevated in both RA and gout when compared to respective plasma levels. Plasma levels of H2S were not different from those in healthy controls in patients with either RA or gout. In OA, plasma levels of H2S were significantly elevated compared to healthy controls. In RA, SF-H2S levels correlated with Disease Activity Score (DAS)-28 and tender joint count. Conclusion: H2S is present in the joint and acts as a pro-inflammatory mediator in rheumatic diseases. H2S may be a novel therapeutic target for these conditions. [ABSTRACT FROM AUTHOR]

Background: Hydrogen sulfide (H2S), produced by the activity of cystathionine-gamma-lyase (CSE), is a key mediator of inflammation in sepsis. The liver sinusoidal endothelial cells (LSECs) are important target and mediator of sepsis. The aim of this study was to investigate the role of CSE-derived H2S on inflammation and LSECs fenestrae in caecal-ligation and puncture (CLP)-induced sepsis using CSE KO mice. Methods: Sepsis was induced by CLP, and mice (C57BL/6J, male) were sacrificed after 8 hours. Liver, lung, and blood were collected and processed to measure CSE expression, H2S synthesis, MPO activity, NF-κB p65, ERK1/2, and cytokines/chemokines levels. Diameter, frequency, porosity and gap area of the liver sieve were calculated from scanning electron micrographs of the LSECs. Results: An increased CSE expression and H2S synthesizing activity in the liver and lung of wild-type mice following CLP-induced sepsis. This was associated with an increased liver and lung MPO activity, and increased liver and lung and plasma levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and the chemokines MCP-1 and MIP-2α. Conversely, CSE KO mice had less liver and lung injury and reduced inflammation following CLP-induced sepsis as evidenced by decreased levels of H2S synthesizing activity, MPO activity, and pro-inflammatory cytokines/chemokines production. Extracellular-regulated kinase (ERK1/2) and nuclear factor-κB p65 (NF-κB) became significantly activated after the CLP in WT mice but not in CSE KO mice. In addition, CLP-induced damage to the LSECs, as indicated by increased defenestration and gaps formation in the LSECs compared to WT sham control. CSE KO mice showed decreased defenestration and gaps formation following sepsis. Conclusions: Mice with CSE (an H2S synthesising enzyme) gene deletion are less susceptible to CLP-induced sepsis and associated inflammatory response through ERK1/2-NF-κB p65 pathway as evidenced by reduced inflammation, tissue damage, and LSECs defenestration and gaps formation. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide is an endogenous inflammatory mediator produced by the activity of cystathionine γ-lyase (CSE) inmacrophages. The objective of this study was to explore the mechanism by which hydrogen sulfide acts as an inflammatory mediator in lipopolysaccharide- (LPS-) induced macrophages. In this study, we used small interfering RNA (siRNA) to inhibit CSE expression in macrophages. We found thatCSE silencing siRNAcould reduce the LPS-induced activation of transcription factor nuclear factor- κB (NF-κB) significantly. Phosphorylation and activation of extra cellular signal-regulated kinase 1/2 (ERK1/2) increased in LPSinduced macrophages. We showed that phosphorylation of ERK in LPS-induced RAW 264.7 cells reached a peak 30 min after activation. Our findings show that silencing CSE gene by siRNA reduces phosphorylation and activation of ERK1/2 in LPS-induced RAW264.7 cells. These findings suggest that siRNA reduces the inflammatory effects of hydrogen sulfide through the ERK-NF-κB signalling pathway and hydrogen sulfide plays its inflammatory role through ERK-NF-κB pathway in these cells. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) has been reported to be involved in the signaling of the inflammatory response; however, there are differing views as to whether it is pro- or anti-inflammatory. In this study, we sought to determine whether endogenously synthesized H2S via cystathionine-?-lyase (CSE) plays a pro- or anti-inflammatory role in caerulein-induced pancreatitis. To investigate this, we used mice genetically deficient in CSE to elucidate the function of CSE in caerulein-induced acute pancreatitis. We compared the inflammatory response and tissue damage of wild-type (WT) and CSE knockout (KO) mice following 10 hourly administrations of 50 µg/kg caerulein or saline control. From this, we found that the CSE KO mice showed significantly less local pancreatic damage as well as acute pancreatitis-associated lung injury compared with the WT mice. There were also lower levels of pancreatic eicosanoid and cytokines, as well as reduced acinar cell NF-?B activation in the CSE KO mice compared with WT mice. Additionally, in WT mice, there was a greater level of pancreatic CSE expression and sulfide-synthesizing activity in caerulein-induced pancreatitis compared with the saline control. When comparing the two saline-treated control groups, we noted that the CSE KO mice showed significantly less pancreatic H2S-synthesizing activity relative to the WT mice. These results indicate that endogenous H2S generated by CSE plays a key proinflammatory role via NF-?B activation in caerulein-induced pancreatitis, and its genetic deletion affords significant protection against acute pancreatitis and associated lung injury. [ABSTRACT FROM AUTHOR]