Release Of Inflammatory Mediators Research Articles

Treatment of Microcirculatory Disturbances in Acute Pancreatitis: Where Are We Now?

Acute pancreatitis is a serious inflammatory condition. Research has shown an increase in the number of pancreatitis-associated hospitalizations, with a marked decline in the mortality rates down to 0.79% in patients with acute pancreatitis and 0.26% in patients with exacerbation of chronic pancreatitis. Up to one-third of patients develop pancreatic tissue necrosis, with a mortality rate of 30%. One of the mechanisms is the disturbances in pancreatic microcirculation due to the release of endothelin, a long-acting vasoconstrictor. The development of pancreatitis causes the release of other inflammatory mediators, which reduce blood flow in the microcirculation. The activation of intracellular trypsinogen initiates a cascade of mechanisms in pancreatitis. There is no specific treatment for acute pancreatitis. Protease inhibitors are not effective in treating severe acute pancreatitis. There is an important role of low-molecular-weight heparin in attenuating necrosis and restoring perfusion of the pancreas. Other drugs used are endothelin receptor antagonists, antagonist of interleukin-1 and interleukin-6 receptors, α-tocopherol, tumor necrosis factor-α and platelet-activating factor inhibitors, acetylsalicylic acid, and local intra-arterial injection of lidocaine. The prophylactic use of antibiotics is not recommended. The treatment outcome of acute pancreatitis is still unsatisfactory.

Electronic Nicotine Delivery Systems Exhibit LowerToxicity Compared to Cigarettes: “The Replica Study Experience”

Electronic nicotine delivery systems (ENDS) can reduce the health risks associated with chronic smoke exposure, and their potential benefits are the subject of intense scientific debate. The international “Replica Study Group” replicated independently three relevant studies from the tobacco industry on the cytotoxic and inflammatory effects of cigarette smoke and ENDS aerosol. Our primary goal was to establish the reliability of the results and the robustness of the conclusions.In order to assess cytotoxicity of smoke and aerosol, we exposed human bronchial epithelial cell (H292) to cigarette smoke and to ENDS aerosol at air‐liquid interface (ALI). Moreover, we aimed to assess different inflammatory and remodeling mediators release (IL‐6, IL‐8 and MMP‐1) from cells exposed to whole smoke (WS) and to smoke deprived of total particulate matter (vapor phase; VP).We were able to replicate the results obtained in the original studies on cytotoxicity confirming that almost 80% of the cytotoxic effect of smoke is due to the vapor phase of smoke. Moreover, our results substantiated the significantly reduced cytotoxic effects of ENDS aerosol vs. cigarette smoke. However, our data were notably different in terms of inflammatory and remodeling activity triggered by smoke.Altogether, the data obtained independently in different laboratories clearly confirm the reduced toxicity of ENDS products compared to smoke, thus providing a valuable tool to the harm reduction strategies in smokers. Otherwise, we were not able to replicate the results on inflammatory and remodeling mediators released from smoke exposed cells. This could be due to the lack of normalization of the quantity of cytokines released, with the number of viable cells, in the original paper, since the production of cytokines itself requires the metabolic capability of cells.

The Role of PKM2 in Diabetic Microangiopathy.

Diabetic microangiopathy is among the most common complications affecting patients with diabetes, and includes both diabetic retinopathy (DR) and diabetic nephropathy (DKD). Diabetic microangiopathy remains a persistent threat to the health and quality of life of affected patients. Mechanistically, the severity of DR and DKD is tied to mitochondrial and glucose metabolism abnormalities, with the activation of the glycolytic enzyme pyruvate kinase M2 (PKM2) contributing to mitochondrial and glomerular dysfunction, abnormal renal hemodynamics, and retinopathy. PKM2 can activate inflammatory bodies in macrophages to promote the release of inflammatory mediators, and serves as a key regulator of inflammatory factors, chemokines and adhesion molecules. As such, there is sufficient evidence that PKM2 can be used as a biomarker for the diagnosis of diabetes and diabetic microangiopathy. Here, we survey the mechanisms whereby PKM2 contributes to diabetes-related microvascular diseases, associated regulatory roles, post-translational modifications, and the potential utility of PKM2 as a therapeutic target. Through this literature review, we have determined that PKM2 offers promise as both a diagnostic marker and therapeutic target with direct relevance to research pertaining to diabetic microangiopathy.

Intestinal Barrier Permeability in Allergic Diseases.

The role of intestinal permeability (IP) markers among children and adults with food allergies is not fully understood, and the identification of biological indicators/markers that predict growth retardation in children with allergic diseases and atopy has not been well explained. Studies have shown that patients with atopic diseases respond abnormally to food allergens. Accordingly, differences in the types of immune complexes formed in response to antigen challenges are significant, which seems to underlie the systemic signs of the food allergy. Increased intestinal permeability over the course of a food allergy allows allergens to penetrate through the intestinal barrier and stimulate the submucosal immune system. Additionally, the release of cytokines and inflammatory mediators enhances the degradation of the epithelial barrier and leads to an improper cycle, resulting in increased intestinal permeability. Several studies have also demonstrated increased permeability of the epithelial cells in those afflicted with atopic eczema and bronchial asthma. Ongoing research is aimed at finding various indicators to assess IP in patients with atopic diseases.

Dietary polysaccharides from guavira pomace, a co-product from the fruit pulp industry, display therapeutic application in gut disorders

Inflammatory bowel disease (IBD) includes two distinct diseases: Crohn's disease (CD) and ulcerative colitis (UC). IBD is a chronic systemic disease of the gastrointestinal tract, characterized by an inflammatory process. The mechanisms by which diseases develop are still unknown, but it is known that it results from a complex interaction between genetic variability, the host's immune system, and environmental factors. One of the main complaints of patients is abdominal pain, which may be associated with the release of inflammatory mediators, changes in the normal motility of the digestive tract, and increased intestinal permeability. Currently available drugs for abdominal pain are not satisfactory, therefore, it is extremely necessary to seek new therapeutic options for the treatment of abdominal pain. Polysaccharides extracted from fruits have attracted interest, as these molecules protect the intestinal mucosa and promote wound healing, attenuating inflammation, pain, and altered intestinal motility. In this study, we investigated the ability of pectic polysaccharides obtained from guavira pomace, named CPW to reduce visceral hypersensitivity, regulate intestinal motility, and control diarrhea in mice. Acetic acid, capsaicin, or mustard oil were used to assess visceral pain in normal mice. CPW reduced abdominal writhing, cell migration, and capsaicin-induced visceral nociception. Furthermore, it regulated intestinal motility and all measured parameters of castor oil-induced diarrhea. CPW treatment reversed the increase in mucosal permeability, TEER, and tissue weight caused by acetic acid. In addition, molecular docking analysis showed that specific the CPW units binds to the 3N8V, 5COX, 2J67 and 6RBF proteins. Thus, the results suggest that CPW has attractive therapeutic characteristics for the treatment of abdominal pain and ulcerative colitis.

MDL-800, the SIRT6 Activator, Suppresses Inflammation via the NF-κB Pathway and Promotes Angiogenesis to Accelerate Cutaneous Wound Healing in Mice.

Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase belonging to the sirtuin family. It has been shown to participate in wound healing and some inflammation-related disorders. However, the effect of MDL-800, a highly efficient and selective SIRT6 activator, on wound healing and inflammation has not been reported. Therefore, this study investigated whether MDL-800 confers anti-inflammatory effects and promotes wound healing and uncovered the molecular mechanisms involved. This was achieved using mouse models of full-thickness wounds. Results showed that MDL-800 significantly downregulated inflammation by attenuating the release of inflammatory mediators and improved collagen deposition and neovascularization of wounds, thereby accelerating cutaneous wound healing. Furthermore, MDL-800 significantly downregulated expression levels of TNF-α and IL-6 in the dorsal skin tissue of mice via the NF-κB pathway. These results demonstrated that MDL-800 exerted anti-inflammatory and prohealing effects, indicating that the SIRT6/NF-κB/IκB signaling pathway may play an important role in wound healing.

Mechanisms Underlying Curcumin-Induced Neuroprotection in Cerebral Ischemia.

Ischemic stroke is the leading cause of death and disability worldwide, and restoring the blood flow to ischemic brain tissues is currently the main therapeutic strategy. However, reperfusion after brain ischemia leads to excessive reactive oxygen species production, inflammatory cell recruitment, the release of inflammatory mediators, cell death, mitochondrial dysfunction, endoplasmic reticulum stress, and blood–brain barrier damage; these pathological mechanisms will further aggravate brain tissue injury, ultimately affecting the recovery of neurological functions. It has attracted the attention of researchers to develop drugs with multitarget intervention effects for individuals with cerebral ischemia. A large number of studies have established that curcumin plays a significant neuroprotective role in cerebral ischemia via various mechanisms, including antioxidation, anti-inflammation, anti-apoptosis, protection of the blood–brain barrier, and restoration of mitochondrial function and structure, restoring cerebral circulation, reducing infarct volume, improving brain edema, promoting blood–brain barrier repair, and improving the neurological functions. Therefore, summarizing the results from the latest literature and identifying the potential mechanisms of action of curcumin in cerebral ischemia will serve as a basis and guidance for the clinical applications of curcumin in the future.

The Glycocalyx Shedding Influences Hemodynamic and Metabolic Response to Fluid Load in Septic Shock.

Objective:Sepsis-associated endothelial dysfunction and degradation result in release of inflammatory mediators, compromise endothelial permeability, and impair alveolar fluid clearance leading to pulmonary edema. Excessive fluid therapy in septic shock damage the endothelial glycocalyx which will increase capillary leakage. The aim of our study was to assess the relationship of endothelial glycocalyx shedding with hemodynamic and metabolic response to fluid load in patients with septic shock.Methods:Eighteen adult patients were included in prospective observational study. To predict the response to infusion, we performed fluid load test by using crystalloids 7 mL kg−1 for 10 minutes. The plasma concentrations of endothelial glycocalyx components including heparan sulfate proteoglycan and syndecan 1 were measured at baseline, 2, 24 hours after fluid load test.Results:We observed associations of syndecan 1 with extravascular lung water index (rho = 0.48, P = .04) at baseline and of heparan sulfate proteoglycan with extravascular lung water index (rho = −0.56, P = .03) and pulse pressure variation (rho = 0.53, P = .04) at 24 hours after fluid load test. The plasma concentration of syndecan 1 correlated with lactate at baseline (rho = 0.51, P = .02) and at 24 hours after fluid load test (rho = 0.76, P = .009). At 2 hours after fluid load test, the concentration of syndecan 1 correlated with global end-diastolic volume index (rho= 0.93, P = .001) in normovolemic patients.Conclusions:The shedding of endothelial glycocalyx after fluid load test in septic shock is associated with hemodynamic and metabolic responses and related with the severity of pulmonary edema.

The effects of continuous renal replacement therapy with different anticoagulation methods on the expression of cytokines in severe acute pancreatitis

ObjectiveSevere acute pancreatitis (SAP) is a highly morbid condition in general population as well as in solid organ transplant (SOT) recipients. The present study aimed to investigate the effect of continuous renal replacement therapy (CRRT) with different anticoagulation methods on the expression levels of cytokines in SAP. MethodsA total of 120 patients with SAP, admitted into our hospital between September 2017 and July 2020, were enrolled as the research subjects and randomly divided into a control group (60 cases) and a study group (60 cases). CRRT with low molecular weight (LMW) heparin‑calcium anticoagulation was conducted on patients in the control group, and CRRT with topical citrate + low-dose LMW heparin‑calcium anticoagulation was conducted on patients in the study group. The expressions of cytokines in the two groups were compared after treatment. ResultsThere was no significant difference in white blood cells (WBC), C-reactive proteins (CRP), and procalcitonin (PCT) before treatment between the two groups (P > 0.05). After treatment, the levels of WBC (P = 0.006), CRP (P < 0.001), and PCT (P < 0.001) were significantly lower in the study group when compared with those in the control group. There was no significant difference in the concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) between the two groups before treatment (P > 0.05). After treatment, the concentrations of IL-6, IL-8, and TNF-α were significantly lower in the study group when compared with those in the control group. The APACHEII, SOFA and Ranson scores of the two groups were analyzed, and there was no difference between the two groups before treatment (P > 0.05). After treatment, the score of the study group was lower than that of the control group (P < 0.05). ConclusionCRRT with topical citrate + low-dose LMW heparin‑calcium anticoagulation in the treatment of patients with SAP reduces the levels of WBC, CRP, and PCT and the concentrations of cytokines, including IL-6, IL-8, and TNF-α. This inhibits the release of inflammatory mediators in patients with SAP and reduces damage to the body caused by the inflammatory response, thus effectively improving the patients' condition.

Recognizing Kounis Syndrome, the Unusual Possible Culprit of Acute Coronary Syndrome: A Rare Case Report

AbstractKounis syndrome encompasses acute coronary syndrome features associated with severe vasospasm of the coronary artery. It is related to allergic anaphylactic reaction triggered by the release of inflammatory cells and mediators. This entity, however, is often not properly diagnosed. In this report, we aimed to discuss a case of Kounis syndrome mimicking acute coronary syndrome. We presented a 58-year-old man with dyspnea, chest pain, dizziness, and itchiness 30 minutes following sodium diclofenac ingestion. His physical examination was remarkable for shock with hypoxia and features of anaphylactic reaction. An urgent electrocardiogram was obtained, manifesting deep ST-segment depression in anterolateral leads with ST elevation of aVR, which hinted a severe three-vessel disease or left main disease. Allergic acute coronary syndrome was suspected. Thus, the patient was managed with fluid resuscitation, epinephrine, and corticosteroid injection along with acute coronary syndrome treatment algorithm with a favorable clinical response. One-hour serial ECG showed complete resolution of ST depression with aVR normalization. This pointed to possible acute coronary spasm. No further coronary intervention was performed, the patient was discharged after 2 days in good condition and planned for further cardiac evaluation during follow-up. Kounis syndrome is an intriguing process caused by the presence of two disease entities that must be treated simultaneously. The difficulty in treating this condition stems from the fact that treating one of both entities may aggravate the other. Thus, a comprehensive approach and health education are strongly advised to ensure that this condition does not reoccur in the future.

Investigation of Flavonoids in Stereospermum suaveolens DC Leaves (Patala) Using HPTLC Analysis for Inflammatory Pain, Swelling, and Edema Treatment

Background: As per extensive research study, it was observed that Stereospermum suaveolens DC (Patala) is rich sources of flavonoids. These phytoconstituents have played an important role in prevention and maintenance of acute and chronic diseases of pain and inflammation. There is need to explore method for identification and quantification of the presence of flavonoids in S. suaveolens DC leaves (SSL) by qualitatively and quantitatively and to establish its mechanism in pain, swelling and edema Aim: The aim of the study was to identify and assess role of flavonoids in SSL by high-performance thin-layer chromatography (HPTLC) analysis and animal screening models of inflammatory pain, swelling, and edema. Materials and Methods: HPTLC to quantify flavonoid in the ethyl acetate fraction of plant component in comparison with Quarcetin. The inflammatory pain, swelling, and edema method were investigated by acetic acid induced writhing method in mice, histamine-induced edema in Wistar rats, and croton oil-induced ear edema in mice. The test doses 125 mg/kg, 250 mg/kg, and 500 mg/kg oral administration (p.o.) of ethyl acetate fraction of SSL were selected by oral acute toxicity OECD 423. Results: HPTLC analytical method estimated presence of flavonoids and estimated amount was 22.64%. However, inhibition in histamine-induced paw edema and reduction inhibition in ear edema significantly (P &lt; 0.05) observed by dose-dependent effect and antinociceptive activity detected on acetic acid induced writhing response method in mild to moderately using one-way analysis of variance method. Conclusion: It was clear that flavonoids were responsible for direct and indirect release of intermediate inflammatory mediators and promote its role in the treatment of pain and swelling.

Inhibition of Carrageenan-Induced Acute Inflammation in Mice by the Microgramma vacciniifolia Frond Lectin (MvFL).

Most anti-inflammatory drugs used nowadays have an excessive cost and their prolonged use has been connected with several injurious effects. Thus, the search for new anti-inflammatory agents is increasing. Lectins are carbohydrate-interacting proteins that can modulate immune response and the release of inflammation mediators. The Microgramma vacciniifolia frond lectin (MvFL) was previously reported to be an immunomodulatory agent in vitro. This work aimed to evaluate the effects of MvFL on the in vivo inflammatory status in the carrageenan-induced peritonitis and paw edema, using female Swiss mice. The animals were pretreated intraperitoneally with MvFL (5 and 10 mg/kg). In the peritonitis assay, the total and differential migration of white blood cells was evaluated, as well as the levels of cytokines, nitric oxide (NO), and total proteins in the peritoneal fluid. In the paw edema evaluation, the paw volume was measured in the early (from 30 min–2 h) and late (3–4 h) phases of edema formation. MvFL (5 and 10 mg/kg) was efficient in reducing neutrophil infiltration, pro-inflammatory cytokines (IL-6, IL-17, and TNF-α), NO, and protein content in the peritoneal fluid. It also repressed the edema formation in the late phase of the assay. In conclusion, MvFL showed inhibitory effects in in vivo acute inflammation, which encouraged future studies exploiting its immunomodulatory ability.

Chinese expert consensus on the use of Omalizumab in allergic asthma (2021 version)

As the first targeted biotherapy for asthma, Omalizumab, was officially approved in China in August 2017, and was applied in clinical practice since March, 2018. Dozens of experts in Respirology and Allergy from China fully discussed the important clinical issues on the use of Omalizumab in allergic asthma by referring to the relevant publications over the world and the first version of consensus published in March 2018. Until now, over 30, 000 allergic asthma patients have received the treatment of Omalizumab. Therefore, with the latest evidence of clinical and basic research around the world, we updated the consensus with the following issues: (1) The mechanisms and available evidence on anti-IgE treatment; (2) Selection and exclusion criteria for patients using Omalizumab; (3) Cautions on the administration of Omalizumab and highlights of the use of Omalizumab with various vaccines, including novel Coronavirus vaccines, and key points to note during a Novel Coronavirus pandemic; (4) Long-term use and safety; (5) The use of Omalizumab in specific populations; (6) Clinical applications of omalizumab with other targeted therapies and allergen-specific immunotherapy. Omalizumab, combining to the Cε3 area of IgE, reduces the free IgE level, and downregulates the expression of FcεRⅠ, which inhibits the release of inflammatory mediators of mast cell sources, and leads to reduced asthma exacerbation, decreased rate of emergency visit and hospitalization, improved symptoms and quality of life, as well as less concomitant moderate to severe asthma, poorly controlled after at least 3 months treatment of ICS/LABA, and confirmed with allergic status through skin prick test or serum total IgE or specific IgE. Conditions that exclude the use of Omalizumab include patients who are suspected to be allergic to drug ingredients. Omalizumab is administered based on dosing tables by subcutaneous injection. Omalizumab should be administered by a health care professional (doctor or nurse) in a medical institution equipped with facilities for post-injection observation and rescue treatment for anaphylactic shock. After the injection, the patient should be closely monitored whether there is an anaphylactic reaction. The duration of Omalizumab treatment should be at least 16 weeks to judge its effectiveness, after 16 weeks, Omalizumab treatment will be continued or withdrawn based on the overall asthma control evaluation. Patients should be followed every 3 months to assess the disease control and dosing adjustment. The common adverse reactions were injection sites reactions. Based on the latest evidence around the word, we focused on updating the relevant treatment course, administration method and use of specific populations, in order to guide clinicians in the use of Omalizumab. The use of Omalizumab in China still requires long-term observation and further research. With the increase of clinical evidence, this consensus will be continuously improved and supplemented.

Analysis of the Correlation between the Radioactive Iodine Activity and Neutrophil-to-Lymphocyte Ratio in Patients with Differentiated Thyroid Cancer.

Simple SummaryA higher tumor burden in patients with differentiated thyroid cancer undergoing radioactive iodine (131I) therapy may release into the bloodstream large amounts of 131I with a long residence time. We hypothesized that after the 131I intake, the blood concentration of 131I shows a course in several phases. To our knowledge, this research is the first of its kind. The results of the current study demonstrated a 131I blood concentration biphasic course. The time points to be considered are 46 and 69 h. 131I uptake in the residual thyroid tissue peaked after 46 h. The positive correlation between the neutrophil-to-lymphocyte ratio and administered 131I activity or the blood activity shows that the time interval between 46 and 69 h should be associated with the release of hematological inflammatory mediators, such as neutrophils and lymphocytes, to eradicate tumor cells in response to 131I therapy.Publications investigating the effect of radioactive iodine (131I) therapy on the circulating peripheral blood cells in patients with differentiated thyroid cancer (DTC) are limited to blood samples collected more than 92 h after 131I. Studies conducted on blood samples collected up to 92 h are rare due to the radioactive contamination risk. This research aimed to assess the relationship between the prescribed 131I activity, human whole blood activity, and peripheral blood cells at many time points (6, 22, 46, 69, and 92 h after 131I). The study enrolled 50 female patients with DTC who received a 131I median activity of 90.54 mCi (3.35 GBq). The neutrophil-to-lymphocyte ratio (NLR) was measured as an inflammatory marker. 131I uptake in the residual thyroid tissue peaked after 46 h. Blood activity decreased in the first 46 h and increased 69 h after the 131I intake. Blood activity was associated with the absolute lymphocyte count and the NLR at 69 h (r = −0.49 and r = 0.52, p < 0.001). Our results demonstrate that the time interval between 46 and 69 h should be associated with the release of hematological inflammatory mediators, such as neutrophils and lymphocytes, to eradicate tumor cells in response to 131I therapy.

Insights into CX3CL1/Fractalkine during experimental Trypanosoma cruzi infection.

Trypanosoma cruzi triggers a progressive myocarditis in mammalians through activation and recruitment of leukocytes and release of inflammatory mediators. The chemokine CX3CL1 has been highlighted for its potential role in the parasite controlling in end-pathological status of infected hosts. This study investigated the systemic and cardiac release of CX3CL1 in experimental T. cruzi infection and how this chemokine correlates with endothelin-1 and TNF. Male Fisher rats (n=20) were infected, or not, by the Y strain of T. cruzi and parasitemia was daily evaluated and immunoassays performed in the cardiac tissue macerated supernatant and in serum to evaluate CX3CL1, endothelin, and TNF production on days 5 and 15 of infection. T. cruzi infection induced a higher serum and cardiac production of these mediators on days 5 and 15 of infection. In both periods of infection, respectively, CX3CL1 showed a positive correlation with TNF (r=0.833, p<0.001 and r=0.723, p<0.001) and endothelin-1 (r=0.801, p<0.05 and r=0.857, p<0.001), which reinforce its participation in the T. cruzi-induced myocarditis development.

A comparative study of low molecular weight heparin in the management of acute pancreatitis VS conventional treatment- a prospective comparitive clinical study

Acute pancreatitis is serious disorder in any kind of severity with a mortality up to 20-40% and with a high magnitude of morbidity due to other kinds of systemic complications and despite of the various aetiologies, the final outcome is premature activation and retention of proteolytic enzymes. The main triggering factor and the etiological factor in development of Severe Acute Pancreatitis leading to multiple organ failure is the disturbance in microcirculation of the pancreas. The standard treatment for pancreatitis that is given is fluid management, nutritional care, gastrointestinal decompression, antibiotics (when indicated) The need for introducing Low molecular weight heparin (LMWH) in the treatment line of acute pancreatitis is that LMWH can reduce the release of cytokines and inflammatory mediators, resulting in an improvement of the microcirculation of pancreas thereby minimising the severity of pancreatic necrosis.

Designer Functional Nanomedicine for Myocardial Repair by Regulating the Inflammatory Microenvironment

Acute myocardial infarction is a major global health problem, and the repair of damaged myocardium is still a major challenge. Myocardial injury triggers an inflammatory response: immune cells infiltrate into the myocardium while activating myofibroblasts and vascular endothelial cells, promoting tissue repair and scar formation. Fragments released by cardiomyocytes become endogenous “danger signals”, which are recognized by cardiac pattern recognition receptors, activate resident cardiac immune cells, release thrombin factors and inflammatory mediators, and trigger severe inflammatory responses. Inflammatory signaling plays an important role in the dilation and fibrosis remodeling of the infarcted heart, and is a key event driving the pathogenesis of post-infarct heart failure. At present, there is no effective way to reverse the inflammatory microenvironment in injured myocardium, so it is urgent to find new therapeutic and diagnostic strategies. Nanomedicine, the application of nanoparticles for the prevention, treatment, and imaging of disease, has produced a number of promising applications. This review discusses the treatment and challenges of myocardial injury and describes the advantages of functional nanoparticles in regulating the myocardial inflammatory microenvironment and overcoming side effects. In addition, the role of inflammatory signals in regulating the repair and remodeling of infarcted hearts is discussed, and specific therapeutic targets are identified to provide new therapeutic ideas for the treatment of myocardial injury.

Diet-Microbiota Interplay: An Emerging Player in Macrophage Plasticity and Intestinal Health.

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract with an increasing prevalence worldwide. Targeted therapies for IBD are limited by several factors, including the therapeutic ceiling and the high incidence of non-responders or loss-of-response. In order to improve therapeutic efficacy, there is critical need to decipher disease pathogenesis, currently not well understood. Macrophages, innate immune cells that exhibit high plasticity, perpetuate inflammatory signalling in IBD through excessive release of inflammatory mediators. In recent years, pioneering research has revealed the importance of the interplay between macrophages and gut microbiota in maintaining intestinal homeostasis. Particular attention is focusing on microbiota-derived metabolites, believed to possess immunomodulatory properties capable of manipulating macrophage plasticity. Microbiota-derived short-chain fatty acids (SCFAs) and indole compounds, along with dietary sourced omega-3 (ω-3) polyunsaturated fatty acids (PUFA), exert anti-inflammatory effects, attributable to interactions with macrophages. Before we can effectively incorporate these metabolites into IBD therapies, a deeper understanding of microbiota–macrophage interactions at a molecular level is necessary. Therefore, the aim of this review is firstly to detail current knowledge regarding how diet and microbiota-derived metabolites modify macrophage plasticity. Later, we discuss the concept of therapeutic strategies directed at microbiota–macrophage interactions, which could be highly valuable for IBD therapies in the future.

Nortriptyline overcomes corticosteroid resistance in NK and NKT-like cells from peripheral blood of patients with chronic obstructive pulmonary disease

Introduction: An antidepressant nortriptyline potentiates glucocorticoid (GC) action with synergistic suppression of inflammatory mediator release, but the precise molecular mechanism is unknown.&#x0D; Materials and methods: Peripheral blood cells from patients with chronic obstructive pulmonary disease (COPD) (n = 21) were incubated with nortriptyline (1 μM or 10 μM), budesonide (10 nM), or their combinations, followed by stimulation with phorbol myristate acetate (PMA) and ionomycin. Cytokine production, glucocorticoid receptor β (GRβ), histone deacetylase 2 (HDAC2) and histone H4 acetylation of K8 (HAT) expression, p65 NF-kB and p38 mi­togen-activated protein kinase (p38 MAPK) phosphorylation in NK (CD3-CD56+) and NKT-like (CD3+CD56+) cells were analyzed by flow cytometry.&#x0D; Results: We observed that nortriptyline (10 μM) significantly attenuated the effects of PMA/ionomycin on the synthe­sis of interferon γ (IFNγ), interleukin 4 (IL-4), and IL-8, expression of GRβ and HAT, as well as p65 NF-kB and p38 MAPK phosphorylation in NK and NKT-like cells, whereas nortriptyline (1 μM) only inhibited IL-4 production by NK and NKT-like cells.&#x0D; Discussion: The combination of nortriptyline (10 μM) and budesonide decreased IFNγ, tumor necrosis factor α, IL-4, IL-8, and GRβ expression, as well as phosphorylated p38 MAPK and p65 NF-κB levels by NK and NKT-like cells above that of budesonide alone. Furthermore, the same association of drugs enhanced HDAC2 expression in NK and NKT-like cells.&#x0D; Conclusion: Collectively, our results show that nortriptyline might enhance GC function through modulation of HAT, HDAC2, GRβ, phospho-p38 MAPK expression. These data provide a strong rationale for combining nortriptyline with budesonide to treat COPD.

Black Ginseng Extract Suppresses Airway Inflammation Induced by Cigarette Smoke and Lipopolysaccharides In Vivo.

Cigarette smoke (CS) is a risk factor that can induce airway enlargement, airway obstruction, and airway mucus hypersecretion. Although studies have shown that Korean black ginseng extract (BGE) has potent anti-inflammatory and antioxidant activities, the CS-induced inflammatory responses and molecular mechanisms are yet to be examined. The aim of this study was to examine the effect of BGE on the airway inflammatory response and its molecular mechanisms, using CS/lipopolysaccharides (LPS)-exposed animals and PMA-stimulated human airway epithelial NCI-H292 cells. The results show that BGE inhibited the recruitment of immune cells and the release of inflammatory mediators, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, elastase, and reactive oxygen species (ROS) in the airways of CS/LPS-exposed animals. BGE inhibited mucus secretion and the expression of Mucin 5AC (MUC5AC). Furthermore, BGE exhibited an anti-inflammatory effect by downregulating a signaling pathway mediated by transforming growth factor-β-activated kinase (TAK) 1, an important protein that accelerates inflammation by cigarette smoke (CS). Overall, the findings show that BGE inhibits lung inflammation and mucus secretion by decreasing the activation of TAK1 both in human epithelial cells and in CS/LPS-exposed animals, and could be a potential adjuvant in the treatment and prevention of airway inflammatory diseases caused by airway irritants such as CS.