Blood Levels Of Pro-inflammatory Cytokines Research Articles

Human umbilical cord-derived mesenchymal stromal cells improve myocardial fibrosis and restore miRNA-133a expression in diabetic cardiomyopathy

BackgroundDiabetic cardiomyopathy (DCM) is a serious health-threatening complication of diabetes mellitus characterized by myocardial fibrosis and abnormal cardiac function. Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are a potential therapeutic tool for DCM and myocardial fibrosis via mechanisms such as the regulation of microRNA (miRNA) expression and inflammation. It remains unclear, however, whether hUC-MSC therapy has beneficial effects on cardiac function following different durations of diabetes and which mechanistic aspects of DCM are modulated by hUC-MSC administration at different stages of its development. This study aimed to investigate the therapeutic effects of intravenous administration of hUC-MSCs on DCM following different durations of hyperglycemia in an experimental male model of diabetes and to determine the effects on expression of candidate miRNAs, target mRNA and inflammatory mediators.MethodsA male mouse model of diabetes was induced by multiple low-dose streptozotocin injections. The effects on severity of DCM of intravenous injections of hUC-MSCs and saline two weeks previously were compared at 10 and 18 weeks after diabetes induction. At both time-points, biochemical assays, echocardiography, histopathology, polymerase chain reaction (PCR), immunohistochemistry and enzyme-linked immunosorbent assays (ELISA) were used to analyze blood glucose, body weight, cardiac structure and function, degree of myocardial fibrosis and expression of fibrosis-related mRNA, miRNA and inflammatory mediators.ResultsSaline-treated diabetic male mice had impaired cardiac function and increased cardiac fibrosis after 10 and 18 weeks of diabetes. At both time-points, cardiac dysfunction and fibrosis were improved in hUC-MSC-treated mice. Pro-fibrotic indicators (α-SMA, collagen I, collagen III, Smad3, Smad4) were reduced and anti-fibrotic mediators (FGF-1, miRNA-133a) were increased in hearts of diabetic animals receiving hUC-MSCs compared to saline. Increased blood levels of pro-inflammatory cytokines (IL-6, TNF, IL-1β) and increased cardiac expression of IL-6 were also observed in saline-treated mice and were reduced by hUC-MSCs at both time-points, but to a lesser degree at 18 weeks.ConclusionIntravenous injection of hUC-MSCs ameliorated key functional and structural features of DCM in male mice with diabetes of shorter and longer duration. Mechanistically, these effects were associated with restoration of intra-myocardial expression of miRNA-133a and its target mRNA COL1AI as well as suppression of systemic and localized inflammatory mediators.

Lactiplantibacillus plantarum HY7718 Improves Intestinal Integrity in a DSS-Induced Ulcerative Colitis Mouse Model by Suppressing Inflammation through Modulation of the Gut Microbiota.

Inflammatory bowel disease (IBD), a chronic condition that causes persistent inflammation in the digestive system, is closely associated with the intestinal microbiome. Here, we evaluated the effects of Lactiplantibacillus plantarum HY7718 (HY7718) on IBD symptoms in mice with dextran sulfate sodium (DSS)-induced colitis. Oral administration of HY7718 led to significant improvement in the disease activity index score and the histological index, as well as preventing weight loss, in model mice. HY7718 upregulated the expression of intestinal tight junction (TJ)-related genes and downregulated the expression of genes encoding pro-inflammatory cytokines and genes involved in the TLR/MyD88/NF-κB signaling pathway. Additionally, HY7718 reduced the blood levels of pro-inflammatory cytokines, as well as reversing DSS-induced changes to the composition of the intestinal microbiome. HY7718 also increased the percentage of beneficial bacteria (Lactiplantibacillus and Bifidobacterium), which correlated positively with the expression of intestinal TJ-related genes. Finally, HY7718 decreased the population of pathogens such as Escherichia, which correlated with IBD symptoms. The data suggest that HY7718 improves intestinal integrity in colitis model mice by regulating the expression of TJ proteins and inflammatory cytokines, as well as the composition of the intestinal microflora. Thus, L. plantarum HY7718 may be suitable as a functional supplement that improves IBD symptoms and gut health.

Life-long consumption of high level of fruits and vegetables reduces tumor incidence and extends median lifespan in mice.

Epidemiological studies suggest that consumption of fruits and vegetables (FV) is negatively associated with the incidence of certain cancers and mortality. However, a causal relationship has not been demonstrated. Thus, we investigated the effect of life-long consumption of high level of FV on median lifespan, key biological functions, and pathologies in mice fed low-fat (LF) or high-fat (HF) diets and the underlying mechanisms. Using a 2 × 2 factorial design, 5 weeks-old male C57BL/6J mice were randomly assigned to one of four groups (n = 60/group): LF (LF-C, 10% kcal fat), HF (HF-C, 45% kcal fat) or each supplemented with 15% (w/w) of a unique FV mixture (LF + FV and HF + FV, respectively). Mice were euthanized when one group reached 50% mortality. Body weight and composition, tumor incidence, and death were monitored. Blood levels of lipids and pro-inflammatory cytokines were assessed. After 21 months of feeding, HF-C group reached 50% mortality, at which time mice in all groups were terminated. HF-C had higher mortality (50.0%) compared to the LF-C group (18.3%, p = 0.0008). Notably, HF-FV had lower mortality (23.3%) compared to HF-C group (p = 0.008); there was no significant difference in mortality between HF-FV and LF-C groups. Tumors were found in all groups, and were predominantly present in the liver, followed by those of lung, intestine, and seminal vesicle. Tumor incidence in the HF-C group (73.3%) was higher than that in LF-C group (30.0%, p < 0.0001). HF + FV group had 23.3% lower tumor incidence compared to the HF-C group (p = 0.014). No significant difference in tumor incidence between the LF-C and LF + FV groups was observed. Long-term FV supplementation reduced systemic inflammation and blood lipids. We provide the first causal evidence that life-long intake of a diet, containing a high level and large variety of FV, decreases tumor incidence and extends median lifespan in mice fed a western-style high-fat diet. These effects of FV are at least in part due to reduced blood levels of pro-inflammatory cytokines and improved dyslipidemia.

Abrogation of Acute Inflammation in ICR Mice with Topical Administration of Philippine Stingless Bee (Tetragonula biroi Friese) Honey

Pharmacognosy Research,2023,15,2,258-266.DOI:10.5530/pres.15.2.028Published:February 2023Type:Original Article Authors:Mark Joseph Maranan Desamero, Mikaela Bernadette Andres Rabino, Maria Angelica Rimas Tayao, Mary Jasmin Cabillon Ang, Jussiaea Valente Bariuan, Roxanne Posilero Gapasin, Therese Marie Avena Collantes, Melissa Marie Risos Rondina, Cherry Pambid Fernandez-Colorado, Cleofas Rodriguez Cervancia, and Maria Amelita Celino Estacio Author(s) affiliations:Mark Joseph Maranan Desamero1,2,*, Mikaela Bernadette Andres Rabino1, Maria Angelica Rimas Tayao1, Mary Jasmin Cabillon Ang1, Jussiaea Valente Bariuan1,2, Roxanne Posilero Gapasin1,2, Therese Marie Avena Collantes3, Melissa Marie Risos Rondina4, Cherry Pambid Fernandez-Colorado3, Cleofas Rodriguez Cervancia2,5, Maria Amelita Celino Estacio1,2 1Department of Basic Veterinary Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna, PHILIPPINES. 2UPLB Bee Program, University of the Philippines Los Baños, Laguna, PHILIPPINES. 3Department of Veterinary Paraclinical Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna, PHILIPPINES. 4Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna, PHILIPPINES. 5Institute of Biological Sciences, College of Arts and Sciences, University of the Philippines Los Baños, Laguna, PHILIPPINES Abstract:Background: Honey, a sweet sugar-rich bee-derived product, has been widely recognized in the realm of Ayurveda and Pharmacognosy for the treatment of various inflammatory conditions including inflammatory bowel disease, asthma, arthritis, and gastric ulcer. However, the anti-inflammatory effect of Philippine honey obtained from local stingless bees remains unexplored and poorly investigated. Hence, this study delved on the anti-inflammatory potential of topically applied Philippine stingless bee honey (PSH) using the λ-Carrageenan-induced mouse model of paw edema. Materials and Methods: A total of 30, male ICR mice of six weeks of age were randomly divided into the following groups (n=10 per group) as follows: Distilled water-, 1% Diclofenac sodium-, and Honey-treated group. All treatments were administered immediately after Carrageenan injection and then every 8 hr during the 24-hr test duration. Results: Repeated topical application of PSH significantly attenuated the gross hind paw swelling observed at the onset of the 6 hr post-induction (pi) until the 24 hr pi with Carrageenan in contrast to the Distilled water-treated group. This corresponded histologically to a marked reduction in dermal thickness, dermal edema, and leukocytic infiltration. Whereas, at the cytokine level, this correlated to significant suppression of the circulating blood levels of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6. Conclusion: Based on these results, honey from the Philippine stingless bees shows convincing anti-inflammatory activity which is partly mediated through the regulation of the expression of inflammation-associated cytokines. Keywords:Anti-inflammatory, Honey, IL-1β, IL-6, Philippine stingless bees, TNF-α.View:PDF (1.75 MB)

Effects of transcranial direct current stimulation (tDCS) on pro-inflammatory cytokines: a systematic review

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that causes alterations in the synthesis of several proteins, including cytokines (e.g., Interleukins). Pro-inflammatory cytokines are associated with the presence of pain and their reduction occurs in several pathologies. The aim of this study was to investigate the effects of tDCS on the variation of tissue and serum blood levels of pro-inflammatory cytokines and its relationship with behavioral changes, through a systematic review. PubMed, Embase and Lilacs database searches were performed for articles published in all languages ​​before October 1, 2020. The search was based on the keywords "Transcranial Direct Current Stimulation" or "tDCS" and "IL-1alpha " or "IL-1Beta" or "IL-6" or "IL-8" or "IL-17" or "Tumoral necrosis factor alpha" or "TNF-alpha". The systematic review protocol was registered in PROSPERO (CRD42021283417). Initially, 416 studies were identified in the electronic databases, of which 40 were eliminated because they were duplicates. Of the remaining 376, 358 were excluded after analyzing the title and abstract (selection stage) and 09 were excluded after a complete reading. Nine studies were considered for evaluation. The results demonstrate that tDCS can alter the levels of pro-inflammatory cytokines and modify behaviors in animals, however these findings are variable. Still, the cause and effect relationship between cytokine levels and behavioral changes found was not conclusive. Further studies are needed to establish the mechanisms involved in the action of tDCS on the levels of pro-inflammatory cytokines.

Gut-microbiota-brain axis in the vulnerability to psychosis in adulthood after repeated cannabis exposure during adolescence.

Increasing epidemiological evidence shows that the use of cannabis during adolescence could increase the risk for psychosis in adulthood. However, the precise mechanisms underlying long-lasting cannabis-induced risk for psychosis remain unclear. Accumulating evidence suggests the role of gut microbiota in the pathogenesis of psychiatric disorders. Here, we examined whether gut microbiota plays a role in the risk for psychosis of adult after exposure of cannabinoid (CB) receptor agonist WIN55,212-2 during adolescence. Repeated administration of WIN55,212-2 (2mg/kg/day) during adolescence (P35-P45) significantly increased the expression of Iba1 (ionized calcium-binding adapter molecule 1) in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of adult mice after administration of lipopolysaccharide (LPS: 0.5mg/kg). In contrast, there were no changes in blood levels of pro-inflammatory cytokines between the two groups. Although alpha-diversity and beta-diversity of gut microbiota were no differences between the two groups, there were several microbes altered between the two groups. Interestingly, there were significant correlations between the relative abundance of microbiota and Iba1 expression in the mPFC and NAc. Furthermore, there were also significant correlations between the relative abundance of microbiota and several metabolites in the blood. These findings suggest that gut microbiota may play a role in the microglial activation in the mPFC and NAc of adult mice after repeated WIN55,212-2 exposure during adolescence. Therefore, it is likely that gut-microbiota-microglia crosstalk might play a role in increased risk for psychosis in adults with cannabis use during adolescence.

Increased Serum Levels of Proinflammatory Cytokines Are Accompanied by Fatigue in Military T-6A Texan II Instructor Pilots.

Tactical aviation imposes unprecedented physical challenges including repetitive exposure to hypergravity, hyperoxia, increased work of breathing, and profound cognitive workloads. Each stressor evokes outcomes ranging from musculoskeletal duress and atelectasis to physical and cognitive fatigue, the latter among the foremost threats to aviators. Whereas sleep loss is traditionally considered the primary cause of fatigue in aviators, converging experimental, observational, and medical studies have identified biochemical mechanisms promoting onset of fatigue. Those mechanisms, which fundamentally differ from sleep loss, revolve around increased proinflammatory cytokines, produced and released in response to tissue injury, chronic inflammatory disorders, allergens, or physical duress. This study’s objective was to inform our understanding of potential relationships between serum levels of proinflammatory cytokines and onset of fatigue within a cohort of aviators who experience multiple high-performance sorties on a daily basis. Methods: Active duty and reservist T-6A Texan II instructor pilots were studied on three separate days across their week-long flying schedule. Data collected included a physical assessment, subjective fatigue levels, venous blood samples for measures of chemistry and serum analytes, and urine samples for specific gravity. Results: Twenty-three persons were studied, of which 22 fulfilled minimum study requirements of completing two sorties. The study cohort was comprised of primarily males, age 37.95 ± 4.73 years with a BMI of 26.63 ± 3.15 kg/m2. Of 37 measurable serum analytes, 20 differed significantly (p < 0.05) between baseline values with those measured at the study endpoint. Thirteen of the aviators reported increased fatigue scores across their flying schedule whereas nine did not. Eleven blood serum analytes were associated with increasing levels of fatigue. Discussion: Fatigue in aviators has been attributed almost solely to sleep loss, nocturnal sorties, or disrupted circadian rhythmicity. In contrast, our study findings suggest an alternative mechanism that can promote onset of fatigue: increased blood levels of proinflammatory cytokines. Specific mechanisms triggering synthesis and release of those cytokines and other analytes are yet to be determined. However, their expression patterns suggest responses to both chronic and acute inflammation, hyperoxia, or bronchopulmonary responses to inspiration of dry gas, positive airway pressure, or perhaps atelectasis.

Methamphetamine induces intestinal injury by altering gut microbiota and promoting inflammation in mice

Methamphetamine (METH) is a psychostimulant abused worldwide. Its abuse induces intestinal toxicity. Moreover, the gut microbiota is altered by drugs, which induces intestinal injury. Whether gut microbiota mediates METH-induced intestinal toxicity remains to be validated. In the present study, wild-type and TLR4−/− mice were treated with METH. Gut microbiota was determined using 16S rRNA gene sequencing. Transcriptomics of the intestinal mucosa was performed by RNA-Sequencing. Blood levels of pro-inflammatory cytokines and lipopolysaccharide (LPS), the intestinal barrier, and inflammation were also assessed. METH treatment weakened the intestinal barrier and increased pro-inflammatory cytokines and LPS levels in the blood. Moreover, METH treatment significantly decreased the diversity of probiotics but increased the abundance of pathogenic gut microbiota, contributing to the over-production of LPS and disruption of intestinal barrier. Inflammatory pathways were enriched in the intestinal mucosa of METH-treated mice by KEGG analysis. Consistently, activation of the TLR4 pathway was determined in METH-treated mice, which confirmed intestinal inflammation. However, pretreatment with antibiotics or Tlr4 silencing significantly alleviated METH-induced gut microbiota dysbiosis, LPS over-production, intestinal inflammation, and disruption of the intestinal barrier. These findings suggested that the gut microbiota and LPS-mediated inflammation took an important role in METH-induced intestinal injury. Taken together, these findings suggest that METH-induced intestinal injury is mediated by gut microbiota dysbiosis and LPS-associated inflammation.

Lactate Is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue.

Numerous evidence indicates that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, there is poor understanding of what triggers obesity-induced inflammation. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of proinflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of proinflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this link.

Effect of Azithromycin on Myocardial Resistance to Ischemia/Reperfusion in Systemic Inflammatory Response Syndrome and Alimentary Obesity.

The study focuses on the effects of azithromycin on severity of ischemia/reperfusion myocardial injury during simulated systemic inflammatory response syndrome (SIRS) in primary visceral obesity (PVO). Total ischemia/reperfusion was modeled by Langendorff perfusion of isolated heart with following estimation of the size of myocardial infarction. SIRS was accompanied by an increase in blood levels of proinflammatory cytokines and LPS. Combination of PVO and SIRS produced no significant changes in the infarct size compared to the control. Administration of azithromycin to rats with PVO and SIRS resulted in pronounced alterations of biochemical and immunological parameters, although it did not affect the infarct size. In contrast, the use of tetracycline increased the size of myocardial infarction. This phenomenon should be taken into consideration in antimicrobial therapy.

Selective brain cooling achieves peripheral organs protection in hemorrhagic shock resuscitation via preserving the integrity of the brain-gut axis.

Background: Although whole-body cooling has been reported to improve the ischemic/reperfusion injury in hemorrhagic shock (HS) resuscitation, it is limited by its adverse reactions following therapeutic hypothermia. HS affects the experimental and clinical bowel disorders via activation of the brain-gut axis. It is unknown whether selective brain cooling achieves beneficial effects in HS resuscitation via preserving the integrity of the brain-gut axis.Methods: Male Sprague-Dawley rats were bled to hypovolemic HS and resuscitated with blood transfusion followed by retrograde jugular vein flush (RJVF) with 4 °C or 36 °C normal saline. The mean arterial blood pressure, cerebral blood flow, and brain and core temperature were measured. The integrity of intestinal tight junction proteins and permeability, blood pro-inflammatory cytokines, and multiple organs damage score were determined.Results: Following blood transfusion resuscitation, HS rats displayed gut barrier disruption, increased blood levels of pro-inflammatory cytokines, and peripheral vital organ injuries. Intrajugular-based infusion cooled the brain robustly with a minimal effect on body temperature. This brain cooling significantly reduced the HS resuscitation-induced gut disruption, systemic inflammation, and peripheral vital organ injuries in rats.Conclusion: Resuscitation with selective brain cooling achieves peripheral vital organs protection in hemorrhagic shock resuscitation via preserving the integrity of the brain-gut axis.

Is it possible to use Proton Pump Inhibitors in COVID-19 treatment and prophylaxis?

Coronaviruses (CoV), discovered after 1960, caused human life-threatening outbreaks. SARS-CoV2, which appeared in Wuhan, China in December 2019, causing Severe Acute Respiratory Syndrome and has different features than other coronaviruses, has been determined and the disease caused by the virus has been called “Coronavirus Disease-2019” (COVID-19). This disease activates both the natural and acquired immune system. The cytokin storm, in which blood levels of proinflammatory cytokines are detected excessively high is developing and the uncontrolled inflammatory response causes local and systemic tissue damages. Although a spesific drug has not been found yet, the medications currently in use for other indications, whose pharmacokinetic- pharmacodynamic properties and toxic doses are already known; are included in the treatment practice of COVID-19. These drugs affect the entry of the virus into the cell and its intracellular distribution. They also have anti-inflammatory and immunomodulating effects too. Therefore, we think that Proton Pump Inhibitors (PPI’s) with similar mechanisms of action may also be involved in COVID-19 treatment and prophylaxis.

Effect of Combined Antimicrobial Therapy on Ischemia/Reperfusion Myocardial Injury in Rats with Acute Inflammation of the Large Intestine against the Background of Alimentary Obesity.

We studied the effect of combined antimicrobial therapy with amoxicillin, metronidazole, and clarithromycin on the severity of ischemia/reperfusion myocardial injury in Wistar rats with alimentary obesity and acute inflammation of the large intestine. General ischemia/reperfusion was reproduced on Langendorff-perfused isolated hearts and infarct size was estimated. Acute inflammation of the large intestine was accompanied by an increase in the blood levels of proinflammatory cytokines. The presence of obesity and acute inflammation of the large intestine did not significantly affect the infarct size in comparison with the control. Administration of antimicrobial drugs to animals with obesity and acute inflammation of the large intestine led to a significant increase in the infarct size, which should be considered when prescribing antimicrobial therapy to patients with comorbidity.

Recombinant human milk fat globule-EGF factor VIII (rhMFG-E8) as a therapy for sepsis after acute exposure to alcohol

BackgroundAlcohol intake predisposes to infections and sepsis. Alcohol and sepsis inhibit the expression of milk fat globule epidermal growth factor-factor VIII (MFG-E8), a glycoprotein essential for optimal efferocytosis, resulting in the release of proinflammatory molecules and increased sepsis severity. We previously reported that recombinant mouse (rm) MFG-E8 attenuates sepsis-induced organ injury in rats with acute alcohol intoxication. In order to develop a therapy that can be safely used in humans, we have produced recombinant human (rh) MFG-E8 and evaluated its efficacy to ameliorate sepsis after acute exposure to alcohol.MethodsWe induced acute alcohol intoxication with a bolus injection of alcohol (1.75 g/kg BW) followed by an intravenous infusion of 300 mg/kg/h alcohol for 10 h. Sepsis was then induced by cecal ligation and puncture (CLP). At -10, 0, and 10 h relative to CLP, rats received MFG-E8 or vehicle (albumin) intravenously. Animals were euthanized at 20 h after CLP for blood and tissue collection. Additional groups of animals were used for a survival study.ResultsCompared to vehicle, rhMFG-E8 treatment ameliorated blood levels of proinflammatory cytokines (% improvement: TNF-α 49.8%, IL-6 34.7%) and endotoxin (61.7%), as well as of transaminases (AST 36.2%, ALT 40.1%) and lactate (18.4%). Rats treated with rhMFG-E8 also had a significant histological attenuation of the acute lung injury, as well as a reduction in the number of apoptotic cells in the thymus (43.4%) and cleaved caspase 3 (38.7%) in the spleen. In addition, rhMFG-E8 improved the 10-day sepsis survival rate from 45 to 80%ConclusionrhMFG-E8 significantly ameliorated sepsis in rats with acute alcohol exposure, demonstrating rhMFG-E8’s potential to be developed as an effective therapy for sepsis in alcohol abusers.

Neuroprotection of Resveratrol Against Focal Cerebral Ischemia/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis.

Increasing evidences have shown that resveratrol could protect the brain from ischemic injury; the mechanisms underlying its neuroprotective effects are multifactorial and not fully understood. It remains unclear whether resveratrol could exert neuroprotection through modulating gut-brain axis, which plays important rolesin stroke pathology. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60min) followed by reperfusion for 3 days. Resveratrol, when applied immediately after MCAO onset for 3 days, promoted Th1/Th2 balance towards Th2 polarization and skewed Treg/Th17 balance towards Treg in the small intestinal lamina propria (SI-LP), and decreased small intestinal pro-inflammatory cytokines expression through modulating intestinal flora at 3days post-ischemia (dpi). Resveratrol attenuated cerebral ischemia-induced increase in the epithelial and vascular permeability of small intestine as evidenced by reduced evans blue extravasasion and decreased protein leakage by feces/plasma albumin ratio at 3 dpi. The blood levels of pro-inflammatory cytokines at 3 dpi were also attenuated by resveratrol due to inhibiting intestinal pro-inflammatory immunity and decreasing epithelial and vascular permeability. Resveratrol robustly protected against post-stroke inflammation-induced blood-brain barrier disruption not only in the cortex but also in the striatum at 3 dpi. Furthermore, resveratrol mediated smaller cerebral infarcts and less neurological deficits via decreasing the levels of pro-inflammatory cytokines in the peri-infarct area at 3 dpi. Our results for the first time demonstrated that resveratrol may inhibit systemic post-stroke inflammation and neuroinflammation via modulating intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift in SI-LP, which may be one of the mechanisms underlying the neuroprotective effects of resveratrol.

PRO – AND ANTI-INFLAMMATORY CYTOKINES ARE EARLY MARKERS OF ACUTE REJECTION OF THE TRANSPLANTED KIDNEY

Aim. Determination of diagnostic significance of pro − and anti-inflammatory cytokines in early prognosis of posttransplant renal failure in patients with chronic renal disease.Materials and methods. In the peripheral blood of patients with chronic kidney disease 6 hours before kidney transplantation, multiplex analysis using Simplex ProcartaPlex panel (Bioscience, USA) and xMAP technology (principle of flow cytometry) was used to estimate the content of 10 cytokines: 7 proinflammatory (IL-1b, IL-6, IL-12p70, IL-27, IL-17A, IL-18) and 3 antiinflammatory (IL-1RA, IL-4, IL-13). Identification of HLA-antibodies was carried out with the help of multiplex immunological analysis, using test systems (Gen-Prob, USA), flow analyzer Luminex 200 xMAP technology (bimolecular reactions on the surface of microspheres).Results. The limited diagnostic significance of HLA-antibodies is due to the fact that their detection in the posttransplantation period can be either in the development of acute graft rejection, or in the favorable course of the period after the operation. Meanwhile, the determination of a number of blood cytokines before kidney transplantation allows predicting post-transplantation rejection. In particular, certain criteria favorable course of the period after kidney transplantation by absence of HLA antibodies in patients with chronic renal failure can be considered as the initial (within 6 hours of transplantation) low levels of IL1β, IL6, IL17а. Prognostically the increase in the blood levels of proinflammatory cytokines − IL6, IL17a and anti-inflammatory IL1-RA is a significant marker of acute rejection of a transplanted kidney. Along with this, it is important to note that the appearance of HLA antibodies in patients with a favorable course of the post-transplantation period is associated with an initially elevated level of proinflammatory cytokines such as Il1ß and IL6.Conclusion. Diagnostic value of the evaluated cytokines at the pre-transplant kidney patients determines the feasibility of the inclusion of evaluation of the serum concentration of IL1β, IL6, IL17a, IL1-RA in the programme of pre-transplant laboratory tests .

In Vitro and In Vivo Characterization of Novel Stable Peptidic Ghrelin Analogs: Beneficial Effects in the Settings of Lipopolysaccharide-Induced Anorexia in Mice.

Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment of anorexia and cachexia. However, its biologic stability is highly limited; therefore, a number of both peptide and nonpeptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under nonpathologic conditions and in the context of lipopolysaccharide (LPS)-induced anorexia. These analogs were based on our previous series modified by replacing the Ser3 with diaminopropionic acid (Dpr), the N-terminal Gly with sarcosine, and Phe4 with various noncoded amino acids. New analogs were further modified by replacing the n-octanoyl bound to Dpr3 with longer or unsaturated fatty acid residues, by incorporation of the second fatty acid residue into the molecule, or by shortening the peptide chain. These modifications preserved the ability of ghrelin analogs to bind to the membranes of cells transfected with GHS-R1a, as well as the GHS-R1a signaling activation. The selected analogs exhibited long-lasting and potent orexigenic effects after a single s.c. administration in mice. The stability of new ghrelin analogs in mice after s.c. administration was significantly higher when compared with ghrelin and [Dpr3]ghrelin, with half-lives of approximately 2 hours. A single s.c. injection of the selected ghrelin analogs in mice with LPS-induced anorexia significantly increased food intake via the activation of orexigenic pathways and normalized blood levels of proinflammatory cytokines, demonstrating the anti-inflammatory potential of the analogs.

Comparison of lipid profiles and inflammation in pre- and post-menopausal women with cerebral infarction and the role of atorvastatin in such populations

BackgroundThe risks of atherosclerotic cardiovascular and cerebrovascular diseases in women rapidly increase with age in post-menopausal women. We aimed to investigate the lipid profiles in peri-menopausal women with cerebral infarction and to explore the effects of atorvastatin intervention.MethodsWe collected women aged 40-60 with cerebral infarction between January 2013 and December 2016. Atorvastatin was applied for 6 months in all included patients. Blood lipid profiles, serum pro-inflammation cytokines, intracranial plaque and NIH stroke scale (NIHSS) scores were evaluated before and after atorvastatin treatment.ResultsTotally 210 patients were included. Before atorvastatin treatment, post-menopausal patients had significantly higher levels of triglyceride, cholesterol, low-density lipoprotein and a reduced level of high-density lipoprotein than those in pre-menopausal patients. Blood levels of pro-inflammatory cytokines including interleukin (IL)-1, IL-6 and tumor necrosis factor-α were higher in post-menopausal patients, who had larger intracranial plaques than pre-menopausal patients. Consistently, post-menopausal patients had higher NIHSS scores than pre-menopausal ones. Atorvastatin reduced NIHSS scores and improved dyslipidemia in patients and eliminated the differences of these parameters between pre- and post-menopausal patients.ConclusionsPost-menopausal patients were severer than pre-menopausal patients in terms of dyslipidemia, systemic inflammation and NIHSS scores. Atorvastatin may be beneficial for women with cerebral infarction.

Effects of Transcutaneous Electrical Nerve Stimulation on Proinflammatory Cytokines: Systematic Review and Meta-Analysis.

The mechanism of pain reduction involves bidirectional processes of pain blocking (nociception) and reductions in the levels of proinflammatory cytokines in the blood. Does transcutaneous electrical nerve stimulation (TENS) reduce blood levels of proinflammatory cytokines? For this systematic review, we searched in six databases to identify randomized controlled trials with the criteria: humans older than 18 years (adults), use of TENS in the experimental group, and having at least one pre- and postintervention blood level of at least one proinflammatory cytokine. The risk of bias and the level of evidence were assessed. Five studies were included involving 240 participants. The heterogeneity of the studies was high (I 2: 85%); therefore, we used a random-effects meta-analysis. It was observed through the meta-analysis synthesis measures that there were statistically significant differences following the use of TENS to reduce the general group of cytokines. When grouped by chronic disease, by postoperative settings, or by individual studies in the case of IL-6, it was observed that the significant reduction of cytokines related to the use of TENS was maintained. The use of TENS reduced the blood levels of proinflammatory cytokines (we observed a protective factor of TENS in relation to inflammation). The protocol of the systematic review was registered in PROSPERO, CRD42017060379.

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice

Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice. These results show that OXA enhances the anti-inflammatory and insulin-sensitizing effects of MET through the inhibition of tissue lactate production in db/db mice.