Plasma Levels Of IL-6 Research Articles

Significance of triggering receptor expressed on myeloid cells-2 prognostic evaluation in hepatitis B virus-related acute-on-chronic liver failure

Objective: To explore the significance of triggering receptor expressed on myeloid cells-2 (TREM-2) prognostic evaluation so as to provide novel biological markers in clinical practice for patients with hepatitis B virus-related acute-on-chronic liver failure ( HBV-ACLF). Methods: The research subjects of this study were divided into an experimental group and a control group. Fifty HBV-ACLF cases admitted to the Department of Infectious Diseases of the First Affiliated Hospital of Nanchang University from January 1, 2019 to December 31, 2019 were selected as the experimental group. Patients were divided into survival and death groups according to the actual prognosis at discharge (self-discharge and dead patients were considered death groups, and all enrolled patients were hospitalized for more than 28 days). Twenty-five healthy subjects were chosen as the control group. Peripheral venous blood was collected from the experimental group and the control group. Plasma and peripheral blood mononuclear cells (PBMC) were isolated. The concentrations of TREM-2, interleukin (IL)-6, and IL-8 were detected in the plasma. TREM-2 mRNA expression was detected in PBMC. A single blood sample was collected from the control group, whereas five blood samples were dynamically collected from the experimental group on the day of admittance and at 7, 14, 21, and 28 days after treatment commenced. Simultaneously, upon admission, the relevant clinical indicators of HBV-ACLF patients were monitored, including the liver function test: alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, coagulation function test: international normalized ratio, prothrombin time, and other indicators. Measurement data were expressed as mean±standard deviation (x±s). Count data were compared and analyzed using the χ(2) test. The intra-group factor mean was compared using a repeated measures ANOVA. The means were analyzed by t-tests between the two groups. Bivariate correlation analysis was used to analyze the correlation between the two variables. The value of TREM-2 as a diagnostic marker was analyzed using the receiver operating characteristic (ROC) curve. Results: The mRNA expression of TREM-2 in the PBMC of HBV-ACLF patients showed a gradually increasing trend at various time points and was significantly higher in the survival group than that of the control group at 28 days (P < 0.01), while the death group showed a gradually weakening trend at various time points and was significantly lower than the control group at 28 days (P < 0.01). (1) The levels of TREM-2 in the plasma of HBV-ACLF patients generally showed a gradually increasing trend at various time points in the survival group. The levels on the day of admission and 7, 14, 21, and 28 days after the initiation of treatment were (1.49±0.85), (1.62±0.58), (1.95±0.69), (2.33±0.71), and (2.00±0.67) ng/ml, respectively. The expression of TREM-2 in the death group showed a gradually weakening trend at various time points. The levels on the day of admission and 7, 14, 21, and 28 days after initiation of treatment were (1.40±0.73), (1.59±0.79), (1.56±0.80), (1.05±0.49), and (0.81±0.21) ng/ml, respectively. The survival group's various detection time points were higher than those of the death group, and the difference was statistically significant. The plasma level of TREM-2 in the healthy control group was (1.25±0.35) ng/ml. (2) The concentrations of IL-6 and IL-8 in the plasma of HBV-ACLF patients showed a gradually decreasing trend at various time points in the survival group. The levels on the day of admission and 7, 14, 21, and 28 days after initiation of treatment were (46.70±26.31), (33.98±20.28), (19.07±10.24), (14.76±7.84), (9.12±7.65) and (108.29±47.07), (93.85±26.53), (79.27±34.63), (56.72 ±18.30), (37.81±13.88) pg/ml, respectively. However, its concentration in the death group fluctuated within a relatively high range. The levels on the day of admission and 7, 14, 21, and 28 days after the initiation of treatment were (41.94±24.19), (36.99±19.78), (34.30±20.62), (34.14±14.52), (36.64±23.61) and (104.65±50.16), (112.98±45.03), (118.43±45.00), (111.67±40.44), (109.55±27.54) pg/ml, respectively. (3) Bivariate correlation analysis results indicated that the plasma TREM-2 content was negatively correlated with the plasma levels of pro-inflammatory cytokines IL-6 and IL-8 (r = -0.224, P = 0.025; r = - 0.223, P = 0.026). ROC curve analysis showed that the mRNA levels of TREM-2 in PBMCs at various time points for prognostic evaluation of HBV-ACLF patients were 1d=0.667, 7d=0.757, 14d=0.979, 21d=0.986, and 28d= 0.993. The areas under the ROC curve of the TREM-2 content in the plasma at various time points were 1d=0.522, 7d=0.571, 14d=0.658, 21d=0.927, and 28d=0.994. Conclusion: TREM-2 mRNA expression in PBMC and TREM-2 content in plasma have a significant relationship to the prognosis of HBV-ACLF patients and may inhibit the liver inflammatory response by regulating the secretion of pro-inflammatory cytokines IL-6 and IL-8. Dynamic monitoring of TREM-2 expression in peripheral blood is favorable for evaluating the prognostic condition of HBV-ACLF patients.

Plasma levels of IL-6, IL-10, IL-18, TNFα under the conditions of tobacco intoxication and after treatment with aminophthalhydrazide

In response to damaging factors, a cascade of cytokines is released, triggering the processes of inflammation and fibrogenesis. The purpose of our study was to evaluate the levels of cytokines (IL-6, IL-10, IL-18, TNFα) in blood plasma under conditions of tobacco intoxication and with intramuscular administration of aminophthalhydrazide. The experiment was performed with 40 outbred white male rats. Intact group (n = 10) were in a priming chamber in absence of tobacco smoke. Experimental groups (1, 2, and 3) – n = 30, 10 animals in each group. The first and second groups of animals were exposed to tobacco smoke for one and two months. The third experimental group underwent intramuscular injections with sodium aminodihydrophthalazindione for 3, 7, 14 days. The content of IL-6, IL-10, IL-18, TNFα in blood plasma was determined by enzyme immunoassay technique. In 1st group, the TNFα level in blood plasma increased to 452.14±176.18 pg/mL (in intact animals, 15.23±3.13 pg/mL); in the 2nd group, this index decreased to 9.8; in group 3, these values showed a sharp increase (to 167.44±5.93 pg/mL). The level of IL-6 showed maximal values after 4 months of tobacco intoxication (group 3). The following IL-10 changes were observed: in the 1st group, its amounts increased by 1.2-fold; in the 2nd group a sharp decrease in the indindex was noted (13.7 times); in the 3rd group a decreased content of the cytokine was found (28.8 times) as compared with intact animals. After administration of aminodihydrophthalazinedione for 3 and 7 days, the content of TNFα showed sharp increas (14.8 times and 7.6 times, respectively); after 14 days of treatment, the level of TNFα decreased by 1.3 times compared to intact animals. We noted fluctuations in the levels of pro-inflammatory cytokines (IL-6 and IL-18). The level of IL- 10 in blood plasma had a statistically significant increase (5.3-fold at 3 days after drug administration); 8.2-fold 7 days after administration of the drug, and 23-fold after 14 days of treatment, as compared with the 3rd group. The plasma concentrations of TNFα, IL-6, IL-10, IL-18 showed sufficient changes under the conditions of tobacco intoxication. The immune response is characterized by increased levels of pro-inflammatory cytokines in blood plasma. Upon corrective therapy with sodium aminodihydrophthalazindione, an increase in the antiinflammatory IL-10 cytokine occurs, along with systemic decrease in the TNFα, IL-6, and IL-18 contents.

Maternal immune activation mediated prenatal chronic stress induces Th17/Treg cell imbalance may relate to the PI3K/Akt/NF-κB signaling pathway in offspring rats

Maternal immune activation (MIA), defined as elevated levels of inflammatory markers beyond the normal range, can occur due to psychological stress, infection, and other disruptions during pregnancy. MIA affects the immune system development in offspring and increases the risk of immune-related disorders. Limited studies have investigated the effects of prenatal stress on offspring's immune system. In this study, pregnant rats were exposed to chronic unpredictable mild stress (CUMS) during pregnancy, involving seven different stressors. We examined the impact of prenatal stress stimuli on the offspring's immune system and observed activation of the PI3K/Akt/NF-κB signaling pathway, resulting in an imbalance of Th17/Treg cells in the offspring's spleen. Our findings revealed increased plasma levels of corticosterone, IL-1β, and IL-6 in female rats exposed to prenatal stress, as well as elevated serum levels of IL-6 and TNF-α in the offspring. Furthermore, we identified a correlation between cytokine levels in female rats and their offspring. Transcriptome sequencing and qPCR experiments indicated differentially expressed mRNAs in offspring exposed to prenatal stress, which may contribute to the imbalance of Th17/Treg cells through the activation of the Gng3-related PI3K/Akt/NF-κB pathway.

The Effect of Fat Intake with Increased Omega-6-to-Omega-3 Polyunsaturated Fatty Acid Ratio in Animal Models of Early and Late Alzheimer’s Disease-like Pathogenesis

This work aims to clarify the effect of dietary polyunsaturated fatty acid (PUFA) intake on the adult brain affected by amyloid pathology. McGill-R-Thy1-APP transgenic (Tg) rat and 5xFAD Tg mouse models that represent earlier or later disease stages were employed. The animals were exposed to a control diet (CD) or an HFD based on corn oil, from young (rats) or adult (mice) ages for 24 or 10 weeks, respectively. In rats and mice, the HFD impaired reference memory in wild-type (WT) animals but did not worsen it in Tg, did not cause obesity, and did not increase triglycerides or glucose levels. Conversely, the HFD promoted stronger microglial activation in Tg vs. WT rats but had no effect on cerebral amyloid deposition. IFN-γ, IL-1β, and IL-6 plasma levels were increased in Tg rats, regardless of diet, while CXCL1 chemokine levels were increased in HFD-fed mice, regardless of genotype. Hippocampal 3-nitrotyrosine levels tended to increase in HFD-fed Tg rats but not in mice. Overall, an HFD with an elevated omega-6-to-omega-3 ratio as compared to the CD (25:1 vs. 8.4:1) did not aggravate the outcome of AD regardless of the stage of amyloid pathology, suggesting that many neurobiological processes relevant to AD are not directly dependent on PUFA intake.

Can curcumin supplementation break the vicious cycle of inflammation, oxidative stress, and uremia in patients undergoing peritoneal dialysis?

Background & AimsTurmeric (a source of curcumin) is an excellent food to modulate oxidative stress, inflammation, and gut dysbiosis in patients with chronic kidney disease (CKD). However, no studies report the benefits of curcumin in patients undergoing peritoneal dialysis (PD). This study aims to evaluate the effects of curcuminoid supplementation on oxidative stress, inflammatory markers, and uremic toxins originating from gut microbiota in patients with CKD undergoing PD. MethodsThis longitudinal, randomized, single-blind, placebo-controlled trial evaluated 48 patients who were randomized into two groups: Curcumin (three capsules of 500mg of Curcuma longa extract, with 98.42% total curcuminoids) or placebo (three capsules of 500mg of starch) for twelve weeks. In the peripheral blood mononuclear cells (PBMCs), the transcriptional expression levels of Nrf2, HOX-1 and NF-κB were evaluated by quantitative real-time PCR. Oxidative stress was evaluated by malondialdehyde (MDA) and total Thiol (T-SH). TNF-α and IL-6 plasma levels were measured by ELISA. P-cresyl sulphate plasma level, a uremic toxin, was evaluated by high-performance liquid chromatography (HPLC) with fluorescent detection. ResultsTwenty-four patients finished the study: 10 in the curcumin group (57.5 ± 11.6 years) and 14 in the placebo group (56.5 ± 10.0 years). The plasma levels of MDA were reduced after 12 weeks in the curcumin group (p = 0.01), while the placebo group remained unchanged. However, regarding the difference between the groups at the endpoint, no change was observed in MDA. Still, there was a trend to reduce the p-CS plasma levels in the curcumin group compared to the placebo group (p = 0.07). Likewise, the concentrations of protein thiols, mRNA expression of Nrf2, HOX-1, NF-κB, and cytokines plasma levels did not show significant changes. ConclusionCurcuminoid supplementation for twelve weeks attenuates lipid peroxidation and might reduce uremic toxin in patients with CKD undergoing PD. This study was registered on Clinicaltrials.gov as NCT 04413266

Soluble P2X7 Receptor Plasma Levels in Obese Subjects before and after Weight Loss via Bariatric Surgery

Obesity is a systemic disease frequently associated with important complications such as type 2 diabetes and cardiovascular diseases. It has also been proven that obesity is a disease associated with chronic low-grade systemic inflammation and that weight loss improves this low-grade chronic inflammatory condition. The P2X7 purinergic receptor (P2X7R), belonging to the family of the receptors for extracellular ATP, is a main player in inflammation, activating inflammasome and pro-inflammatory cytokine production. In this study, we evaluated the plasma levels of soluble P2X7R (sP2X7R) measured in a group of obese patients before and one year after bariatric surgery. Furthermore, we evaluated the relation of sP2X7R to inflammatory marker plasma levels. We enrolled 15 obese patients who underwent laparoscopic sleeve gastrectomy, evaluating anthropometric parameters (weight, height, BMI and waist circumference) before and after surgery. Moreover, we measured the plasma levels of inflammatory markers (CRP, TNFα and IL-6) before and after weight loss via bariatric surgery. The results of our study show that one year after bariatric surgery, obese patients significantly decrease body weight with a significant decrease in CRP, TNF-alfa and IL-6 plasma levels. Similarly, after weight loss, obese subjects showed a significant reduction in sP2X7R plasma levels. Moreover, before surgery, plasma levels of sP2X7R were inversely related with those of CRP, TNF-alfa and IL-6. Given the role of P2X7R in inflammation, we hypothesized that, in obese subjects, sP2X7R could represent a possible marker of chronic low-grade inflammation, hypothesizing a possible role as a mediator of obesity complications.

Autonomic and cytokine mechanisms of acute electroacupuncture in a rodent model of functional dyspepsia.

Cytokines have been presumed to play an important role in the pathophysiology of functional dyspepsia (FD). Electroacupuncture (EA) has been used for FD treatment; however, its mechanisms remain largely unknown. This study aimed to (1) compare the plasma levels of cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, in "FD" rats with normal control rats; (2) investigate whether EA, using chronically implanted electrodes, could inhibit the release of these cytokines; and (3) explore the correlation of cytokine levels with plasma norepinephrine (NE) levels and gastric emptying (GE). A rodent model of FD was established via neonatal treatment with intragastric iodoacetamide. After 8 weeks, the rats were implanted with electrodes at acupoint ST36 for EA. The plasma levels of cytokines and NE were measured using enzyme-linked immunosorbent assay. We explored the correlations of cytokine levels with NE levels and GE. (i) "FD" rats demonstrated increased levels of TNF-α, IL-1β, and IL-6 (p < 0.05 each) compared with the control rats. (ii) EA significantly decreased the plasma levels of TNF-α, IL-1β, and IL-6 in "FD" rats (p < 0.05 each) compared with sham EA. (iii) The plasma levels of NE were positively correlated with those of IL-6 (r = 0.86, p < 0.05) and IL-1β (r = 0.81, p < 0.05), whereas NE levels and GE were negatively correlated with IL-10 levels (r = -0.870, p < 0.05 and r = -0.791, p < 0.05, respectively). EA inhibits the release of proinflammatory cytokines probably via the suppression of sympathetic activity in "FD" rats.

SARS-CoV-2 infection as a model to study the effect of cinnamaldehyde as adjuvant therapy for viral pneumonia

BackgroundThe recent pandemic outbursts, due to SARS-CoV-2, have highlighted once more the central role of the inflammatory process in the propagation of viral infection. The main consequence of COVID-19 is the induction of a diffuse pro-inflammatory state, also defined as a cytokine storm, which affects different organs, but mostly the lungs. We aimed to prove the efficacy of cinnamaldehyde, the active compound of cinnamon, as an anti-inflammatory compound, able to reduce SARS-CoV-2 induced cytokine storm.ResultsWe enrolled 53 COVID-19 patients hospitalized for respiratory failure. The cohort was composed by 39 males and 13 females, aged 65.0 ± 9.8 years. We reported that COVID-19 patients have significantly higher IL-1β and IL-6 plasma levels compared to non-COVID-19 pneumonia patients. In addition, human mononuclear cells (PBMCs) isolated from SARS-CoV-2 infected patients are significantly more prone to release pro-inflammatory cytokines upon stimuli. We demonstrated, using in vitro cell models, that macrophages are responsible for mediating the pro-inflammatory cytokine storm while lung cells support SARS-CoV-2 replication upon viral infection. In this context, cinnamaldehyde administration significantly reduces SARS-CoV-2-related inflammation by inhibiting NLRP3 mediated IL-1β release in both PBMCs and THP-1 macrophages, as well as viral replication in CaLu-3 epithelial cells. Lastly, aerosol-administered cinnamaldehyde was able to significantly reduce IL-1β release in an in vivo lung-inflammatory model.ConclusionThe obtained results suggest the possible use of cinnamaldehyde as a co-adjuvant preventive treatment for COVID-19 disease together with vaccination, but also as a promising dietary supplement to reduce, more broadly, viral induced inflammation.

Does liraglutide alleviate inflammation in brain-dead donors? A randomized clinical trial.

Brain death triggers an inflammatory cascade that damages organs before procurement, adversely affecting the quality of grafts. This randomized clinical trial aimed to compare the efficacy of liraglutide compared to placebo in attenuating brain death-induced inflammation, endoplasmic reticulum stress, and oxidative stress. We conducted a double-blinded, placebo-controlled, randomized clinical trial with brain-dead donors. Fifty brain-dead donors were randomized to receive subcutaneous liraglutide or placebo. The primary outcome was the reduction in IL-6 plasma levels. Secondary outcomes were changes in other plasma pro-inflammatory (IL-1β, interferon-γ, TNF) and anti-inflammatory cytokines (IL-10), expression of antiapoptotic ( BCL2 ), endoplasmic reticulum stress markers ( DDIT3/CHOP , HSPA5/BIP ), and antioxidant ( superoxide dismutase 2 , uncoupling protein 2 ) genes, and expression TNF, DDIT3, and superoxide dismutase 2 proteins in liver biopsies. The liraglutide group showed lower cytokine levels compared to the placebo group during follow-up: Δ IL-6 (-28 [-182, 135] vs. 32 [-10.6, 70.7] pg/mL; p = 0.041) and Δ IL-10 (-0.01 [-2.2, 1.5] vs. 1.9 [-0.2, 6.1] pg/mL; p = 0.042), respectively. The administration of liraglutide did not significantly alter the expression of inflammatory, antiapoptotic, endoplasmic reticulum stress, or antioxidant genes in the liver tissue. Similar to gene expression, expressions of proteins in the liver were not affected by the administration of liraglutide. Treatment with liraglutide did not increase the organ recovery rate [OR = 1.2 (95% CI: 0.2-8.6), p = 0.82]. Liraglutide administration reduced IL-6 and prevented the increase of IL-10 plasma levels in brain-dead donors without affecting the expression of genes and proteins related to inflammation, apoptosis, endoplasmic reticulum stress, or oxidative stress.

In patients with acute myocardial infarction interleukin-8 levels are related to impaired renal function and predict recurrent infarction or death at 1-year follow-up - a case-control study

Abstract Introduction Acute myocardial infarction (AMI) induces a surge of inflammatory cytokines. IL-8, secreted by endothelial cells and monocyte-macrophages, rapidly recruits immune cells to the infarcted tissue. Previous studies in chronic kidney disease reported IL-8 to be associated with an increased inflammatory burden. Little is known about the diagnostic and prognostic value of IL-8 plasma levels in patients with AMI. Purpose We aimed to explore the diagnostic and prognostic value of IL-8 plasma levels in AMI patients. Methods Patients with AMI (STEMI and NSTEMI) were included from the SPUM-ACS cohort selecting a time window &amp;lt;24 h from symptom onset to blood sampling before PCI. Patients with malignancies or on immunosuppressive therapies were excluded. 160 patients with recurrent AMI or death within 1-year follow-up (cases) were compared to 160 counterparts with favorable outcome matched for age, sex, AMI subtype, and pain onset time (controls). 45 healthy blood donors (HD) without cardiovascular disease were added as an age- and sex-matched reference group. Heparin-plasma was used for Mesoscale U Plex cytokine analyses. The median and interquartile ranges (IQR) were compared using the non-parametric Kruskal-Wallis test. Relation of baseline characteristics to IL-8 levels within cases and controls was assessed with linear regression analyses. Kaplan-Meier curves were computed, selecting the cut-off value in consideration of the overall median IL-8 level. Results Cases (median=59.5, IQR=112.0 pg/mL) showed higher IL-8 plasma levels than HD (median=38.6, IQR=25.1 pg/mL, p=0.0006, Figure 1). Cases also had higher plasma IL-8 levels compared to controls (median=41.2, IQR=51.7 pg/mL, p=0.0006, Figure 1). Considering the median IL-8 level (50.1 pg/ml) as cut-off, cases with higher IL-8 had higher rates of recurrent MI or all-cause death than those with lower IL-8 levels within one year (log-rank p=0.002, Figure 2) with divergence between the subgroups seen early within the first two months. After correction for possible confounding factors (BMI, hypertension history, dyslipidaemia, diabetes, smoking, use of statins, LDL, Troponin, LVEF, and NT-proBNP), eGFR (estimated glomerular filtration rate) remained the only predictor for increased IL-8 (SRC: -0.178, p=0.016) in AMI patients. Conclusions In patients with AMI increased IL-8 levels predict subsequent MI or death at one-year follow-up. Lower eGFR is related to elevated IL-8 levels. Patients with AMI may thus profit from early IL-8 blocking therapies, particularly in the setting of impaired renal function.

High dose NAD+ boosting as pan-sirtuin activation increases atherosclerotic plaques and systemic inflammation in Apoe knockout mice

Abstract Background NAD+ (nicotinamide adenine diphosphate) is a cosubstrate of sirtuins (SIRT) that are activated upon caloric restriction. The nuclear SIRT1 and SIRT6 exert protective effects on atherothrombosis through immunometabolic pathways. By supplementing its precursors, an increase in the NAD+ pool has been reported to extend life span in mice. However, supplementing NAD+ precursors may also stimulate inflammation depending on the context. Nicotinamide riboside (NR) is a precursor of NAD+, whose supplementation has been used to combat metabolic syndromes and liver steatosis. Notably, the effects of pan-sirtuin activation using NR on atherosclerosis remain unknown. Purpose We hypothesized that NR supplementation confers atheroprotection by activating the NAD+ sirtuin axis. We aimed to test this hypothesis by investigating the effects of NR supplementation on plaque formation using an atherosclerosis-prone mouse model. Methods 8-week-old male apolipoprotein E (ApoE) knockout (KO) mice were fed for 12 weeks a high-cholesterol diet (HCD, 1.25 wt%) supplemented with three NR doses: 0, 1.2, and 2.4 g/kg diet. The groups were designated as NR-, NR+, and NR++, respectively (n=14/group). After overnight fasting, aortae, liver, and blood were collected. Cytokines were analyzed using a multiplex ELISA. Triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels were determined by colorimetry and the Friedewald equation. Cross sections of the aortic root were stained with Oil-Red O. Results High-dose (HD) NR supplementation increased plaque thickness in NR++ ApoE KO mice, compared with NR+ mice (Figure 1A and B). In parallel, plasma expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 as well as TG and LDL-C levels were increased in NR++ mice (Figure 1C-F) suggesting that NR supplementation induced systemic inflammation and disturbed lipid metabolism. Analyses of liver lysates showed that expression levels of SIRT1 were decreased and CD38 increased in NR++ mice. Full length PARP1 remained unchanged, while both cleaved PARP1 and total PARylation in liver decreased. NAD+ concentrations in liver and plasma remained unchanged. These data suggest that an increase in hepatic CD38 might consume more NAD+ in the atherosclerotic environment and could be the culprits for worsening atherosclerotic progression and systemic inflammation (Figure 2). Conclusions HD NR supplementation increased plaque thickness, as well as IL-6 and LDL-C plasma levels, moderate NR dose had neutral effects. Elevated hepatic expression levels of CD38 and decreased SIRT1 may at least in part explain the atherosclerotic phenotype. Thus, HD NR supplementation in mice does not decrease but worsen atherosclerosis and induce systemic inflammation. A cautious approach should be considered when applying NAD+ boosting in patients with atherosclerotic disease.

Abstract 16198: Targeting Lipid Nanoparticles to the Blood Brain Barrier to Ameliorate Acute Ischemic Stroke

There are more than 7.6 million new cases of ischemic strokes annually. Despite numerous unsuccessful drug trials for acute ischemic stroke (AIS), one common reason for their failure is the limited concentration of drugs reaching the at-risk penumbra. To address this issue, we have utilized nanotechnology to significantly enhance drug concentrations in the blood-brain barrier (BBB) of the penumbra. The increased BBB permeability during AIS is believed to be detrimental to neurons due to exposure to toxic plasma proteins. To develop drug-loaded nanocarriers targeted to the BBB, we have conjugated them with antibodies that bind to various cell adhesion molecules (CAMs) on the BBB endothelium. In a mouse model of AIS induced by transient middle cerebral artery occlusion, we compared the accessibility of nanocarriers targeting platelet endothelial CAM (PECAM), intercellular CAM (ICAM), and vascular CAM (VCAM), including liposomes and lipid nanoparticles (LNP). VCAM-targeted liposomes exhibited significantly higher uptake in the ipsilateral hemisphere compared to the contralateral counterpart, and superior targeting with a 2.5-fold higher uptake than ICAM, 1.9-fold higher than PECAM, and 20-fold higher than the untargeted control IgG counterpart (A). Similarly, VCAM-targeted LNP displayed a 3.4-fold, 2.4-fold, and 12.2-fold higher uptake than ICAM, PECAM, and IgG, respectively (B). Flow cytometry analysis revealed that VCAM-targeted liposomes were primarily associated with endothelial cells and leukocytes (C). In a therapeutic study, VCAM-targeted dexamethasone-loaded liposomes or IL-10 mRNA-loaded LNP reduced the infarct volume by 35% and 73%, respectively (D). VCAM/IL-10 mRNA LNP also achieved a 100% survival rate (E) and elevated plasma levels of IL-10. In conclusion, VCAM-targeted lipid nanoparticles provide a novel platform for effectively concentrating drugs within the compromised BBB of the penumbra, thereby improving the outcomes of AIS.

Timed adoptive T cell transfer during chemotherapy in patients with recurrent platinum-sensitive epithelial ovarian cancer

BackgroundThe presence of T cells and suppressive myeloid cells in epithelial ovarian cancer (EOC) correlate with good and bad clinical outcome, respectively. This suggests that EOC may be sensitive to...

Assessing the gene expression of the adenosine 5'-monophosphate-activated protein kinase (AMPK) and its relation with the IL-6 and IL-10 plasma levels in COVID-19 patients.

Metabolic dysregulation and excessive inflammation are implicated in the pathogenesis of the highly infectious disease of coronavirus disease 2019 (COVID-19), which is caused by a newly emerging coronavirus (i.e., severe acute respiratory syndrome-coronavirus 2; SARS-CoV-2). The adenosine 5'-monophosphate-activated protein kinase (AMPK), an energy sensor regulating the metabolic pathways in diverse cells, exerts a regulatory role in the immune system. This study aims to examine the mRNA expression level of AMPK and the plasma levels of interleukin-6 (IL-6) and IL-10 cytokines in patients with different grades of COVID-19. Peripheral blood was collected from 60 patients with COVID-19 (Moderate, severe, and critical). The plasma levels of IL-6 and IL-10 were quantified by enzyme-linked immunosorbent assay (ELISA), and the mRNA expression level of AMPK was determined using real-time PCR. The results showed that the plasma levels of IL-6 increased significantly in critical and severe patients compared to moderate cases of COVID-19 (P < 0.001). Moreover, IL-10 plasma concentrations were significantly higher in critical and severe cases than in moderate cases of COVID-19 (P < 0.01 and P < 0.05, respectively). Also, the gene expression of AMPK was meaningfully enhanced in critical patients relative to moderate and severe cases of COVID-19, in order (P < 0.001 and P < 0.01, respectively). There was a positive association between AMPK gene expression and plasma levels of IL-6 and IL-10 (P = 0.006, r = 0.348, P = 0.028, r = 0.283, respectively). Increasing AMPK gene expression is likely a necessary effort of the immune system to inhibit inflammation in critical COVID-19. However, this effort seems to be inadequate, probably due to factors that induce inflammation, like erythrocyte sedimentation rate (ESR) and IL-6.

Biological correlates of treatment resistant depression: a review of peripheral biomarkers.

Many patients fail to respond to multiple antidepressant interventions, being defined as "treatment-resistant depression" (TRD) patients. TRD is usually associated with increased severity and chronicity of symptoms, increased risk of comorbidity, and higher suicide rates, which make the clinical management challenging. Efforts to distinguish between TRD patients and those who will respond to treatment have been unfruitful so far. Several studies have tried to identify the biological, psychopathological, and psychosocial correlates of depression, with particular attention to the inflammatory system. In this paper we aim to review available studies assessing the full range of biomarkers in TRD patients in order to reshape TRD definition and improve its diagnosis, treatment, and prognosis. We searched the most relevant medical databases and included studies reporting original data on possible biomarkers of TRD. The keywords "treatment resistant depression" or "TRD" matched with "biomarker," "inflammation," "hormone," "cytokine" or "biological marker" were entered in PubMed, ISI Web of Knowledge and SCOPUS databases. Articles were included if they included a comparison with healthy controls (HC). Of the 1878 papers identified, 35 were included in the present study. Higher plasma levels of IL-6 and TNF-α were detected in TRD patients compared to HC. While only a few studies on cortisol have been found, four papers showed elevated levels of C-reactive protein among these patients and four articles focused on immunological cells. Altered kynurenine metabolism in TRD patients was reported in two studies, while contrasting results were found with regard to BDNF. Only a few biological alterations correlate with TRD. TNF-α seems to be the most relevant biomarker to discriminate TRD patients from both HC and treatment-responsive MDD patients. Moreover, several discrepancies among studies have been found, due to methodological differences and the lack of a standardized diagnostic definition of TRD.

Therapeutic Efficacy of Mesenchymal Stem/Stromal Cell Small Extracellular Vesicles in Alleviating Arthritic Progression by Restoring Macrophage Balance.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and damage, often associated with an imbalance in M1/M2 macrophages. Elevated levels of anti-inflammatory M2 macrophages have been linked to a therapeutic response in RA. We have previously demonstrated that mesenchymal stem/stromal cell small extracellular vesicles (MSC-sEVs) promote M2 polarization and hypothesized that MSC-sEVs could alleviate RA severity with a concomitant increase in M2 polarization. Here, we treated a mouse model of collagen-induced arthritis (CIA) with MSC-sEVs. Relative to vehicle-treated CIA mice, both low (1 μg) and high (10 μg) doses of MSC-sEVs were similarly efficacious but not as efficacious as Prednisolone, the positive control. MSC-sEV treatment resulted in statistically significant reductions in disease progression rate and disease severity as measured by arthritic index (AI), anti-CII antibodies, IL-6, and C5b-9 plasma levels. There were no statistically significant differences in the treatment outcome between low (1 μg) and high (10 μg) doses of MSC-sEVs. Furthermore, immunohistochemical analysis revealed that concomitant with the therapeutic efficacy, MSC-sEV treatment increased anti-inflammatory M2 macrophages and decreased pro-inflammatory M1 macrophages in the synovium. Consistent with increased M2 macrophages, histopathological examination also revealed reduced inflammation, pannus formation, cartilage damage, bone resorption, and periosteal new bone formation in the MSC-sEV-treated group compared to the vehicle group. These findings suggest that MSC-sEVs are potential biologic disease-modifying antirheumatic drugs (DMARDs) that can help slow or halt RA joint damage and preserve joint function.

Characterization of IL-10 Family of Cytokines in Acute and Convalescent COVID-19 Individuals.

Cytokines are major players in orchestrating inflammation, disease pathogenesis, and severity during COVID-19. Members of the interleukin (IL)-10 family of cytokines play important roles in regulating immune responses to various inflammatory and infectious diseases. However, the role of the IL-10 family of cytokines in COVID-19 remains elusive. Hence, we determined the plasma levels of the IL-10 family of cytokines (IL-10, IL-19, IL-20, IL-22, and IL-24) in 7 groups of COVID-19 individuals, based on days since real-time reverse transcriptase-polymerase chain reaction confirmation of SARS-CoV-2 infection. Our data show that the levels of IL-10, IL-19, IL-20, IL-22, and IL-24 cytokines decreased from days 15-30 to days 61-90 and plateaued thereafter. Severe COVID-19 patients exhibit increased plasma levels of IL-10, IL-19, IL-20, IL-22, and IL-24 compared to mild patients. Thus, our study provides evidence of alterations in the plasma levels of the IL-10 family of cytokines in convalescent COVID-19 individuals.

Effects of Lactobacillus rhamnosus Supplementation on Growth Performance, Immune Function, and Antioxidant Capacity of Newborn Foals.

This study aimed to explore the effects of Lactobacillus rhamnosus GG (LGG) supplementation on the growth performance, immune function, and antioxidant capacity of foals. Fifteen newborn foals with similar birth weight (51.67 ± 6.07 kg) and good health were randomly assigned to three groups: control group and test groups I and II, which were supplemented with 5.0 × 109 CFU/day and 1.0 × 1010 CFU/day LGG, respectively, for 150 days. LGG intake increased the daily body height (P < .01) and weight (P < .01) gain of foals aged 120 to 150 days. The foals' IgA (P < .05) and IgG (P < .01) plasma levels increased at 30 and 150 days, respectively, and IL-6 plasma level increased at 90 days (P < .01). Plasma total antioxidant capacity level was significantly higher in test group I than in the control and test group II at 30 days (P < .01), whereas glutathione peroxidase level was significantly higher in test group II than in the control and test group I at 30 days (P < .01). Both test groups had significantly higher superoxide dismutase level than the control group (P < .01) and significantly decreased malondialdehyde plasma level at 90 and 150 days (P < .05). Overall, our findings indicate that dietary supplementation of LGG can improve the growth performance, immune function, and antioxidant capacity of newborn foals.

Genetic and inflammatory effects on childhood trauma and cognitive functioning in patients with schizophrenia and healthy participants

Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.

The potential immuno-stimulating effect of curcumin, piperine, and taurine combination in hepatocellular carcinoma; a pilot study

BackgroundThis is a phase II clinical trial to investigate the immunotherapeutic effect of Curcumin, Piperine, and Taurine (CPT) combination in hepatocellular carcinoma (HCC).MethodsTwenty-six HCC patients aged (50–80 years) were recruited for administration of a daily dose of 5 g of curcumin, 50 mg of piperine, and 500 mg of taurine divided into three doses for successive 3 months. The three components (CPT) were prepared in one capsule. Patients were assessed after each month (cycle) for the plasma levels of CD4, CD8, CD25, Interleukins-2 (IL-2), IL-6, IL-12, Interferon-gamma (IFN- γ), Lactate dehydrogenase (LDH), and Vascular endothelial growth factor (VEGF), FOXP3 mRNA, and miRNA 21.ResultsThere was a significant increase in the plasma levels of CD4 and CD8, while a significant decrease in the CD25 level after the second and third cycles compared to the baseline level [P < 0.001 for both]. Also, there was a significant increase in the plasma levels of IL-2, IL-12, and IFN-γ [ P = 0.001, P = 0.006, and P = 0.029; respectively], while there was a significant decrease in IL-6, VEGF-α, LDH, and Alpha-fetoprotein (AFP) after CPT administration compared to the baseline levels [P < 0.001, P < 0.001, P = 0.020, and P = 0.004; respectively].The expression level of miRNA-21 was significantly decreased after CPT administration compared to the baseline level [5.5±0.88, 4.1±0.78, 3±0.75, and 2.5±0.76; respectively, P<0.001]. Though there was a noticeable decrease in the FOXP3 expression after each cycle, however, it didn’t reach a significant level [5.3±0.8, 4.2±0.76, 3.2±0.67, and 2.5±0.79; respectively, P=0.184].ConclusionCPT could exhibit a potential immune-stimulating effect in HCC patients. The current trial had been registered at the National Hepatology and Tropical Medicine Research Institute (NHTMRI), with a registration number of NHTMRI-IRB 2-21 on 5th January 2021.