Levels Of Anti-inflammatory Cytokines Research Articles

Kaempferol sophoroside glucoside mitigates acetaminophen-induced hepatotoxicity: Role of Nrf2/NF-κB and JNK/ASK-1 signaling pathways

APAP (Acetaminophen)-induced hepatic injury is a major public health threat that requires continuous searching for new effective therapeutics. KSG (Kaempferol-3-sophoroside-7-glucoside) is a kaempferol derivative that was separated from plant species belonging to different genera. This study explored the protective effects of KSG on ALI (acute liver injury) caused by APAP overdose in mice and elucidated its possible mechanisms. The results showed that KSG pretreatment alleviated APAP-induced hepatic damage as it reduced hepatic pathological lesions as well as the serum parameters of liver injury. Moreover, KSG opposed APAP-associated oxidative stress and augmented hepatic antioxidants. KSG suppressed the inflammatory response as it decreased the genetic and protein expression as well as the levels of inflammatory cytokines. Meanwhile, KSG enhanced the mRNA expression and level of anti-inflammatory cytokine, IL-10 (interleukin-10). KSG repressed the activation of NF-κB (nuclear-factor kappa-B), besides it promoted the activation of Nrf2 signaling. Additionally, KSG markedly hindered the elevation of ASK-1 (apoptosis-signal regulating-kinase-1) and JNK (c-Jun-N-terminal kinase). Furthermore, KSG suppressed APAP-induced apoptosis as it decreased the level and expression of Bax (BCL2-associated X-protein), and caspase-3 concurrent with an enhancement of anti-apoptotic protein, Bcl2 in the liver. More thoroughly, Computational studies reveal indispensable binding affinities between KSG and Keap1 (Kelch-like ECH-associated protein-1), ASK1 (apoptosis signal-regulating kinase-1), and JNK1 (c-Jun N-terminal protein kinase-1) with distinctive tendencies for selective inhibition. Taken together, our data showed the hepatoprotective capacity of KSG against APAP-produced ALI via modulation of Nrf2/NF-κB and JNK/ASK-1/caspase-3 signaling. Henceforth, KSG could be a promising hepatoprotective candidate for ALI.

Human umbilical cord-derived mesenchymal stem cells and nitric oxide modulators attenuate the proinflammatory cytokine pattern in experimental antiphospholipid syndrome in mice

Antiphospholipid syndrome is an autoimmune disease characterized by vascular thrombosis and/or obstetric pathology and the presence of antibodies against membrane phospholipids or certain phospholipid-related proteins. Objective. The aim of the research is to study the effect of mesenchymal stem cells, nitric oxide modulators (L-arginine and aminoguanidine) on the level of cytokines in bronchoalveolar lavage in experimental antiphospholipid syndrome in mice. Material and methods. Antiphospholipid syndrome was modeled on female BALB/c mice by intramuscular injections of cardiolipin 1.2 mg/kg 4 times with a 14-day interval. Cryopreserved human umbilical cord-derived mesenchymal stem cells (5×106 cells/kg) were injected once intraperitoneally, L-arginine (25 mg/kg) and aminoguanidine (10 mg/kg) were administered intraperitoneally 1 time per day during 10 days after APS had developed. The cytokines concentration in bronchoalveolar lavage from the lungs was assessed by means of ELISA in 10 days after APS development. Results. In the bronchoalveolar lavage of the BALB/c mice with experimental APS, an increased level of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and decreased level of anti-inflammatory IL-4 and IL-10 were found. It was established that in cases of APS and administration of stem cells the concentration of proinflammatory cytokines decreased: IL-1β by 32.4 %, IL-6 by 30.6 % and TNF-α by 36.1 %, respectively, compare to the APS animals. At the same time the level of IL-4 increased by 50.5 % and IL-10 – by 57.5 % in the group of animals administered with stem cells compare to those with APS. Conclusion. In cases of correction of modeled antiphospholipid syndrome in mice using mesenchymal stem cells and combined application of mesenchymal stem cells and nitric oxide modulators (L-arginine and aminoguanidine), a decrease in the level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α ) and an increase in the level of anti-inflammatory cytokines (IL-4 and IL-10) in bronchoalveolar lavage has been established.

Piroxicam reduced the intensity of epileptic seizures in a kindling seizure model

ABSTRACT Introduction: The close relationship between inflammatory processes and epileptic seizures is already known, although the exact pathophysiological mechanism is unclear. In this study, the anticonvulsant capacity of piroxicam, an anti-inflammatory drug, was evaluated. A rat pentylenetetrazole kindling model was used. Methods: Male Wistar rats, 8–9 weeks old, received piroxicam (0.15 and 0.30 mg/kg), diazepam (2 mg/kg) or saline for 14 days, and PTZ, on alternate days. Intraperitoneal was chosen as the route of administration. The intensity of epileptic seizures was assessed using a modified Racine scale. The open field test and object recognition analysis were performed at the beginning of the study to ensure the safety of the drugs used. At the end of the protocol, the animals were euthanized to measure the levels of inflammatory (TNF-a and IL-6) and anti-inflammatory (IL-10) cytokines in the cortex, hippocampus, and serum. Results:There were no changes in the open field test and object recognition analysis. Piroxicam was found to decrease Racine scale scores at both concentrations. The reported values for IL-6 levels remained steady in all structures, whereas the TNF-alpha level in the cortex was higher in animals treated with piroxicam than in the saline and diazepam subjects. Finally, animals treated with the anti-inflammatory drug presented reduced IL-10 levels in the cortex and hippocampus. onclusions: Using inflammation as a guiding principle, the anticonvulsant effect of PIRO could be associated with the hippocampal circuits, since this structure showed no increase in inflammatory cytokines.

Anti-cancer Effect of Neocuproine on Oxidative Stress and Inflammatory Levels Induced by Neuroblastoma Cancer Cells

Neocuproine is a free radical scavenger. Neuroblastoma cancer is seen mostly in children. It accounts for approximately 15% of all pediatric cancer deaths. Treatments against SH-SY5Y may be ineffective due to the development of drug resistance, resulting in poor survival in high-risk patients. The goal of this study was to find out how the anti-cancer concentration of Neocuproine affected the levels of oxidants, antioxidants, and cytokines in the SH-SY5Y cell line. Five different concentrations of Neocuproine (12.5, 25, 50, 100, and 200 µM) were applied to the cell line for 24 h. MTT cytotoxicity tests, total oxidant status and total antioxidant capacity tests, and anti-inflammatory cytokine tests were used to look at the uses of Neocuproine. In our results, 100 µM Neocuproine application reduced cancer cell viability up to 69.76%. In addition, it was determined that 100 µM Neocuproine reduced oxidant activity, increased antioxidant capacity, and regulated anti-inflammatory cytokine levels in neuroblastoma cells, consistent with the cytotoxicity test. As a result, it was concluded that Neocuproine has an anti-cancer effect on the SH-SY5Y cell line.

Immunomodulation of Ethyl pyruvate on gestational diabetes mellitus in Mice; The impact on Th17/Treg balance

Gestational diabetes mellitus (GDM) is recognized as one of the most common diseases among pregnant women and inflammatory responses can be a major reason for its induction and development. T helper 17 (Th17)/regulatory T cells (Tregs) imbalance resulting in the increased levels of pro-inflammatory and decreased levels of anti-inflammatory cytokines has been showed as major mechanisms involved in the pathogenesis of GDM. There are various treatment options, but none of them are completely therapeutic. Ethyl pyruvate (EP) is a stable derivate of pyruvate that showed anti-oxidant and anti-inflammatory properties in an in-vivo and in-vitro models. To examine the therapeutic efficacy of EP in GDM, mice were mated and EP (100 mg/kg) was administered intraperitoneally to C57BL/6 mice. EP-treated mice exhibited improved symptoms of GDM by decreased blood glucose levels and body-weight and increased insulin levels and insulin sensitivity. Furthermore, EP could significantly attenuate the impairments to offspring, including birth size and birth weight. The inflammatory responses were also decreased by EP through regulating the production of Th17-related cytokines, such as interleukin (IL)− 17 and IL-21. The levels of other inflammatory cytokines were also inhibited, including IL-1β, IL-6, and tumor necrosis factor (TNF)-α. In addition, it was found that EP increased the population of Tregs and Treg-related cytokines, IL-10 and transforming Growth Factor-β TGF-β, in GDM mice. In conclusion, EP could modulate GDM in mice and might be a potential therapeutic strategy candidate for the treatment of patients with GDM.

Lysophosphatidic Acid Receptor 1 Plays a Pathogenic Role in Permanent Brain Ischemic Stroke by Modulating Neuroinflammatory Responses.

Lysophosphatidic acid receptor 1 (LPA1) plays a critical role in brain injury following a transient brain ischemic stroke. However, its role in permanent brain ischemic stroke remains unknown. To address this, we investigated whether LPA1 could contribute to brain injury of mice challenged by permanent middle cerebral artery occlusion (pMCAO). A selective LPA1 antagonist (AM152) was used as a pharmacological tool for this investigation. When AM152 was given to pMCAO-challenged mice one hour after occlusion, pMCAO-induced brain damage such as brain infarction, functional neurological deficits, apoptosis, and blood-brain barrier disruption was significantly attenuated. Histological analyses demonstrated that AM152 administration attenuated microglial activation and proliferation in injured brain after pMCAO challenge. AM152 administration also attenuated abnormal neuroinflammatory responses by decreasing expression levels of pro-inflammatory cytokines while increasing expression levels of anti-inflammatory cytokines in the injured brain. As underlying effector pathways, NF-κB, MAPKs (ERK1/2, p38, and JNKs), and PI3K/Akt were found to be involved in LPA1-dependent pathogenesis. Collectively, these results demonstrate that LPA1 can contribute to brain injury by permanent ischemic stroke, along with relevant pathogenic events in an injured brain.

CSF levels of proinflammatory and anti-inflammatory cytokines as predictors of cognitive decline across Alzheimer’s disease spectrum (N4.004)

CSF levels of proinflammatory and anti-inflammatory cytokines as predictors of cognitive decline across Alzheimer’s disease spectrum (N4.004)

Role of angiotensin pathway and its target therapy to rescue from experimental cerebral malaria

Cerebral malaria (CM) induced by Plasmodium falciparum is a devastating neurological complication that may lead the patient to coma and death. This study aimed to protect Plasmodium-infected C57BL6 mice from CM by targeting the angiotensin II type 1 (AT1) receptor, which is considered the common connecting link between hypertension and CM. In CM, AT-1 mediates blood–brain barrier (BBB) damage through the overexpression of β-catenin. The AT-1-inhibiting drugs, such as irbesartan and losartan, were evaluated for the prevention of CM. The effectiveness of these drugs was determined by the down regulation of β-catenin, TCF, LEF, ICAM-1, and VCAM-1 in the drug-treated groups. The expression levels of VE-cadherin and vinculin, essential for the maintenance of BBB integrity, were found to be restored in the drug-treated groups. The pro-inflammatory cytokine levels were decreased, and the anti-inflammatory cytokine levels increased with the treatment. As a major highlight, the mean survival time of treated mice was found to be increased even in the absence of treatment with an anti-malarial agent. The combination of irbesartan or losartan with the anti-malarial agent α/β-arteether has contributed to an 80% cure rate, which is higher than the 60% cure rate observed with α/β-arteether alone treatment.

Features of the spectrum of immune markers in patients with juvenile depression with clinically high risk of psychosis

IntroductionIdentification of biomarkers associated with the risk of psychosis manifestation in juvenile patients with depression may contribute to a better understanding of the pathogenesis of mental disorders and early diagnosis.ObjectivesTo determine the level of pro-inflammatory and anti-inflammatory cytokines and other inflammatory indicators in the plasma of juvenile patients with depression and clinically high risk of psychosis, and to study the correlation of these markers with the severity of psychopathologic symptoms.Methods80 young men aged 16-24 years with the first depressive episode (F32.1-2, F32.38, F32.8) were examined. Based on the severity of attenuated psychotic symptoms (APS) in the structure of depression according to the SOPS scale, all patients were divided into two groups - with clinically high risk of psychosis (n=58) and with depression without APS (n=22). The HDRS-21 and SANS scales were also used for psychometric assessment. Serum level of cytokines TNF-α, IL-6, IL-8, IL-10, TNF-α/IL-6 ratio, TNF-α/IL-10 ratio, leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) activity, C-reactive protein (CRP) concentration, and the level of autoantibodies to S-100B protein were determined.ResultsBoth groups of patients showed a high level of inflammation assessed by LE and α1-PI activity (p>0.05). Significantly higher level of IL-6 (p=0.03), CRP concentration (p=0.026) and TNF-α/IL-10 ratio (p=0.032) were found in patients with clinically high risk of psychosis. This group was also characterised by high level of autoantibodies to the S-100B protein compared to patients with depression without APS (p=0.048). In the high clinical risk group, correlations were found between the SOPS positive subscale score and the level of TNF-α (R=0.32, p=0.017), IL-8 (R=-0.3, p=0.034), TNF-α/IL-6 ratio (R=0.30, p=0.021) and TNF-α/IL-10 ratio (R=0.32, p=0.014). The SOPS negative subscale score correlated with CRP concentration (R=0.3, p=0.043). The SOPS total score correlated with TNF-α/IL-10 ratio (R=0.31, p=0.021). In this group of patients, the level of IL-10 was found to correlate with the duration of the disease (R=0.48, p<0.001). In patients with depression without APS, the level of IL-6 was correlated with the severity of depression according to the HDRS scale, and the level of TNF-α was associated with the duration of the depressive episode (R=0.51, p=0.029).ConclusionsThe obtained results confirm the involvement of inflammation in the development of juvenile depression. Qualitative and quantitative characteristics of the spectrum of immune markers and the cytokine profile, and correlations with the severity of psychopathologic symptoms were revealed in patients with clinically high risk of psychosis.Disclosure of InterestNone Declared

Irradiated riboflavin over nonradiated one: Potent antimigratory, antiproliferative and cytotoxic effects on glioblastoma cells.

Riboflavin is a water-soluble yellowish vitamin and is controversial regarding its effect on tumour cells. Riboflavin is a powerful photosensitizer that upon exposure to radiation, undergoes an intersystem conversion with molecular oxygen, leading to the production of ROS. In the current study, we sought to ascertain the impact of irradiated riboflavin on C6 glioblastoma cells regarding proliferation, cell death, oxidative stress and migration. First, we compared the proliferative behaviour of cells following nonradiated and radiated riboflavin. Next, we performed apoptotic assays including Annexin V and caspase 3, 7 and 9 assays. Then we checked on oxidative stress and status by flow cytometry and ELISA kits. Finally, we examined inflammatory change and levels of MMP2 and SIRT1 proteins. We caught a clear antiproliferative and cytotoxic effect of irradiated riboflavin compared to nonradiated one. Therefore, we proceeded with our experiments using radiated riboflavin. In all apoptotic assays, we observed a dose-dependent increase. Additionally, the levels of oxidants were found to increase, while antioxidant levels decreased following riboflavin treatment. In the inflammation analysis, we observed elevated levels of both pro-inflammatory and anti-inflammatory cytokines. Additionally, after treatment, we observed reduced levels of MMP2 and SIRT. In conclusion, radiated riboflavin clearly demonstrates superior antiproliferative and apoptotic effects on C6 cells at lower doses compared to nonradiated riboflavin.

Effect of postbiotic Lactiplantibacillus plantarum LRCC5314 supplemented in powdered milk on type 2 diabetes in mice

Type 2 diabetes (T2D) is a chronic multifactorial disease characterized by a combination of insulin resistance and impaired glucose regulation. The alleviative effects of probiotics on T2D have been widely studied. However, studies on the effects of postbiotics, known as inactivated probiotics, on dairy products are limited. This study aimed to evaluate the effectiveness of postbiotic Lactiplantibacillus plantarum LRCC5314 in milk powder (MP-LRCC5314) in a stress-T2D mouse model. Compared with probiotic MP-LRCC5314, postbiotic MP-LRCC5314 significantly influenced stress-T2D-related factors. The administration of heat-killed MP-LRCC5314 reduced corticosterone levels, increased short-chain fatty acid production by modulating gut microbiota, and regulated immune response, glucose metabolism, stress-T2D-related biomarkers in the brain, gut, and adipose tissues, as well as glucose and insulin sensitivity. Additionally, heat-killed MP-LRCC5314 treatment led to a decrease in pro-inflammatory cytokine levels and an increase in anti-inflammatory cytokine levels. Overall, these findings suggest that adding postbiotic MP-LRCC5314 to milk powder could serve as a potential supplement for stress-T2D mitigation.

The involvement of neuroinflammation in an animal model of dementia and depression

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Comparison of bioactive substances in novel-developed freeze-dried platelet-rich plasma (PRP) and activated normal PRP, and investigation of bioactive substance levels after long-term storage

IntroductionIn recent years, biotherapy in orthopedics has become widespread, and platelet-rich plasma (PRP) has been readily used to treat sports injuries and osteoarthritis. Production of freeze-dried PRP (PRP-FD) results in PRP that is in powder form, allowing it to be stored for long periods at room temperature. Using this technology, we have developed Valuable Platelet-Derived Factor Concentrate Freeze Dry (VFD). However, whether VFD contains sufficient levels of bioactive substances (BS) remains unknown and retains the same levels of BS during long-term storage. In this study, we examined whether VFD contains sufficient amounts of BS and whether they retain these BS levels during long-term storage. MethodsPeripheral blood was collected from 10 healthy men (mean ± SD: 46.5 ± 15 years old) and various BS, including transforming growth factor β (TGF-β), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), tissue inhibitors of metalloproteinases-1 (TIMP-1), interleukin-1 receptor antagonist (IL-1ra), matrix metallopeptidase-9 (MMP-9), and interleukin-6 (IL-6), were compared between VFD and normal PRP samples, including both leukocyte-rich PRP (LR-PRP) and leukocyte-poor PRP (LP-PRP). VFD was prepared using two rounds of centrifugation. LP-PRP and LR-PRP were activated by freezing and thawing before measurement. To evaluate the effects of long-term storage, the BS of VFD purified from five professional football players was compared between baseline and 1 year after storage. ResultsIn terms of the growth factors, the TGF-β and EGF levels were higher in LR-PRP than in VFD and LP-PRP (p < 0.05), while the bFGF levels were higher in VFD than in the LR-PRP and LP-PRP groups (p < 0.01). In terms of anti-inflammatory cytokines, the TIMP-1 level was lower in VFD than that in the other groups (p < 0.01), whereas the IL-1ra levels were higher in VFD than those in LP-PRP (p < 0.05) and lower than those in LR-PRP (p < 0.01). In terms of inflammatory enzymes and cytokines, the IL-1ra level was higher in VFD than that in LP-PRP (p < 0.05) and lower than that in LR-PRP (p < 0.01), whereas the IL-6 levels did not differ among the groups. Furthermore, the TGF-β, bFGF, TIMP-1, and IL-1ra levels were 5.61 → 3.38 (x103 pg/μL), 61.0 → 63.0 (pg/μL), 3.4 → 2.7 (x105 pg/μL), and 14.9 → 14.5 (x103 pg/μL) at baseline and 1 year later, respectively. No significant differences in the BS levels were observed between baseline and 1 year after storage. ConclusionsThe VFD samples prepared in this study exhibited higher levels of anti-inflammatory cytokines than LP-PRP and contained growth factor levels similar to LP-PRP and LR-PRP. In addition, the BS levels in VFD samples were maintained after one year of storage. These results suggest that VFD can be prepared and stored and may serve as a novel treatment strategy for sports injuries in high-risk groups, such as athletes.

Abstract 5312: Agonist CD40 engineered smart immunosomes induced anti-tumor immunity, reduced associated toxicities and showed tumor free survival in murine glioblastoma model

Abstract CD40 agonist antibodies (αCD40) have proven great potential as an anti-cancer immunotherapeutic by showing promising anti-tumor response in both preclinical and early clinical studies. However, it has been observed that the systemic administration of αCD40, even at low dose, is associated with serious immune- and hepato- toxicities. In addition, αCD40 showed low tumor retention and induced PD-L1 expression which makes tumor microenvironment (TME) immunosuppressive. To overcome these issues, in this study, we have developed an immunosome where αCD40 is conjugated on the surface and VJ23, a small molecule immune-modulator was encapsulated inside it . Immunosome showed higher tumor accumulation till 96 hr of administration and displayed sustained release of αCD40 in vivo. Immunosome significantly delayed tumor growth and showed tumor free survival in mice bearing GL-261 glioblastoma tumor by increasing the population of CD45+CD8+ T cells, CD45+CD20+ B cells, CD45+CD11c+ DCs and F4/80+CD86+M1 macrophage in TME. In addition, Immunosome significantly reduced the population of T-regulatory cells, M2 macrophage, and MDSCs and lowered the expression of PD-L1 to modulate immunosuppressive TME. Moreover, Immunosomes significantly enhanced the level of pro-inflammatory cytokines (IFN-γ, IL-6, IL-2) and lowered anti-inflammatory cytokines (IL-4 and IL-10) level which supported anti-tumor response. Most interestingly, Immunosomes averted the in vivo toxicities associated with free αCD40 by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-1α and reduced the degree of liver damage. Our results suggested that this novel formulation can be further explored in clinics to improve the in vivo anti-tumor efficacy of αCD40 while reducing the associated toxicities. Citation Format: Vidit Gaur, Witty Tyagi, Sanjeev Das, Surajit Ganguly, Jayanta Bhattacharyya. Agonist CD40 engineered smart immunosomes induced anti-tumor immunity, reduced associated toxicities and showed tumor free survival in murine glioblastoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5312.

Effect of rifampicin on TLR4-signaling pathways in the nucleus accumbens of the rat brain during abstinence of long-term alcohol treatment.

The treatment with the antibiotic rifampicin (Rif) led to a decrease in the frequency of neurodegenerative pathologies. There are suggestions that the mechanism of action of Rif may be mediated by its effect on toll-like receptor (TLR)4-dependent pathways. We evaluated the expression status of TLR4-dependent genes during abstinence from long-term alcohol treatments in the nucleus accumbens (NAc) of the rat brain, and also studied the effects of Rif to correct these changes. The long-term alcohol treatment was performed by intragastric delivery of ethanol solution. At the end of alcohol treatment intraperitoneal injections of Rif (100mg/kg) or saline were made. Extraction of the brain structures was performed on the 10th day of abstinence from alcohol. We used the SYBR Green qPCR method to quantitatively analyze the relative expression levels of the studied genes. The long-term alcohol treatment promotes an increase in the level of TLR4 mRNA and mRNA of its endogenous ligand high-mobility group protein B1 during abstinence drop alcohol in NAc of rats. The use of Rif in our study led to a decrease in the increased expression of high-mobility group protein B1, Tlr4, and proinflammatory cytokine genes (Il1β, Il6) in the NAc of the rat brain during abstinence of long-term alcohol treatment. In addition, Rif administration increased the decreased mRNA levels of anti-inflammatory cytokines (Il10, Il11). The data obtained indicate the ability of Rif to correct the mechanisms of the TLR4 system genes in the NAc of the rat brain during alcohol abstinence.

Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes

RationaleHeterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating...

Specific transcription factors Ascl1 and Lhx6 attenuate diabetic neuropathic pain by modulating spinal neuroinflammation and microglial activation in mice

Gamma-aminobutyric acid (GABA) neuronal system-related transcription factors (TFs) play a critical role in GABA production, and GABA modulates diabetic neuropathic pain (DNP). The present study investigated the therapeutic effects of intrathecal delivery of two TFs achaete-scute homolog 1 (Ascl1) and LIM homeobox protein 6 (Lhx6) in a mouse model of DNP and elucidated their underlying mechanisms. GABA-related specific TFs, including Ascl1, Lhx6, distal-less homeobox 1, distal-less homeobox 5, the Nkx2.1 homeobox gene, and the Nkx2.2 homeobox gene, were investigated under normal and diabetic conditions. Among these, the expression of Ascl1 and Lhx6 was significantly downregulated in mice with diabetes. Therefore, a single intrathecal injection of combined lenti-Ascl1/Lhx6 was performed. Intrathecal delivery of lenti-Ascl1/Lhx6 significantly relieved mechanical allodynia and heat hyperalgesia in mice with DNP. Ascl1/Lhx6 delivery also reduced microglial activation, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-1β, increased the levels of anti-inflammatory cytokines including IL-4, IL-10, and IL-13, and reduced the activation of p38, c-Jun N-terminal kinase, and NF-κB in the spinal cord of mice with DNP, thereby reducing DNP. The results of this study suggest that intrathecal Ascl1/Lhx6 delivery attenuates DNP via upregulating spinal GABA neuronal function and inducing anti-inflammatory effects.

The Impact of Metabolic Memory on Immune Profile in Young Patients with Uncomplicated Type 1 Diabetes.

Metabolic memory refers to the long-term effects of achieving early glycemic control and the adverse implications of high blood glucose levels, including the development and progression of diabetes complications. Our study aimed to investigate whether the phenomenon of metabolic memory plays a role in the immune profile of young patients with uncomplicated type 1 diabetes (T1D). The study group included 67 patients with uncomplicated type 1 diabetes with a mean age of 15.1 ± 2.3 years and a minimum disease duration of 1.2 years. The control group consisted of 27 healthy children and adolescents with a mean age of 15.1 ± 2.3 years. Patients were divided into three groups according to their HbA1c levels at the onset of T1D, and the average HbA1c levels after one and two years of disease duration. The subgroup A1 had the lowest initial HbA1c values, while the subgroup C had the highest initial HbA1c values. Cytokine levels (including TNF-α, IL-35, IL-4, IL-10, IL-18, and IL-12) were measured in all study participants. Our data analysis showed that subgroup A1 was characterized by significantly higher levels of IL-35 and IL-10 compared to all other groups, and significantly higher levels of IL-4 compared to group B. Additionally, a comparative analysis of cytokine levels between the groups of diabetic patients and healthy controls demonstrated that subgroup A1 had significantly higher levels of anti-inflammatory cytokines. The lipid profile was also significantly better in subgroup A1 compared to all other patient groups. Based on our findings, it appears that an inflammatory process, characterized by an imbalance between the pro- and anti-inflammatory cytokines, is associated with poor glycemic control at the onset of diabetes and during the first year of disease duration. These findings also suggest that both metabolic memory and inflammation contribute to the abnormal lipid profile in patients with type 1 diabetes.

Effects of Mesenchymal Stem Cell-conditioned Media with Natural Immunomodulatory Agent Resveratrol on Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is a condition marked by elevated blood sugar levels and primarily recognized by the destruction of beta cells caused by an autoimmune attack, which is a significant characteristic of T1DM. Recent studies have demonstrated the regenerative potential of conditioned medium therapy. In light of this, the current research sought to assess the impact of Mesenchymal Stem Cell conditioned media (CM) and CM with resveratrol (CM+ Resveratrol) on the management of T1DM in Swiss albino mice. By leveraging and modifying existing conditioned medium therapy, this study aims to evaluate its effectiveness in treating T1DM. Diabetes was induced in animals using the diabetes-inducing agent streptozotocin (STZ). The animals were then divided into five groups: Normal control, Disease Control, Resveratrol, Condition Media, and CM + Resveratrol. Treatments were given to the animals accordingly. The study period was 28 days. During this time, the animals were monitored for foodwater intake twice a week, blood glucose levels, and body weight. At the conclusion of the 28-day study period, biochemical estimations were performed for serum insulin levels, C-peptide levels, anti-inflammatory cytokines levels and pro-inflammatory cytokines levels. Additionally, histopathology of the pancreas was performed. The test groups showed a significant decrease in blood glucose levels, an increase in Cpeptide levels, and a decrease in pro-inflammatory cytokine levels compared to the disease group. However, no statistically significant change within groups was observed in terms of serum insulin and anti-inflammatory cytokine levels. The improvement in diabetic symptoms, such as polyphagia, polydipsia, and weight loss, was observed in the treatment group, along with pancreatic regeneration, which indicated improved insulin secretion. In the current investigation, we concluded that CM and CM+ Resveratrol, as natural immunomodulators, have the capacity to regenerate injured pancreatic beta cells and have antidiabetic action, together with immunomodulating impact. Nonetheless, future studies on this therapy appear to be promising.

Effect of eight weeks of combined exercise and omega-3 supplementation on the levels of inflammatory and anti-inflammatory cytokines in elderly women

Abstract Exercise training and omega-3 supplementation are known to have anti-inflammatory effects; however, the simultaneous effect of exercise training and omega-3 supplementation has received little attention so far. The present study aimed to investigate the effect of combined training (resistance endurance) and omega-3 supplementation on the levels of inflammatory and anti-inflammatory cytokines in older women. The 40 participating older adults, with an average age of 66.7 ± 4.13 years, were randomly assigned to four groups: placebo, omega-3, training and training + omega-3. Combined exercise training (consisted of 30 mins running with 40-70% of reserve heart rate and resistance training included ten exercises, two sets, and each set consisted of 18-20 repetitions) performed for eight weeks and three sessions per week. Omega-3 supplementation was 2,000 mg daily (two 1000 mg capsules, one in the morning and one at night). Blood sampling was performed in pre and post-test (48 h after the last training session and omega-3 supplementation) stages, and interleukin (IL)-6, tumour necrosis factor (TNF)-α, and IL-10 levels were measured by ELISA. The dependent t-test results (pre- and post-test) indicated that there was a statistically significant difference (decrease) in HOMA-IR index, body fat percentage, body mass index, IL-6, and TNF-α in training and training + omega-3 groups, post-exercise (). TNF-α was lower in the omega-3 () training () and training + omega-3 () groups compared to the placebo group, post exercise. Moreover, IL-6 levels in the training () group were lower than in the placebo group, post exercise. Combined training may reduce both TNF-α and IL-6 compared to placebo. In contrast, omega-3 alone or combined with combined training may only reduce TNF-α but not IL-6 concentrations compared to placebo.