Levels Of Pro-inflammatory Cytokines Research Articles

Racial differences in systemic immune parameters in individuals with lung cancer

IntroductionRacial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer. MethodsPatients scheduled to receive cancer immunotherapy were enrolled in a multi-institutional prospective biospecimen collection registry. Clinical and demographic information were obtained from electronic medical records. Pre-treatment peripheral blood samples were collected and analyzed for cytokines using a multiplex panel and for immune cell populations using mass cytometry. Differences between Black and White patients were determined and corrected for multiple comparisons. ResultsA total of 187 patients with non-small cell lung cancer (Black, 19; White, 168) were included in the analysis. Compared to White patients, Black patients had greater comorbidity (median Charlson Comorbidity Index 5 vs. 3; P=0.04) and were more likely to have received prior chemotherapy (79% vs. 47%; P=0.03). Black patients had significantly lower levels of CCL23 and CCL27, and significantly higher levels of CCL8, CXCL1, CCL26, CCL25, CCL1, IL-1b, CXCL16, and IFN-γ (all P<0.05, FDR<0.1). Black patients also exhibited greater populations of non-classical CD16+ monocytes, NKT-like cells, CD4+ cells, CD38+ monocytes, and CD57+ gamma delta T cells (all P<0.05). ConclusionsBlack and White patients with lung cancer exhibit several differences in immune parameters, with Black patients exhibiting greater levels of numerous pro-inflammatory cytokines and cell populations. The etiology and clinical significance of these differences warrant further evaluation.

In Vivo Chemosuppressive Effects of Kolaviron on 7,12-Dimethylbenzanthracene-Induced Mammary Lesions are Associated with Changes in Levels of Estrogen Receptor-α, CYP 1A1, Proinflammatory Cytokines, and Alterations to Metabolic Pathways Implicated in Mammary Carcinogenesis.

Garcinia kola is a medicinal food commonly consumed in Sub-Sahara Africa, for which Kolaviron (KV) is the active portion. As a follow-up to our earlier chemopreventive studies, we investigated the chemotherapeutic effects of KV on experimentally induced mammary carcinogenesis in female Wistar rats. Mammary carcinogenesis was induced using 80 mg/kg of 7,12-dimethylbenzanthracene (DMBA) administered by oral gavage. One hundred-fifty days post-DMBA induction, estrogen receptor-α (ER-α) levels were determined in the experimental rats before treatment with KV commenced. Treatment was done using 50, 100, and 200 mg/kg KV thrice a week for 4 weeks, after which the experiment was terminated. Significantly higher levels of estrogen receptor-α, CYP 1A1, malondialdehyde, formation of lobular neoplastic cells, epithelial hyperplasia, lymphocyte infiltration, and increased cytokine (interleukin-6 and tumor necrosis factor-α) activity were observed in DMBA-induced rats, which were attenuated in KV-treated rats. Tyrosine metabolism was exclusively enriched in DMBA-induced rats in contrast to KV-treated rats. Collectively, the results point to the chemotherapeutic potential of KV.

Serum-Derived Extracellular Vesicles for the Treatment of Severe Ocular Surface Disease

PurposeAutologous serum is widely used for the treatment of severe ocular surface disease with mixed efficacy. Extracellular vesicles (EVs) are small membrane bound structures present in all body fluids, including serum. This study compared the proteomic, metabolomic, and inflammatory cytokine composition of serum-derived EVs (SDEVs) to that of the soluble free protein fraction and the subsequent capacity of SDEVs to induce corneal epithelial cell migration and inflammation. MethodsSDEVs were isolated from human serum using size exclusion chromatography. SDEVs were analyzed using nanoparticle tracking analysis, transmission electron microscopy, and western blotting. The effects of SDEVs on corneal epithelial cell migration were tested using a standard scratch assay. Inflammatory cytokines in SDEVs and the free protein fraction were quantified using a microarray. A mutli-omics approach was further used to define SDEV cargo. The ability of SDEVs to modulate inflammation in corneal epithelial cells was quantified using ELISAs. ResultsWestern blot and TEM confirmed the presence of SDEVs. Proinflammatory cytokines, along with complement proteins and TGF-β, were decreased in SDEVs compared to serum. Metabolites present in SDEVs were mostly involved in amino acid biosynthesis, the TCA cycle and oxidative phosphorylation. SDEVs exhibited pro-migratory effects similar to serum however, SDEVs did not induce secretion of IL-6 or IL-8. ConclusionsSDEVs exhibit reduced levels of pro-inflammatory cytokines while retaining the beneficial wound healing properties of serum. Unlike serum, SDEVs do not induce inflammation. SDEVs may represent an alternative option for patients with severe ocular surface disease where traditional autologous serum has failed.

Stratum corneum hydration levels are negatively correlated with HbA1c levels in the elderly Chinese.

Highlights Stratum corneum hydration levels are negatively correlated with HbA1c levels and positively correlated with skin surface pH. Individuals with type 2 diabetes display lower levels of stratum corneum hydration. Because low stratum corneum hydration levels can increase circulating levels of proinflammatory cytokines, which are linked to the pathogenesis of type 2 diabetes, improvement in stratum corneum hydration can be an alternative approach in the management of type 2 diabetes.

Maternal exposure to 4-tert-octylphenol causes alterations in the morphology and function of microglia in the offspring mouse brain

4-tert-Octylphenol (OP), an endocrine disrupting chemical is widely used in the production of industrial products. Prenatal exposure to endocrine-disrupting chemicals negatively affects the brain. However, the influence of OP exposure during neurodevelopment in adult offspring remains unclear. Thus, in the present study, we investigated the effects of maternal OP exposure on brain development in adult offspring by analyzing primary glial cell cultures and mice. Our findings revealed that OP exposure led to a specific increase in the mRNA expression of the ionized calcium-binding adapter molecule 1 (Iba-1) and the proportion of amoeboid microglia in the primary glial cell culture and adult offspring mice. Exposure to OP increased the transcriptional activation of Iba-1 and estrogen response element, which were counteracted by estrogen receptor antagonists ICI 182,780. Moreover, OP exposure increased the nuclear localization of the estrogen receptor. Remarkably, OP exposure decreased the mRNA expression levels of proinflammatory cytokines and genes associated with immune response in the brains of the offspring. OP exposure upregulated actin filament-related genes and altered cytoskeletal gene expression, as demonstrated by microarray analysis. The morphological changes in microglia did not result in an inflammatory response following lipopolysaccharide treatment. Taken together, the effects of OP exposure during neurodevelopment persist into adulthood, resulting in microglial dysfunction mediated by estrogen receptor signaling pathways in the brains of adult offspring mice.

Aberrant overexpression of the autoantigen protein vimentin promotes Th17 cell differentiation and autoimmune arthritis via activation of STAT3 signaling

Vimentin contributes to the positioning and function of organelles, cell migration, adhesion, and division. However, secreted vimentin accumulates on the cell surface (Mor-Vaknin et al., 2003; Ramos et al., 2020 [1,2]) where it acts as a coreceptor for viral infection and as an autoantigen in inflammatory and autoimmune diseases. The roles of vimentin in Th17 cells were examined in mice with knockdown of vimentin. We also examined whether STAT3 is required for vimentin expression.Vimentin expression was significantly increased in Th17 cells through STAT3 activation, and vimentin+ IL-17+ T cells were markedly increased in the joint and spleen tissues of CIA mice. The arthritis score and expression levels of proinflammatory cytokines were significantly decreased in CIA mice treated with vimentin shRNA vector.In this study, we demonstrated that vimentin is significantly expressed in Th17 cells through STAT3 activation. Our results provide new insights into the role of vimentin in Th17 cells and the complex pathogenesis of RA.

Correlation Between Reduced IL-1β Levels in Acne Lesions and the Decrease in Acne Inflammatory Lesions Following Topical Vitamin D Administration: A Double-Blind Randomized Controlled Trial.

The inflammatory process in acne vulgaris (AV) is characterized by the upregulation of specific pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and IL-8, within sebocytes and keratinocytes. Sebocytes have been identified as target cells for bioactive vitamin D. Experimental studies on animal models have demonstrated the potent comedolytic effects of topical vitamin D. However, further research is required to specifically evaluate the impact of vitamin D on inflammatory lesions in acne vulgaris (AV). To evaluate the effectiveness of topical vitamin D in treating acne vulgaris (AV) lesions by investigating its anti-inflammatory effects on pro-inflammatory cytokine modulation, specifically assessing the correlation between IL-1β levels in acne lesions and the reduction in AV severity. This study is a double-blind, randomized, placebo-controlled clinical trial with a 2-arm design over an 8-week intervention period. Participants were randomly assigned to either the topical vitamin D group (cholecalciferol 50 mcg) or the topical placebo group, with each group comprising 32 subjects. All participants received concomitant treatment with topical adapalene 0.1%. Cytokine levels within acne lesions were assessed using Luminex Polystyrene Screening Assays to detect and quantify IL-1β levels. The effectiveness of the treatment was evaluated by monitoring the reduction in the number of inflammatory lesions, while the safety of topical vitamin D was assessed by documenting and analyzing any reported side effects. The study found a significant correlation between the reduction in IL-1β levels within acne lesions and the decrease in moderate and severe inflammatory lesions in acne vulgaris (p = 0.028). The topical application of vitamin D led to a significant reduction in inflammatory AV lesions (p = 0.045). No significant topical side effects were observed in either the vitamin D or placebo groups. This study demonstrates that the topical administration of vitamin D in acne vulgaris (AV) lesions is effective in reducing pro-inflammatory cytokine levels within acne lesions and in decreasing the severity of AV. NCT05758259. September 5, 2022.

Cadmium-induced lung injury disrupts immune cell homeostasis in the secondary lymphoid organs in mice

Cadmium is a well-known toxic heavy metal that poses significant health risks, particularly through inhalation, smoking, and the consumption of contaminated food. Exposure to cadmium is linked to the development and exacerbation of chronic lung diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). This study investigated the systemic effects of intratracheal cadmium chloride (0.5mg/kg) instillation in C57BL/6 mice. All parameters, including inflammation assessment, lung function evaluation (using Flexi-vent), and immunophenotyping of T-cells in secondary lymphoid organs (spleen and mediastinal lymph nodes), were analyzed 14 days after Cd exposure. The results demonstrated that cadmium exposure led to significant immune cell infiltration in bronchoalveolar lavage (BAL) fluid, altered pro-inflammatory cytokine levels, and was associated with impaired lung function, characterized by increased lung resistance and Newtonian resistance. Analysis of T-cell populations revealed no significant changes in total T-cells in mediastinal lymph nodes and spleen, but a decrease in CD4+ T-cells and an increase in CD8+ T-cells were observed. These findings suggest that cadmium disrupts T-cell homeostasis in secondary lymphoid organs. Further research is crucial to elucidate the mechanisms underlying cadmium-induced lung injury and immune dysregulation, essential for developing effective therapeutic interventions against chronic lung diseases caused by cadmium exposure.

Probiotic Lactiplantibacillus plantarum subsp. plantarum Dad-13 Alleviates 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis Through Short-Chain Fatty Acid Production and Inflammatory Cytokine Regulation.

The development of inflammatory bowel disease (IBD) is closely linked to inflammatory damage and dysbiosis. Recently, probiotics are being increasingly used to improve intestinal health. Probiotic-based therapies can prevent IBD by restoring the balance of gastrointestinal microbiota, reducing gut inflammation, and increasing the concentration of short-chain fatty acids (SCFAs). The present study aimed to investigate the protective effects of Lactiplantibacillus plantarum subsp. plantarum Dad-13, a novel probiotic strain derived from dadih (Indonesian curd from buffalo milk), on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in BALB/c mice. The results showed that probiotic Dad-13 supplementation at a dose of 107 or 109 CFU/mL improved the clinical symptoms of IBD and enhanced the production of SCFAs, particularly propionate and butyrate. Moreover, probiotic Dad-13 supplementation significantly decreased the levels of pro-inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-6, and IL-1β] and significantly increased the levels of anti-inflammatory cytokines (IL-10). These findings show that L. plantarum Dad-13 can effectively prevent TNBS-induced colitis by modulating SCFA production and inflammatory cytokines.

Bee Venom Reduces Early Inflammation and Oxidative Stress Associated with Lipopolysaccharide-induced Alpha-synuclein in the Substantia Nigra-striatum Axis.

Neuroinflammation and oxidative stress are important features in the pathogenesis and development of synucleinopathies, the glial activation and upregulation of pro-inflammatory and oxidative mediators induce alpha-synuclein (α-syn) accumulation. Recent studies have shown that bee venom (BV) has beneficial effects on symptoms of these neurodegenerative diseases. BV is known to exert anti-inflammatory and anti-oxidative effects. Here, we investigated the effects of BV over the different inflammatory and oxidative markers, and in the expression of α-syn and tyrosine hydroxylase (TH) in a lipopolysaccharide (LPS)-induced rat model of synucleinopathies. We examined whether BV (1.5 mg/kg by acupoint injection ST36 six times every 48 h) could change the α-syn and TH expression measured by western blotting, also, observed the activation of microglia and astrocytes by immunofluorescence, quantified the proinflammatory cytokines levels of tumoral necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β) by enzyme-linked immunosorbent assay (ELISA), and estimated the lipid peroxidation and the activity of superoxide dismutase (SOD) and catalase (CAT) by colorimetric kits in LPS-treated rats (2.5 µg by a single dose intranigral injection) in substantia nigra (SN) and striatum (STR) brain areas. In the LPS-injected rat brain, BV treatment reduced α-syn levels and increased the TH levels. In addition, we observed lower microglia and astrocyte activation in SN and STR. Furthermore, BV decreases IL-1β and lipid peroxidation and increases the CAT activity in the STR. These results indicate that BV can restore the α-syn and TH levels possibly by the inhibition of LPS-induced neuroinflammation and oxidation, also, these results suggest that BV could be a promising treatment option for synucleinopathies.

Ternary inulin hydrogel with long-term intestinal retention for simultaneously reversing IBD and its fibrotic complication.

Excessive accumulation of reactive oxygen and nitrogen species (RONS) and dysbiosis of intestinal microbiota are pivotal symptoms for inflammatory bowel disease (IBD) and its associated complications, such as intestinal fibrosis. This research introduces a probiotic inulin hydrogel loaded with polypyrrole (PPy) nanozymes and antifibrotic drug pirfenidone (PFD) (PPy/PFD@Inulin gel) designed for the concurrent amelioration of IBD and its fibrotic complication. Upon oral administration, the inulin gel matrix could extend the gastrointestinal residence time of PPy nanozymes and PFD, facilitating the efficient reduction of pro-inflammatory cytokine levels and enhancement of the intestinal epithelial barrier repair as well as the suppression of intestinal fibrosis through sustained RONS scavenging, modulation of gut microbiota and attenuation of the TGF-β/Smad signaling pathway to inhibit fibroblast proliferation. Notably, the PPy/PFD@Inulin gel demonstrated significant prophylactic and therapeutic efficacy in acute and chronic colitis as well as intestinal fibrosis induced by dextran sodium sulfate (DSS) in mouse models. Thus, the engineered ternary PPy/PFD@Inulin gel offered a pioneered paradigm for simultaneous reversal of IBD and its associated complications, such as intestinal fibrosis, in a single therapeutic regimen.

Cytokine imbalance as a factor of postoperative complications of third mandibular molar extraction

Background. Tooth extraction is considered the most frequently performed operation in surgical dentistry, which can often cause inflammatory complications. Modern research has come a long way in terms of developing methods for the prevention, diagnosis and treatment of these complications, but the search for their early laboratory markers remains an urgent task to this day.The aim of the study. To determine prognostic laboratory criteria for the development of local inflammatory complications of third mandibular molar extraction.Methods. The study included 35 people who underwent extraction of a third mandibular (semi-impacted) molar. Before the surgery, immediately after the surgery, 1, 2, 3 and 4 days after the surgery, we assessed the objective status of the patients and collected oral fluid from the oral cavity, in which we determined the concentrations of cytokines using enzyme-linked immunosorbent assay. After the surgery, patients were divided into a control group and a group with complications with determination of their cytokine status.Results. Immediately after the surgery, patients from the group with complications, compared with patients from the control group, had significantly higher levels of proinflammatory cytokines – interleukin (IL) 1, IL-8 and comparable levels of tumor necrosis factor α and anti-inflammatory cytokines IL-4 and IL-10. Integral cytokine indices in both groups showed a sharp shift towards pro-inflammatory direction in patients with complications. This fact determines the protracted or progressive nature of the inflammatory process after the surgery.Conclusion. Determining the level of individual cytokines and cytokine indices in the oral fluid after the extraction of a third mandibular molar allows us to identify early markers for the chronicity of the inflammatory process, to predict its further course and to take appropriate measures to prevent the development of expected complications.

Cytokine Storm in Pathogenesis of COVID-19 Complications

The aim. To explore the current literature and key findings concerning the cytokine storm contribution to pathogenesis of COVID-19 complications and mortality, and summarize clinical and pathologic features of cytokine storm in COVID-19 patients. A cytokine storm is a hyperinflammatory state secondary to excessive production of cytokines by deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading in most severe cases even to death. Cytokine storm has recently emerged as key aspect in COVID-19 disease, as affected patients show high levels of several key pro-inflammatory cytokines, some of which also correlate with disease severity. The current review describes the role of critical cytokines in COVID-19-mediated cytokine storm. Key findings of the studies are provided further. A cytokine storm is associated with COVID-19 severity and is also a crucial cause of death from COVID-19. Impaired acquired immune responses and uncontrolled inflammatory innate responses may be associated with the mechanism of cytokine storm in COVID-19. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. In COVID-19 patients, pyroptosis triggers the release of proinflammatory cytokines and affects macrophage and lymphocyte functions, causing peripheral lymphopenia. Cytokine storm is characterized by a clinical presentation of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, and multi-organ failure. The cytokine storm clinical findings are attributed to the action of pro-inflammatory cytokines like interleukin-1, interleukin-6, tumor necrosis factor alpha, vascular endothelial growth factor.

Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes

BackgroundPatients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated.MethodsTo explore this, we generated pericyte-like cells from human induced pluripotent stem cells (iPSCs) harboring the Swedish mutation in the amyloid precursor protein (APPswe) along with cells from healthy controls. We initially verified the expression of classic pericyte markers in these cells. Subsequent functional assessments, including permeability, tube formation, and contraction assays, were conducted to evaluate the functionality of both the APPswe and control cells. Additionally, bulk RNA sequencing was utilized to compare the transcriptional profiles between the two groups.ResultsOur study reveals that iPSC-derived pericyte-like cells (iPLCs) can produce Aβ peptides. Notably, cells with the APPswe mutation secreted Aβ1-42 at levels ten-fold higher than those of control cells. The APPswe iPLCs also demonstrated a reduced ability to support angiogenesis and maintain barrier integrity, exhibited a prolonged contractile response, and produced elevated levels of pro-inflammatory cytokines following inflammatory stimulation. These functional changes in APPswe iPLCs correspond with transcriptional upregulation in genes related to actin cytoskeleton and extracellular matrix organization.ConclusionsOur findings indicate that the APPswe mutation in iPLCs mimics several aspects of CAA pathology in vitro, suggesting that our iPSC-based vascular cell model could serve as an effective platform for drug discovery aimed to ameliorate vascular dysfunction in AD.

Comparison of Protective Effects of Polyphenol-Enriched Extracts from Thinned Immature Kiwifruits and Mature Kiwifruits against Alcoholic Liver Disease in Mice.

Alcoholic liver disease (ALD) is regarded as one of the main global health problems. Accumulated evidence indicates that fruit-derived polyphenols can lower the risk of ALD, this attributed to their strong antioxidant capacities. Thinned immature kiwifruits (TIK) are the major agro-byproducts in the production of kiwifruits, which have abundantly valuable polyphenols. However, knowledge about the protective effects of polyphenol-enriched extract from TIK against ALD is still lacking, which ultimately restricts their application as value-added functional products. To promote their potential applications, phenolic compounds from TIK and their corresponding mature fruits were compared, and their protective effects against ALD were studied in the present study. The findings revealed that TIK possessed extremely high levels of total phenolics (116.39 ± 1.51 mg GAE/g DW) and total flavonoids (33.88 ± 0.59 mg RE/g DW), which were about 7.4 times and 4.8 times greater than those of their corresponding mature fruits, respectively. Furthermore, the level of major phenolic components in TIK was measured to be 29,558.19 ± 1170.58 μg/g DW, which was about 5.4 times greater than that of mature fruits. In particular, neochlorogenic acid, epicatechin, procyanidin B1, and procyanidin B2 were found as the predominant polyphenols in TIK. In addition, TIK exerted stronger in vitro antioxidant and anti-inflammatory effects than those of mature fruits, which was probably because of their higher levels of polyphenols. Most importantly, compared with mature fruits, TIK exhibited superior hepatoprotective effects on alcohol-induced liver damage in mice. The administration of polyphenol-enriched extract from TIK (YK) could increase the body weight of mice, reduce the serum levels of ALP, AST, and ALT, lower the levels of hepatic TG and TC, and diminish lipid droplet accumulation and hepatic tissue damage. In addition, the treatment of YK could also significantly restore the levels of antioxidant enzymes (e.g., SOD and CAT) in the liver and lower the levels of hepatic proinflammatory cytokines (e.g., IL-6, IL-1β, and TNF-α), indicating that YK could effectively ameliorate ALD in mice by reducing hepatic oxidative stress and hepatic inflammation. Collectively, our findings can provide sufficient evidence for the development of TIK and their extracts as high value-added functional products for the intervention of ALD.

Rap1A Modulates Store-Operated Calcium Entry in the Lung Endothelium: A Novel Mechanism Controlling NFAT-Mediated Vascular Inflammation and Permeability.

Store-operated calcium entry mediated by STIM (stromal interaction molecule)-1-Orai1 is essential in endothelial cell (EC) functions, affecting signaling, NFAT (nuclear factor for activated T cells)-induced transcription, and metabolic programs. While the small GTPase Rap1 isoforms, including the predominant Rap1B, are known for their role in cadherin-mediated adhesion, EC deletion of Rap1A after birth uniquely disrupts lung endothelial barrier function. Here, we elucidate the specific mechanisms by which Rap1A modulates lung vascular integrity and inflammation. The role of EC Rap1A in lung inflammation and permeability was examined using in vitro and in vivo approaches. We explored Ca2+ signaling in human ECs following siRNA-mediated knockdown of Rap1A or Rap1B. Rap1A knockdown, unlike Rap1B, significantly increased store-operated calcium entry in response to a GPCR (G-protein-coupled receptor) agonist, ATP (500 µmol/L), or thapsigargin (250 nmol/L). This enhancement was attenuated by Orai1 channel blockers 10 μmol/L BTP2, 10 μmol/L GSK-7975A, and 5 μmol/L Gd3+. Whole-cell patch clamp measurements revealed enhanced Ca2+ release-activated Ca2+ current density in siRap1A ECs. Rap1A depletion in ECs led to increased NFAT1 nuclear translocation and activity and elevated levels of proinflammatory cytokines (CXCL1, CXCL11, CCL5 [chemokine (C-C motif) ligand 5], and IL-6 [interleukin-6]). Notably, reducing Orai1 expression in siRap1A ECs normalized store-operated calcium entry, NFAT activity, and endothelial hyperpermeability in vitro. EC-specific Rap1A knockout (Rap1AiΔEC) mice displayed an inflammatory lung phenotype with increased lung permeability and inflammation markers, along with higher Orai1 expression. Delivery of siRNA against Orai1 to lung endothelium using lipid nanoparticles effectively normalized Orai1 levels in lung ECs, consequently reducing hyperpermeability and inflammation in Rap1AiΔEC mice. Our findings uncover a novel role of Rap1A in regulating Orai1-mediated Ca2+ entry and expression, crucial for NFAT-mediated transcription and endothelial inflammation. This study distinguishes the unique function of Rap1A from that of the predominant Rap1B isoform and highlights the importance of normalizing Orai1 expression in maintaining lung vascular integrity and modulating endothelial functions.

Molecular Dissection of the Arsenic-Induced Leukocyte Incursion into the Inflamed Thymus and Spleen and Its Amelioration by Co-supplementation of L-Ascorbic Acid and α-Tocopherol.

Arsenic, a surreptitious presence in our environment, perpetuates a persistent global menace with its deleterious impacts. It possesses the capability to trigger substantial immunosuppression by instigating inflammation in critical organs like the thymus and spleen. L-Ascorbic acid (L-AA) exhibits robust immunoregulatory prowess by orchestrating the epigenetic terrain through TET and JHDM pathways. Conversely, α-tocopherol (α-T) demonstrates the capacity to dampen the production of pro-inflammatory cytokines by modulating the PI3K-Akt axis. Given these insights, this inquiry embarks on exploring the mitigative potential of L-AA and α-T co-supplementation at the transcriptome level within leukocytes under arsenic exposure. Concurrently, the research endeavours to unravel the potent anti-inflammatory effects of administering α-T and L-AA, alleviating inflammation within the spleen and thymus amidst arsenic-induced insult and delving deeply into their immunomodulatory mechanisms. The rats were randomly allocated into eight distinct groups for subsequent experimentation: (I) the control group was administered solely with distilled water as the vehicle (control); (II) NaAsO2-treated group (As); (III) NaAsO2 treated along with L-ascorbic acid and α-tocopherol supplemented group (As + L-AA + α-T); (IV) L-ascorbic acid and α-tocopherol supplemented group (L-AA + α-T); (V) NaAsO2 treated along with L-ascorbic acid supplemented group (As + L-AA); (VI) only L-ascorbic acid supplemented group (L-AA); (VII) NaAsO2 treated along with α-tocopherol supplemented group (As + α-T); (VIII) only α-tocopherol supplemented group (α-T). Rats treated with NaAsO2 exhibited an increased neutrophil count in their bloodstream, as revealed by a comprehensive transcriptomic analysis showcasing heightened expressions of ItgaM, MMP9, and Itga4 within circulating leukocytes under arsenic exposure. Concurrently, arsenic heightened the expression of pro-inflammatory cytokines within the thymus and spleen. This elevated cytokine activity promoted the upregulation of ICAM-1 on vascular endothelial cells, facilitating the infiltration of Ly6g + leukocytes into the afflicted thymus and spleen. Remarkably, the combination of L-AA acid and α-T demonstrated substantial therapeutic efficacy, adeptly reducing the influx of Ly6g + leukocytes into these immune sites and subsequent reduction of excessive collagen deposition. The dynamic duo of L-AA and α-T achieved this amelioration by suppressing the expression of ItgaM, MMP9, and Itga4 mRNA within circulating leukocytes and moderating tissue levels of pro-inflammatory cytokines in arsenic-exposed thymus and spleen.

Neurological Restorative Effects of (-)-Epicatechin in a Model of Gulf War Illness.

Gulf War Illness (GWI) afflicts US military personnel who served in the Persian Gulf War. Suspect causal agents include exposure to pyridostigmine (PB), permethrin (PM) and N,N-diethyl-m-toluamide (DEET). Prominent symptoms include cognitive deficits, such as memory impairment. In aging animal models, we have documented the beneficial effect of the flavanol (-)-epicatechin (Epi) on hippocampus structure and related function. Using a rat model of GWI, we examined the effects of Epi on hippocampus inflammation, oxidative stress, mitochondrial dysfunction, cell death/survival pathways, and memory endpoints. Male Wistar rats underwent 3 weeks of exposure to either vehicles or DEET, PM, PB, and stress. Subgroups of GWI rats were then allocated to receive orally 15 days of either water (vehicle) or 1 mg/kg/day of Epi treatment. Object recognition tasks were performed to assess memory. Hippocampus samples were analyzed. Epi treatment yields significant improvements in short- and long-term memory versus GWI rats. Hippocampus oxidative stress and pro-inflammatory cytokine levels showed significant increases with GWI that were largely normalized with Epi becoming comparable to controls. Significant increases in markers of hippocampus neuroinflammation and cell death were noted with GWI and were also largely reduced with Epi. Neuronal survival signaling pathways were adversely impacted by GWI and were partially or fully restored by Epi. Markers of mitochondrial function were adversely impacted by GWI and were fully restored by Epi. In conclusion, in an animal model of GWI, Epi beneficially impacts recognized markers of hippocampus neuroinflammation, oxidative stress, cell survival, neurotoxicity and mitochondrial function leading to improved memory.

The involvement of proinflammatory cytokines in the pathogenesis of audiogenic epilepsy

Epilepsy is a heterogeneous disease, which determines the relevance of investigating the mechanisms of pathogenesis of its various types, including reflex epilepsy. Pharmacotherapy is common for the treatment of patients with epilepsy, however, despite the significant recent achievements, 20-30% of patients remain resistant to the ongoing treatment. The urgency of creating new antiepileptic drugs, in particular, immune ones is due not only to a significant proportion of pharmacoresistant cases, but also to the struggle for the quality of life of patients. The neuroinflammation system in animals with different genetically determined audiogenic epilepsy proneness was investigated. These genetic groups were Krushinsky–Molodkina rats (tonic seizures of maximum intensity in response to the action of sound) and “0” strain (control group, non-convulsive phenotype). The main proinflammatory cytokines levels in the dorsal striatum and brain stem in rats of these genetic groups were measured by multiplex immunofluorescence assay. Background levels of IL-1â, IL-6 and TNFá in the dorsal striatum of KM rats were significantly lower than in the control “0” strain rats, whereas in the brain stem in the “background” levels of these metabolites did not differ. Four hours after the sound exposure, the TNFá level in the dorsal striatum of KM rats was significantly lower than in “0” rats. In KM rats, after the sound exposure and subsequent tonic seizures, the levels of IL-1â and IL-6 in the dorsal striatum were significantly higher than in the background. The IL-2 content was not detected in the background in KM rats, whereas after audiogenic seizures its level was 14.01 pg/ml. In the brain stem of KM rats, the levels of IL-1â and TNFá after audiogenic seizures were significantly lower than in the background. In rats of the “0” strain, cytokine levels in the dorsal striatum after the sound exposure did not differ from those in the background, while IL-1ß levels in their brain stem were significantly lower than the background state. Particular modulating role of the studied proinflammatory cytokines in the pathogenesis of audiogenic epilepsy is assumed, as well as certain possibility of anti-inflammatory and immune drugs application in anticonvulsant and antiepileptic therapy.

Ameliorative Effects of Camel Milk and Fermented Camel Milk on Acute Alcoholic Liver Injury

Probiotics, which are prevalent in camel milk (CM) and naturally fermented camel milk (FCM), can regulate the intestinal ecological structure to alleviate alcoholic liver disease (ALD) through the “gut–liver” axis. The protective effects and mechanisms of CM and FCM interventions on alcohol-induced acute liver injury were investigated by combining the behavior observed in rats following alcohol exposure. The results revealed that CM and FCM effectively controlled the increased levels of alcohol-induced ALT, AST, TG, MDA, and proinflammatory cytokines. Alcohol-induced oxidative depletion of hepatic CAT, GPX, GSH, and ALDH was reversed, diminishing lipid accumulation, ameliorating severe pathological damage, increasing antioxidant capabilities, and postponing oxidative stress. Additionally, the abundance of the phylum Bacteroidota (which reduces the F/B ratio); the family Prevotellaceae; the genera Clostridia_vadinBB60_group, parabacteroides, Alloprevotella, and Prevotellaceae_UC_G001; the gastrointestinal barrier; and the microbiological environment was increased. The steroid hormone biosynthesis pathway was altered to reduce alcohol-induced predominant steroid metabolites such as 17-hydroxyprogesterone, cortisol, and dehydroepiandrosterone, preventing alcoholic liver impairment. Taken together, CM could be a therapeutic dietary supplement for preventing alcoholic liver injury by ameliorating the intestinal ecology and hepatic metabolism.