MCP-1 Research Articles

Effect of amifostine on apoptotic inflammatory makers in cisplatin induced brain damage in rats.

To lessen the negative effects of the medication, we assessed the neuroprotective impact of amifostine nanoparticles against the neurotoxicity generated by cisplatin. 60 adult male albino Wistar rats were arranged into six groups. Group 1; received saline intraperitonealy (IP) and served as negative control. Group 2; received IP injection of silica nano-emulsion, Group 3 received cispatin for three consecutive days at the end of the study, Group 4 received amifostine intrapretonealy (IP) before cisplatin injection, Group 5 received silica nano-emulsion alone for one month, group 6 received silica nano-emulsion in combination with cisplatin for three consecutive days at the end of the study. Monocyte chemoattractant protein-1 (MCP-1) and glial fibrillary acidic protein (GFAP) were estimated by ELISA, butrylcholinesterase (BChE) by spectrophotometric method while caspase-3 as a marker of apoptosis by PCR. The mean levels of brain GFAP, MCP-1, and caspase-3 in the cisplatin group were considerably higher than those inthe control group. However, there was a drop in the averagelevel of brain BChE activity. Additionally, theinjection of (SiNPs@AMF+cisplatin) increased BChE activities while reducing GFAP, MCP-1, and caspase-3 levels, thereby reversing the negative effects of cisplatin on the brain tissue. On the other hand, the group treated with SiNPs@AMF+cisplatin showed improvement in overall brain structure and minimal pyknotic nuclei and apoptotic neurons were found. These outcomes demonstrated amifostine's ability to lessen the histological changes brought on by cisplatin. To sum up, SiNPs@AMF may be a suitable and secure supplemental treatment agent to lessen cisplatin's toxicity in the brain and enhance the treatment's effects throughout chemotherapy.

Abstract TP375: Ischemic Insult Under Hyperhomocysteinemic Condition Triggers Early Onset Of Inflammatory Response Causing Exacerbation Of Brain Injury

Hyperhomocysteinemia, a metabolic disorder characterized by systemic elevation of amino acid homocysteine, is linked to deficiency in vitamins and enzymes involved in homocysteine metabolism. The incidence of hyperhomocysteinemia is high in the elderly population due to reduced micronutrient absorption and metabolism. Recent preclinical studies in animal models of stroke showed that predisposition to hyperhomocysteinemia exacerbates ischemic brain injury and worsens behavioral deficits, establishing hyperhomocysteinemia as a potential comorbidity for stroke. These studies further showed that hyperhomocysteinemia-induced stimulation of GluN2A subunit containing NMDA receptors (GluN2A-NMDARs) in conjunction with glutamate-induced stimulation of GluN2B subunit containing NMDARs (GluN2B-NMDARs) exacerbates stroke pathology. However, the precise intracellular mechanisms involved in such exacerbation of ischemic brain injury is not known. The current study sought to investigate whether under hyperhomocysteinemic condition GluN2A-NMDAR mediated early activation of the transcription factor Nuclear Factor-κB (NFκB) and subsequent expression of the pro-inflammatory chemokine Monocyte chemoattractant protein-1 (MCP-1) enhances post-ischemic inflammatory response and exacerbation of brain damage. Adult male Wistar rats were made hyperhomocysteinemic by implantation of Alzet osmotic pumps containing L-homocysteine. The animals were hyperhomocysteinemic within 3 days with a total plasma homocysteine level of ~24 μM. Acute ischemic stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion (6h). Brain tissues were processed for MCP-1 ELISA and RT-PCR. A significant increase in MCP-1 mRNA and protein levels were observed in the ipsilateral cortex of hyperhomocysteinemic rats compared to control rats within 6h of reperfusion. An accelerated brain damage was also observed at this time in the hyperhomocysteinemic rats. Inhibition of GluN2A-NMDAR (NVP-AAM077, i.v.) and NFκB (BMS345541, IKK inhibitor; i.p) at the onset of ischemic insult attenuated increase in MCP-1 mRNA and protein levels, as well as exacerbation of brain injury under hyperhomocysteinemic condition. The study provides compelling evidence for a novel role of GluN2A-NMDAR in promoting neuro-inflammatory response that contributes to exacerbation of stroke pathology under hyperhomocysteinemic condition.

Reduction in MCP-1 production in preadipocytes is mediated by PPARγ activation and JNK/SIRT1 signaling.

Obesity-induced monocyte chemoattractant protein 1 (MCP-1) production leads to the infiltration of monocytes/macrophages into white adipose tissue (WAT), which contributes to systemic insulin resistance. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to reduce MCP-1 production in both humans and mice; however, the underlying mechanism in WAT remains unclear. Here, we propose a novel mechanism for the reduction in MCP-1 production in preadipocytes. The PPARγ agonist rosiglitazone (RSG) reduced MCP-1 production and secretion in response to lipopolysaccharide (LPS) in 3T3-L1 preadipocytes and mouse stromal vascular fraction-derived primary preadipocytes. Both RSG and SP600125 (a c-Jun N-terminal kinase (JNK) inhibitor) inhibited LPS-induced degradation of silent information regulator 2 homolog 1 (SIRT1), a negative regulator of MCP-1 production in 3T3-L1 preadipocytes. Furthermore, RSG inhibited LPS-induced activation of nuclear factor-κB. These effects of RSG were abolished in 3T3-L1 preadipocytes transfected with Pparg siRNA. These findings highlight a novel mechanism by which PPARγ activation inhibits JNK/SIRT1 signaling in preadipocytes and contributes to the reduction in MCP-1 production, suggesting that preadipocytes could be a potential therapeutic target for the treatment of insulin resistance.

Combination of Apigenin and Melatonin with nanostructured lipid carriers as anti-inflammatory ocular treatment.

Ocular inflammation is a complex pathology with limited treatment options. While traditional therapies have side effects, novel approaches, such as natural compounds like Apigenin (APG) and Melatonin (MEL) offer promising solutions. APG and MEL, in combination with nanostructured lipid carriers (NLC), may provide a synergistic effect in treating ocular inflammation, potentially improving patient outcomes and reducing adverse effects. NLC could provide chemical protection of these compounds, while offering a sustained release into the ocular surface. Optimized NLC exhibited suitable physicochemical parameters, physical stability, sustained release of APG and MEL, and were biocompatible in vitro with a corneal cell line, and in ovo by using hen's egg chorioallantoic membrane test. In vitro and in vivo studies confirmed the NLC' ability to attenuate inflammation by reducing interleukin-6 (IL-6), IL-8 and monocyte chemoattractant protein 1 (MCP-1) cytokine levels and by decreasing inflammation in a rabbit model. These findings suggest that the co-encapsulation of APG and MEL into NLC could represent a promising strategy for managing ocular inflammatory conditions.

Oral administration of Folium Artemisiae Argyi-derived exosome-like nanovesicles can improve ulcerative colitis by regulating intestinal microorganisms.

Ulcerative colitis (UC), an inflammatory disease characterized by intestinal barrier dysfunction, poses significant challenges because of the toxicity and adverse effects commonly associated with conventional therapies. Safer and more efficacious treatment strategies are needed. The purpose of this study was to treat UC with Folium Artemisiae Argyi exosome-like nanovesicles (FAELNs) and to explore its related mechanism to provide a safer and more effective means for the treatment of ulcerative colitis. We established an in vivo model of acute UC in mice and an in vitro inflammatory model using HT-29 human colorectal cancer cells. To evaluate the therapeutic effect of FAELNs on UC, we adopted various proxies, including changes in body weight and disease activity index (DAI) of mice, and measurement of colon length. The concentrations of myeloperoxide, interleukin (IL-1β), IL-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interferon-gamma in sera of mice were detected by ELISA. Immunohistochemistry, hematoxylin and eosin staining, and Alyssin blue staining were performed. The effect of HT-29 cells on oxidative stress was detected using an active oxygen probe, diacetyldichlorofluorescein, and flow cytometry. Western blotting was performed to detect the expression levels of Bax and Bcl-2 in HT-29 cells treated with FAELNs. The effects of FAELNs on IL-6 and IL-1β were detected by fluorescence quantitative PCR. Fecal 16S bacteria were detected, and the role of FAELNs was verified by α diversity and β diversity analyses, principal component analysis, species distribution, and function prediction. For microRNA sequencing of FAELNs, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed. To detect the metabolic and lipid groups of FAELNs, the components were identified and a pharmacological network was constructed to explore the related mechanisms and diseases. FAELNs effectively alleviated the pathogenesis of UC induced by dextran sodium sulfate in animal models, restoring the integrity of the intestinal barrier and reversing an imbalance of the intestinal microbiota. Our findings demonstrate the therapeutic potential of FAELNs in UC management, highlighting their scalability for mass production and encouraging prospects for clinical transformation.

Therapeutic Effects of Lavender Oil on Streptozotocin-Induced Diabetes Mellitus and Experimental Thrombosis

Diabetes mellitus is a metabolic disorder associated with oxidative stress, inflammation, and coagulation disturbances, which contribute to microvascular and macrovascular complications. We evaluated the therapeutic effects of lavender oil (Lavandula angustifolia) in a streptozotocin (STZ)-induced rat model of type 1 diabetes mellitus (T1DM) with experimentally induced thrombosis. Sixty male Wistar rats were divided into control, thrombosis, diabetes, thrombosis–diabetes, and lavender oil pretreatment groups (100 and 200 mg/kg body weight [bw]). Lavender oil exhibited dose-dependent benefits, with the 200 mg/kg bw dose leading to significant reductions in proinflammatory cytokines (e.g., tumor necrosis factor α (TNF-α); regulated upon activation, normal T cell expressed and secreted (RANTES); and monocyte chemoattractant protein-1 (MCP-1)) and oxidative stress, along with improved glycemic control, the partial restoration of C-peptide levels, and the attenuation of matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9) activity (p < 0.0001). Histopathological and coagulation analyses confirmed its organ-protective and antithrombotic effects, including reduced tissue damage, vascular inflammation, and thrombus formation, and prolonged bleeding and clotting times. Our findings suggest that lavender oil exhibits dose-dependent antioxidant, anti-inflammatory, hypoglycemic, and organ-protective effects, indicating its potential as a complementary therapy for managing inflammation in T1DM with or without thrombosis.

Nephroprotective potential of robinin to counteract aldicarb induced renal dysfunction via modulating TLR4/MyD88, HMGBI/RAGE, NF-κB pathway: A biochemical and pharmacodynamic approach.

The current investigation was conducted to evaluate the nephroprotective potential of robinin (RBN) to avert aldicarb (ALD) induced renal impairments. Thirty-two adult albino rats (Sprague Dawley) were categorized into four groups including control, ALD (15 mgkg-1), ALD (15 mgkg-1) + RBN (6 mgkg-1) and RBN (6 mgkg-1) alone treated group. The results of the current trial demonstrated that ALD intoxication promoted the gene expression of receptor for advanced glycation end products (RAGE), tumor necrosis factor- α (TNF-α), toll-like receptor 4 (TLR4), high mobility group box1 (HMGB1), nuclear factor- kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and interleukin-1β (IL-1β). Moreover, activities of HO-1, GSH, GPx, SOD, GSR, and CAT were suppressed while the levels of ROS and MDA were escalated following the ALD exposure. ALD intoxication upregulated the levels of cystatin C, KIM-1, creatinine, NAG, uric acid, urea, NGAL and BUN while reducing the levels of creatinine clearance in renal tissues. The levels of Bax, Caspase-9 and Caspase-3 were promoted while the levels of Bcl-2 were suppressed after ALD administration. Histopathological analysis showed ALD disrupted the normal architecture of renal tissues. However, RBN therapy substantially protected the renal tissues owing to its antioxidative, anti-inflammatory and anti-apoptotic potential.

P-2201. A Comprehensive Kidney Biomarker Panel to Assess Kidney Health after Hepatitis C Direct Acting Antiviral Therapy in Persons with HCV monoinfection and HCV/HIV coinfection

Abstract Background Chronic Hepatitis C virus (HCV) infection is associated with greater risk of chronic kidney disease and proteinuria. We examined effects of 12 weeks of elbasvir/grazoprevir, an HCV NS5A inhibitor/NS3/4A Protease Inhibitor on glomerular filtration (creatinine, cystatin C), injury (albuminuria), and 9 novel kidney tubule biomarkers in adults with HCV infection over a 24-week period.Figure.Percent Change (95% Confidence Interval) from Baseline of Urine Kidney Tubule Markers 24 weeks after initiating Elbasvir/Grazoprevir in Patients with HCV Methods We included 36 participants with HCV (7 with HIV coinfection) from the San Francisco Bay Area. Urine biomarkers included kidney tubule function (α-1-microglobulin [α1m], β-2-microglobulin [β2m]) and injury (kidney injury marker-1 [KIM-1], neutrophil gelatinase-associated lipocalcin [NGAL], (interleukin-18 [IL-18]), fibrosis/repair (monocyte chemoattractant protein 1 [MCP-1], chitinase-3-like protein-1 [YKL-40]) and synthetic function (epidermal growth factor [EGF], uromodulin [UMOD]). Biomarkers were measured at baseline, wk 12 (end of treatment), and week 24 (time of assessment for sustained virologic response [SVR]). We used linear mixed regression models with time as the main predictor to assess changes in kidney health, adjusting for demographics and urine creatinine. Results Over two thirds identified as Black/African American;89% were men and median age was 62 years. All but 2 achieved an SVR and 17% had advanced liver fibrosis using the FIB-4 serum marker. Median (interquartile range) for eGFRcr, eGFRcys, and urine albumin to creatinine ratio (ACR) were 82(63-100 ml/min),74(58-87 ml/min), and 10.4(4.9-24 mg/g), respectively at baseline. The percent (%) change from baseline for eGFRcr and ACR at weeks 12 and 24 was not statistically significant; eGFRcys was -11.4% lower (95%CI:-18%,-4.6%) at week 24. After 12 weeks of treatment, there were significant reductions in α1m, β2m, KIM-1, and MCP-1, with smaller reductions seen in most other markers (Figure). At week 24, these reductions were sustained for KIM-1. Conclusion Our findings suggest that HCV treatment with elbasvir/grazoprevir improves proximal tubule function and reduces cellular injury and fibrosis. Further research is needed to understand longer-term trends in kidney health following HCV cure. Disclosures Michelle Estrella, MD, Astra Zeneca: Board Member|Bayer: Grant/Research Support|Boehringer Ingelheim: Board Member Michael Shlipak, MD, Astra-Zeneca: Honoraria|Bayer: Grant/Research Support|Bayer: Honoraria|Boehringer Ingelheim: Honoraria Phyllis C. Tien, MD, MSc, Merck: Grant/Research Support

Revealing distinct treatment mechanisms and outcome correlations in patients with interstitial cystitis/bladder pain syndrome after different bladder therapies through urinary biomarker analysis.

Urinary cytokine changes may serve as biomarkers to assess treatment outcomes for interstitial cystitis/bladder pain syndrome (IC/BPS). This study analyzed the changes in urinary cytokines following various bladder therapies and explored their clinical significance in therapeutic mechanisms. A total of 122 patients with IC/BPS treated with platelet-rich plasma (PRP), botulinum toxin-A (BoTN-A), hyaluronic acid (HA), or low-energy shock wave (LESW) were evaluated. Urinary inflammatory and oxidative stress biomarkers were measured at baseline and at 3months posttreatment. Treatment outcomes were assessed using the Global Response Assessment (GRA), a 10-point visual analog score for pain, and the O'Leary-Saint Symptom Score (OSS). A GRA ≥ 2 was considered indicative of effective treatment. Significant symptom improvement was observed in patients treated with PRP and BoNT-A but not with LESW or HA. At 3months post-treatment, PRP therapy led to decreased urinary 8-isoprostane and total antioxidant capacity levels, while BoNT-A therapy reduced monocyte chemotactic protein-1 and 8-hydroxy-2'-deoxyguanosine levels. HA therapy did not alter urinary biomarker levels, whereas LESW therapy increased macrophage inflammatory protein-1 beta and tumor necrosis factor-α levels. Patients with significant urinary biomarker reductions (GRA ≥ 2) demonstrated clinical improvement at 3months. PRP or BoNT-A exhibits anti-inflammatory effects, reflected by reductions in urinary cytokine levels, correlating with positive treatment outcomes. Urinary cytokine changes may play a role to evaluate the mechanisms of action of various treatments in patients with IC/BPS.

Autosomal Dominant Polycystic Kidney Disease Inflammation Biomarkers in the Tolvaptan Era

With the approval of tolvaptan as the first specific medicine for the treatment of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD), biomarker discovery has gained renewed interest as it is widely recognized that these will be crucial in clinical decision-making, serving as either prognostic or predictive tools. Since the marketing authorization was first issued in 2015 for ADPKD, tolvaptan has remained the sole pharmacological compound specifically targeting the disease. For ADPKD patients it is an invaluable medicine for retarding disease progression. Although the field of overall biomarker discovery and validation has been detailed in several publications, the role of inflammation remains largely overlooked in ADPKD. The current work aims to provide the reader with an updated review of inflammation biomarkers research in ADPKD, highlighting the role of urinary MCP-1 (monocyte chemoattractant protein-1) as the most promising tool.

Pericytes mediate neuroinflammation via Fli-1 in endotoxemia and sepsis in mice

BackgroundSepsis-associated encephalopathy (SAE) often results from neuroinflammation. Recent studies have shown that brain platelet-derived growth factor receptor β (PDGFRβ) cells, including pericytes, may act as early sensors of infection by secreting monocyte chemoattractant protein-1 (MCP-1), which transmits inflammatory signals to the central nervous system. The erythroblast transformation-specific (ETS) transcription factor Friend leukemia virus integration 1 (Fli-1) plays a critical role in inflammation by regulating the expression of key cytokines, including MCP-1. However, the role of pericyte Fli-1 in neuroinflammation during sepsis remains largely unknown.MethodsWT and pericyte-specific Fli-1 knockout mice were subjected to endotoxemia through LPS injection or sepsis via cecal ligation and puncture (CLP). In vitro, Fli-1 was knocked down using small interfering RNA in cultured mouse brain pericytes, followed by LPS stimulation.ResultsElevated Fli-1 levels were observed in isolated brain pericytes 2 h after LPS administration, in brain tissues 4 h after CLP, and in cultured mouse brain pericytes 2 h after LPS stimulation in vitro. In endotoxemic mice, pericyte-specific Fli-1 knockout reduced expression of MCP-1 and IL-6 in brain tissue 2 h after LPS injection. At 24 h post-LPS administration, protein levels of MCP-1 and IL-6, and microglia activation were suppressed in pericyte-Fli-1 knockout mice. Additionally, Fli-1 deficiency in pericytes significantly reduced MCP-1 and IL-6 mRNA levels in the brain tissue 4 h after CLP. Moreover, in cultured brain pericytes, Fli-1 knockdown markedly decreased MCP-1 and IL-6 levels after LPS stimulation. Notably, LPS stimulation increased Fli-1 levels via TLR4-Myd88 signaling, which subsequently led to elevated production of MCP-1 in brain pericytes.ConclusionsFli-1 in pericytes may serve as a crucial mediator of neuroinflammation during sepsis by directly regulating pivotal cytokines such as MCP-1 and IL-6. Therefore, Fli-1 has the potential to serve as a therapeutic target in SAE and other neuroinflammatory disorders.

Anti-arthritic Effects of Undifferentiated and Chondrogenic Differentiated MSCs in MIA-induced Osteoarthritis in Wistar Rats: Involvement of Oxidative Stress and Immune Modulation.

Osteoarthritis (OA) is a degenerative joint disease that can affect the many tissues of the joint. There are no officially recognized disease-modifying therapies for clinical use at this time probably due to a lack of complete comprehension of the pathogenesis of the disease. In recent years, emerging regenerative therapy and treatments with stem cells both undifferentiated and differentiated cells have gained much attention as they can efficiently promote tissue repair and regeneration. To determine how bone marrow-derived mesenchymal stem cells (BM-MSCs) and chondrogenic differentiated MSCs (CD-MSCs) can treat OA in rats, OA was induced in Wistar rats by injecting three doses of 100 μL physiological saline containing 1 mg of MIA into rat ankle joint of the right hind leg for three consecutive days. Following the induction, the osteoarthritic rats were injected weekly with BM-MSCs or CD-MSCs at a dose of 1x106 cells/rat/dose for three weeks. In addition to morphological and histological investigations of the ankle, spectrophotometric, ELISA, and Western blot analyses were applied to detect various immunological and molecular parameters in serum and ankle. The results of the study showed that in osteoarthritic rats, BM-MSCs and CD-MSCs significantly reduced right hind paw circumference, total leucocyte count (TLC), differential leukocyte count (DLC) of neutrophils, monocytes, lymphocytes, and eosinophils, serum rheumatoid factor (RF), prostaglandin E2 (PGE2) and interleukin (IL-) 1β levels, while they elevated serum IL-10 level. Additionally, BM-MSCs and CD-MSCs markedly reduced lipid peroxides (LPO) levels while they elevated superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities. The monocyte chemoattractant protein-1 (MCP-1) level was significantly downregulated in ankle joint articular tissues by treatment with BM-MSCs or CD-MSCs while nuclear factor erythroid 2-related factor 2 (Nrf2) was upregulated; CD-MSCs treatment was more effective. According to these findings, it can be inferred that BM-MSCs and CD-MSCs have anti-arthritic potential in MIA-induced OA; CD-MSCs therapy is more effective than MSCs. The ameliorative anti-arthritic effects may be mediated by suppressing inflammation and oxidative stress through the downregulation of MCP-1 and upregulation of Nrf2. Based on the obtained results, BM-MSCs and CD-MSCs therapies are promising new options that can be associated with other clinical treatments to improve cartilage regeneration and joint healing. However, more preclinical and clinical research is required to assess the benefits and safety of treating osteoarthritic patients with BM-MSCs and CD-MSCs.

P0323 Serum leucine-rich α2-glycoprotein (LRG) and Monocyte chemoattractant protein-1 (MCP-1) as Novel Biomarkers for Predicting Vedolizumab Response in Ulcerative Colitis Patients

Abstract Background Close monitoring of disease activity is essential for the therapeutic management of inflammatory bowel disease. A minimally invasive and reliable serum biomarker is desirable, but its reliability and validity have not yet been fully evaluated. The purpose of this study (UMIN000043185) was to investigate the utility of leucine-rich α-2-glycoprotein (LRG) in the management of vedolizumab therapy in patients with ulcerative colitis (UC), and to identify mucosal signatures and surrogate biomarkers by using serum cytokine and mucosal transcriptome analysis. Methods Serum LRG, C-reactive protein (CRP), serum Mucosal Vascular Addressin Cell Adhesion Molecule 1(MadCAM1), serum vedolizumab levels, 19 serum cytokines, and fecal calprotectin (fCal) were measured over 54 weeks (week 0, 2, 6, 14, 30, and 54) (n=21). Clinical remission (Mayo score <= 2, all subscore < = 1) and mucosal healing (Mayo endoscopic subscore <= 1) at week 14 were compared between the clinical remission (CR) group (n=11) and non-clinical remission (non-CR) group (n=10), and between the mucosal healing (MH) group (n=14) and non-mucosal healing (non-MH) group (n=7). Differentially expressed gene (DEG) extraction was performed by stratifying data at week 0 and comparing two groups: CR (n=10) and non-CR (n=3), and complete MH (Mayo endoscopic subscore = 0) (n=8) and non-complete MH (n=6) at week 14. Results Serum LRG concentrations were significantly lower in CR group compared to the non-CR group at week 0 (19.0 vs. 29.0 ug/mL, p=0.027) and week 6 (13.4 vs. 19.6 ug/mL, p=0.034) and significantly lower in MH group compared to the non-MH group at week 6 (13.7 vs. 21.6 ug/mL, p=0.033). In contrast, there were no significant differences in serum CRP and fecal calprotectin levels at any time point for either CR or MH. Serum MCP-1 levels showed significant differences between CR and non-CR at week 0 (609.0 vs 403.4 pg/mL, p=0.0018), between MH and non-MH at week 0 (587.2 vs 358.9 pg/mL, p<0. 001), week 6 (606.9 vs 451.6 pg/mL, p=0.015). DEGs extracted from colon tissue included LRG1 and LRG-related cytokines, MCP-1, reflecting the effect of vedolizumab treatment. Conclusion Both serum LRG (lower in CR/ MH group) and serum MCP-1 (higher in CR/MH group) were suggested to be promising predictive biomarkers of vedolizumab treatment response in patients with UC. Further studies are needed to assess their reliability and validity as indicators of treatment effectiveness.

Associations of the levels of adipokines and cytokines in individual follicles with in vitro fertilization outcomes in women with different ovarian reserves

BackgroundTo a large extent, the ovarian reserve determines a woman’s reproductive potential. The etiological and pathological mechanisms of diminished ovarian reserve (DOR) remain unclear, and no reliable treatment is currently available for DOR. Adipokines and cytokines in follicular fluid (FF) play pivotal roles in follicular development and maturation. The concentrations of adipokines and cytokines in FF from individual follicles of women with DOR undergoing in vitro fertilization (IVF) were studied. In particular, we investigated the associations between the levels of adipokines and cytokines in individual FFs from women with different ovarian reserves and between the follicular levels of adipokines and cytokines and IVF outcomes in individual follicles.MethodsA total of 115 women who underwent IVF were recruited. Patients diagnosed with DOR, defined as a basal antral follicle count < 5 or an anti-Mullerian hormone concentration < 1.1 ng/mL, were assigned to the DOR group, while patients with a normal ovarian reserve (NOR) were assigned to the NOR group. FF was sampled from the first follicle with a diameter of approximately 18–20 mm from each patient, and the IVF outcome of the oocyte from the corresponding follicle was tracked. The levels of 5 adipokines (including visfatin-1, monocyte chemoattractant protein-1 [MCP-1], resistin, leptin, and chemerin) and 3 cytokines (including interleukin [IL]-6, IL-12p70, and tumor necrosis factor [TNF]-α) in FF were determined by Luminex technology.ResultsThe follicular levels of TNF-α, IL-6, visafatin, MCP-1, IL-12, and chemerin were significantly lower in women with NOR than in those with DOR. The follicular level of IL-6 was negatively correlated with the quality of embryos according to the binary logistic regression analysis, while the follicular levels of adipokines and other cytokines did not correlate with IVF outcomes regardless of the woman’s ovarian reserve.ConclusionsOur study demonstrated that the levels of adipokines and cytokines in individual follicles in women with DOR were different from those in women with NOR, indicating that increased intrafollicular inflammation might be related to DOR. Moreover, a high follicular level of IL-6 might negatively impact embryo quality.

Pine (Pinus koraiensis) Nut Oil Ameliorates Cholesterol Homeostasis and Inflammation via Modulating the miR-34a/122 Pathways in the Liver of Rats Fed a High-Cholesterol Diet.

Pine (Pinus koraiensis) nut oil (PNO) has been reported to have various beneficial effects on hepatic triglyceride accumulation and atherosclerosis in animal models. MicroRNAs (miRs) are involved in various diseases by modulating physiological processes. However, the mechanism underlying PNO's effects on the regulation of miRs involved in hepatic cholesterol homeostasis and inflammation remains unclear. This study investigated the effects of PNO on the regulation of the miR-34a/122 pathways involved in cholesterol homeostasis and inflammation in the liver using a high-cholesterol diet (HCD) rat model. Six-week-old male Sprague-Dawley rats were randomly divided into three groups (n = 8/group) and provided with (1) a cholesterol-free diet, (2) an HCD containing 1% cholesterol and 0.5% cholic acid, or (3) an HCD containing 5% PNO for 4 weeks. Lipid analysis of serum and liver, histological evaluation, and analysis of gene and protein expression were performed. PNO supplementation in HCD improved hepatic lipid profiles and elevated serum high-density lipoprotein cholesterol compared to the HCD group. PNO significantly upregulated hepatic gene expression levels of liver X receptor α and ATP-binding cassette transporter A1/G1, which are involved in cholesterol efflux (P < 0.05). Gene expressions of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, monocyte chemoattractant protein-1, and inducible nitric oxide synthase were downregulated by PNO (P < 0.05). PNO also suppressed TNF-α and IL-6 protein levels by 22.3% and 17.3%, respectively (P < 0.05). PNO reduced hepatic nuclear factor-kappa B activity by 16.4% and decreased nitric oxide production in the liver and serum (P < 0.05). Furthermore, hepatic miR-34a and miR-122 expressions decreased by 16.4% and 15.7% by PNO, respectively (P < 0.05). These results suggest that PNO may affect cholesterol homeostasis and inflammation, which are partially associated with the miR-34a/122 pathways in the liver under an HCD.

Correlation between preoperative aqueous cytokine levels and mid-term corneal endothelial cell loss following penetrating keratoplasty.

To investigate the association between preoperative aqueous humour (AqH) cytokines and mid-term endothelial cell density (ECD) following penetrating keratoplasty (PKP). This study analysed a total of 87 eyes of which 54 underwent PKP and 33 eyes underwent cataract surgery. AqH samples were collected at the beginning of surgery. The levels of cytokines (interleukins [ILs]-1α, -1β, -4, -6, -8, -10, -17A, monocyte chemotactic protein [MCP]-1, interferon [IFN]-α, IFN-γ, E-selectin, P-selectin, and soluble intercellular adhesion molecule-1 [sICAM-1]) in the AqH were measured using a multiplex beads immunoassay. The subjects who underwent PKP were classified into two groups: Group 1: ECD < 1200 cells/mm2 at 36 months and graft failure during follow-up (38 eyes); Group 2 ECD ≥ 1200 cells/mm2 at 36 months (16 eyes). The ECD reduction per year was significantly correlated with the preoperative levels of protein (r = 0.48; P < 0.001), IL-6 (r = 0.29; P = 0.048), IL-8 (r = 0.42; P = 0.003), IL-12p70 (r = 0.46; P = .007), MCP-1 (r = 0.28; P = 0.049), IFN -γ (r = 0.43; P = 0.008), and s-ICAM-1 (r = 0.30; P = 0.03). The preoperative levels of IL-8, and IFN-γ in AqH were significantly higher in eyes with ECD < 1200 cells/mm2 compared to those with ECD ≥ 1200 cells/mm2 at 3 years (P ≤ 0.02). Preoperative AqH cytokine levels are associated with mid-term ECD reduction after PKP. Pathological alterations of the AqH microenvironment may affect mid-term corneal endothelial cell survival.

More Complex Investigations Improved Diagnoses of Community-Acquired Pneumonia in Children With Different Vaccination Histories.

Community-acquired pneumonia (CAP) significantly contributes to high infant mortality in Kazakhstan and developing effective treatment methods is critical. The aim of this study was to explore the microbiological and immunological characteristics of CAP in vaccinated and unvaccinated paediatric patients. The study was carried out in the Regional Children's Clinical Hospital and the research centre of Karaganda Medical University, Republic of Kazakhstan. It comprised 85 children aged 2 months to 3 years who had been diagnosed with CAP and had received inpatient treatment from 2017 to 2019. Of these, 45 had complete pneumococcal vaccinations and 40 had not. Their CAP diagnoses were confirmed by microscopic, bacteriological and radiological methods and vaccination status. General clinical examinations were conducted. The study showed the diagnostic and prognostic value of the level of cytokines, depending on the severity of the children's CAP. The level of monocytic chemoattractant protein-1 was 2.1 pg/mL in the vaccinated children with mild CAP and 3.4 pg/mL in those with impaired immunisation. Pneumococcal vaccination affected the aetiological structure of CAP in early childhood. More complex clinical and immunological diagnostic methods increased the efficiency of diagnosing CAP in children with different vaccination histories.

Association between inflammatory biomarkers and the cognitive response to a multidomain intervention: secondary longitudinal analyses from the MAPT study.

The aim of this study is to evaluate the association of systemic inflammation measured by plasma biomarkers with the change in cognitive function among participants from the Multidomain Alzheimer Preventive Trial (MAPT) exposed to the multidomain intervention (MI). Secondary analysis of the MAPT longitudinal data. MAPT is a randomized, placebo-controlled trial with 3 interventional groups (omega-3 only, MI only, omega-3 plus MI) and a control group. We tested the association of the change in cognitive function with inflammatory biomarkers (tumoral necrosis factor receptor-1 (TNFR1), monocyte chemoattractant protein-1 (MCP1), Growth Differentiation Factor-15 (GDF15), Interleukin-6 (IL6) and C reactive protein (CRP)) using mixed-effects models. A subgroup analysis was performed in those exposed to the MI. The response to the MI was defined as the change in the composite cognitive score over the 2-year clinical follow-up period. by modeling the response to the intervention and identifying "good responders", i.e., those in the 5th quintile of response at the end of the intervention period (2years after the measurement of inflammatory markers). We included 1,527 participants (mean age 75.3, SD = 4.4; 64% female). Higher levels of GDF15 and TNFR1 were associated with a worse trajectory in the cognitive composite score in adjusted models. "Good responders" had an estimated mean change in the composite score of 0.051 (SD 0.062) over two years of intervention, compared to -0.136 (SD = 0.111) for the "not-good responders". Higher IL6 levels were associated with a decreased likelihood of being a "good responder" (OR = 0.22, p = 0.018, 95% CI 0.06; 0.78), with similar results for CRP (OR = 0.48, p = 0.009, 95% CI 0.28; 0.84). Higher inflammation was associated with a worse cognitive trajectory among nondemented participants and a lower likelihood of being classified as a "good responder" in those receiving a MI. Further confirmation of these findings could lead to the use of systemic inflammation as inclusion or stratification criteria in prevention trials.

Design and development of an isatin-1,2,3-triazole hybrid analogue as a potent anti-inflammatory agent with enhanced efficacy and gene expression modulation.

Isatin (1H-indole-2,3-dione) and its derivatives have been found to exhibit various biological activities, including anticancer and antidiabetic properties. In this study, a series of nine isatin-1,2,3-triazole conjugates were synthesized and evaluated for their anti-inflammatory potential via in vitro experiments. Their synthesis involved the propargylation of isatin 1 with propargyl bromide to obtain N-propargyl isatin 2, which was subjected to click reactions with different aromatic azides to yield isatin-N-1,2,3-triazoles (3a-i). The structures of all the compounds were confirmed via NMR and HR-MS. The final isatin analogues were tested for their ability to attenuate the production of proinflammatory cytokines in the lipopolysaccharide (LPS)-induced human leukemia monocytic THP-1 cells. Importantly, none of the compounds had any negative effect on THP-1 cell viability at the tested concentrations of 4 mM and 8 mM. LPS induced the production of the cytokines: Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) by 351.4, 7.9 and 14.3 fold, respectively, in THP-1 cells. However, treatment with compound 3e markedly attenuated the levels of TNF-α (by 6.6 fold and 1.5 fold), IL-6 (by 1.03 fold and 1.41 fold) and MCP-1 (by 3.3 fold and 1.7 fold) by several fold at concentrations of 4 mM and 8 mM, respectively. Furthermore, in the gene expression modulation studies, 3e was found to downregulate the genes responsible for the production of TNF-α (24 and 25 fold), IL-6 (148 and 502 fold) and MCP-1 (50 and 25 fold) at the two tested concentrations compared with their expression in the LPS-induced THP-1 cells (135 fold, 6612 fold, and 68.8 fold, respectively). Thus, 3e markedly attenuated the secretion of TNF-α, IL-6 and MCP-1 from LPS-treated THP-1 cells, and also the expression of the concerned genes. At the lowest dose tested, i.e., 4 mM, 3e had the greatest effect on both gene expression and marker secretion.

Berberine Improves Glucose and Lipid Metabolism in Obese Mice through the Reduction of IRE1/GSK-3β Axis-Mediated Inflammation.

Berberine (BBR) has the characteristics of repressing hyperglycemia, obesity, and inflammation, as well as improving insulin resistance. However, the underlying mechanism remains to be fully understood. This study explores whether BBR regulates inositol requiring enzyme 1 (IRE1)/glycogen synthase kinase 3 beta (GSK-3β) axis to resist obesity-associated inflammation, thereby improving glucolipid metabolism disorders. Mice were fed a high-fat diet and administrated with BBR, followed by measurement of weight change, biochemical indicators, as well as glucose and insulin tolerance. Insulin-resistant 3T3-L1 adipocyte models were established, and the model cells were treated with BBR and IRE1 inhibitors. Cell viability was detected by cell counting kit-8 assay. Inflammatory factor secretion and glucose consumption were measured via specific kits. Oil red O staining was used to observe lipid droplet formation, and protein expressions in the IRE1/GSK-3β axis were determined via Western blot. BBR reduced weight, insulin resistance, levels of triglyceride, total cholesterol, free fatty acid, high-density lipoprotein, and low-density lipoprotein but improved glucose tolerance in obese mice. BBR and IRE1 inhibitors demonstrated no cytotoxicity. BBR and IRE1 inhibitors diminished secretion of tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein 1, lipid droplet formation, and values of p-IRE1/IRE1 and p-GSK-3β/GSK-3β, but elevated glucose consumption in insulin-resistant adipocytes. BBR improves glucose and lipid metabolism in obese mice through the reduction of IRE1/GSK-3β axis-mediated inflammation, showing the great potential of BBR in reversing insulin resistance in obesity.