MCP-1 Research Articles

Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease.

Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer's disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD. Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ. Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment. Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD.

Dynamic control of mTORC1 facilitates bone healing in mice.

Bone healing requires well-orchestrated sequential actions of osteoblasts and osteoclasts. Previous studies have demonstrated that the mechanistic target of rapamycin complex 1 (mTORC1) plays a critical role in the metabolism of osteoblasts and osteoclasts. However, the role of mTORC1 in bone healing remains unclear. Here, we showed that a dynamic change in mTORC1 activity during the process was essential for proper healing and can be harnessed therapeutically for treatment of bone fractures. Low mTORC1 activity induced by osteoblastic Raptor knockout or rapamycin treatment promoted osteoblast-mediated osteogenesis, thus leading to better bone formation and shorter bone union time. Rapamycin treatment in vitro also revealed that low mTORC1 activity enhanced osteoblast differentiation and maturation. However, rapamycin treatment affected the recruitment of osteoclasts to new bone sites, thus resulting in delayed callus absorption in bone marrow cavity. Mechanistically, decreased mTORC1 activity inhibited the recruitment of osteoclast progenitor cells to healing sites through a decrease in osteoblastic expression of monocyte chemoattractant protein-1, thus inhibiting osteoclast-mediated remodeling. Therefore, normal mTORC1 activity was necessary for bone remodeling stage. Furthermore, through the use of sustained-release materials at the bone defect, we confirmed that localized application of rapamycin in early stages accelerated bone healing without affecting bone remodeling. Together, these findings revealed that the activity of mTORC1 continually changed during bone healing, and staged rapamycin treatment could be used to promote bone healing.

Investigation of parasite genetic variation and systemic immune responses in patients presenting with different clinical presentations of cutaneous leishmaniasis caused by Leishmania aethiopica

BackgroundCutaneous leishmaniasis (CL) is a neglected tropical skin disease, caused by the protozoan parasite Leishmania. In Ethiopia, CL is mainly caused by Leishmania aethiopica and can present in different clinical forms. The aim of this study was to assess whether these different forms are associated with differences in parasite genetic and host systemic immune signatures.MethodsHere we analysed the whole genome sequence data for 48 clinical parasite isolates and the systemic immune signature from a cohort of CL patients, who were recruited in Nefas Mewcha, Northern Ethiopia, from January 2019 to January 2022.ResultsOur results show that parasites from CL cases with different presentations in a single Ethiopian setting are from the same genetic population based on a permutation test of genome-wide similarity. Furthermore, a logistic regression test for genome wide association did not identify any individual genetic variants significantly associated with disease presentation. We also measured plasma chemokine and cytokine levels of 129 CL patients presenting with different forms of CL. None of the chemokine [eotaxin, eotaxin-3, interleukin (IL)-8, interferon (IFN)-γ-induced protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, MCP-4, macrophage-derived chemokines (MDC), macrophage inflammatory protein (MIP)-1α, MIP-1β and thymus- and activation-regulated chemokine (TARC)] or cytokine (IFN-γ, IL-1β, interleukin-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, tumor necrosis factor-α) levels measured were significantly different between the different clinical presentations of CL, as measured by Kruskal–Wallis test. We also compared those with healthy nonendemic controls: our results show a chemokine (IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β and TARC) but not a cytokine immune signature in patients with CL as compared to healthy nonendemic controls, as measured by Mann-Whitney test.ConclusionsThe results of our study did not identify a systemic immune signature or parasite genetic factors associated with different clinical presentation of CL.Graphical abstract

Mixed active metabolites of the SNP-6 series of novel compounds mitigate metabolic dysfunction-associated steatohepatitis and fibrosis: promising results from pre-clinical and clinical trials

BackgroundMetabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with no effective pharmacological treatments. SNP-630, a newly developed synthetic molecule with multiple mechanisms of action, and a mixture of two of its active metabolites (SNP-630-MS) inhibit CYP2E1 expression to prevent reactive oxygen species generation, thereby reducing the accumulation of hepatic triglycerides and lowering chemokine levels. This study investigated the SNP-630’s potential to alleviate the liver injury in MASH and its efficacy in both a mouse model and patients with MASH to identify a drug candidate that targets multiple pathways implicated in MASH.MethodsSNP-630 and SNP-630-MS were separately administered to the MASH mouse model. The tolerability, safety, and efficacy of SNP-630-MS were also evaluated in 35 patients with MASH. The primary endpoint of the study was assessment of the changes in serum alanine aminotransferase (ALT) levels from baseline to week 12, while the secondary endpoints included the evaluation of liver inflammation, steatosis, and fibrosis parameters and markers.ResultsSNP-630 treatment in mice improved inflammation, liver steatosis, and fibrosis compared with that in the MASH control group. Both SNP-630 and SNP-630-MS treatments markedly reduced ALT levels, hepatic triglyceride content, and the expression of inflammatory cytokines monocyte chemoattractant protein 1 and fibrotic collagen (i.e., Col1a1, Col3a1, and Timp1) in mice. In the clinical trial, patients treated with SNP-630-MS exhibited significant improvement in ALT levels at week 12 compared with baseline levels, with no reports of severe adverse events. This improvement in ALT levels surpassed that achieved with most other MASH candidates. SNP-630-MS demonstrated potential antifibrotic effects, as evidenced by a significant decrease in the levels of fibrogenesis-related biomarkers such as CCL4, CCL5, and caspase 3. Subgroup analysis using FibroScan measurements further indicated the efficacy of SNP-630-MS in ameliorating liver fibrosis.ConclusionsSNP-630 and SNP-630-MS demonstrated favorable results in mice. SNP-630-MS showed excellent tolerability in mice and patients with MASH. Efficacy analyses indicated that SNP-630-MS improved liver steatosis and injury in patients with MASH, suggesting that SNP-630 and 630-MS are promising therapeutic options for MASH. Larger scale clinical trials remain warranted to assess the efficacy and safety of SNP-630 in MASH.Trial registration: ClinicalTrials.gov NCT03868566. Registered 06 March 2019-Retrospectively registered, https://clinicaltrials.gov/study/NCT03868566

Spent brewer yeast glucan improves metabolic parameters and inflammatory markers reducing health risky changes imposed by the consumption of hypercaloric diet

β-glucans from yeasts are prebiotic health-promoting food ingredients able to boost immune response. An environmentally friendly source of yeast glucans is the spent brewer's yeast. This study investigated the effects of the administration of carboxymethyl glucan (CMG) (20 mg/kg, 12 weeks, orally), a derivative of the β-glucan from spent brewer's yeast, on food intake, weight gain, dyslipidemia, glucose intolerance, pro-inflammatory state, and hepatic steatosis of rats receiving a hypercaloric diet. The animals were divided into three groups: Normocaloric control (NCT); Hypercaloric diet and saline (HCT); and Hypercaloric diet and CMG (H-CMG). CMG administration could reduce rats' caloric value and food intake, reducing the index of adiposity (HCT:7.2±0.4% vs H-CMG:5.3±0.4% p < 0.05) and weight gain (HCT:111.1±3.8g vs H-CMG: 68.3±4.9g p < 0.05). Furthermore, it improved lipemic and glycemic profiles and lowered hepatic lipid accumulation. CMG decreased Monocyte Chemoattractant Protein (MCP)-1 (H-CT: 89.5±1.8 pg/mL vs H-CMG: 50.7±12.2 pg/mL p < 0.05), Interleukin (IL)-12 (H-CT: 206.0±14.0 pg/mL vs H-CMG:132.4±19.9 pg/mL, p < 0.05), and C-reactive protein (CRP) levels and increased IL-10 levels, decreasing the cardiovascular risk and pro-inflammatory state. Therefore, CMG has beneficial effects in preventing weight gain and, consequently, improves the metabolic profile in rats while consuming a hypercaloric diet. Findings indicate the spent brewer's yeast CMG can be a strategy to attenuate the risky metabolic changes related to the consumption of a hypercaloric diet.

Influence of Emulsion Lipid Droplet Crystallinity on Postprandial Endotoxin Transporters and Atherogenic And Inflammatory Profiles in Healthy Men - A Randomized Double-Blind Crossover Acute Meal Study.

Consumption of high-fat meals is associated with increased endotoxemia, inflammation, and atherogenic profiles, with repeated postprandial responses suggested as contributors to chronically elevated risk factors. However, effects of lipid solid versus liquid state specifically have not been investigated. This exploratory randomized crossover study tests the impact of lipid crystallinity on plasma levels of endotoxin transporters (lipopolysaccharide [LPS] binding protein [LBP] and soluble cluster of differentiation 14 [sCD14]) and select proinflammatory and atherogenic markers (tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP], interleukin-1-beta [IL-1β], interferon-gamma [IFN-γ], interleukin-6 [IL-6], soluble intercellular adhesion molecule [sICAM], soluble vascular cell adhesion molecule [sVCAM], monocyte chemoattractant protein-1 [MCP-1/CCL2], plasminogen activator inhibitor-1 [PAI-1], and fibrinogen). Fasted healthy men (n = 14, 28 ± 5.5 years, 24.1 ± 2.6kgm-2) consumed two 50g palm stearin oil-in-water emulsions tempered to contain either liquid or crystalline lipid droplets at 37°C on separate occasions with blood sampling at 0, 2-, 4-, and 6-h post-meal. Timepoint data, area under the curve, and peak concentration values are compared. Overall, no treatment effects are seen (p > 0.05). There are significant effects of time, with values decreasing from baseline, for TNF-α, MCP-1/CCL2, PAI-1, and fibrinogen (p < 0.05). Responder analysis pointed to differential treatment effects associated with some participant baseline characteristics but, overall, palm-stearin emulsion droplet crystallinity does not acutely affect plasma endotoxin transporters nor select inflammatory and atherogenic markers.

Inhalation of Microplastics Induces Inflammatory Injuries in Multiple Murine Organs via the Toll-like Receptor Pathway.

Previous studies have detected microplastics (MPs) in human biological samples, such as lungs, alveolar lavage fluid, and thrombus. However, whether MPs induce health effects after inhalation are unclear. In this study, fluorescent polystyrene microplastics (PS-MPs) were found in the thymus, spleen, testes, liver, kidneys, and brain on day 1 or day 3 after one intratracheal instillation. Furthermore, mice showed inflammation in multiple organs, manifested as obvious infiltration of neutrophils and macrophages, increased Toll-like receptors (TLRs), myeloid differentiation primary response protein 88 (MyD88) and nuclear factor-κB (NF-κB), as well as proinflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β) in the lungs, thymus, spleen, liver, and kidneys after four intratracheal instillations of PS-MPs at once every 2 weeks. Hepatic and renal function indexes were also increased. Subsequently, the inflammatory response in multiple murine organs was significantly alleviated by TLR2 and TLR4 inhibitors. Unexpectedly, we did not find any elevated secretion of monocyte chemotactic protein (MCP)-1 or TNF-α by RAW264.7 macrophages in vitro. Thus, PS-MPs induced inflammatory injuries in multiple murine organs via the TLRs/MyD88/NF-κB pathway in vivo, but not macrophages in vitro. These results may provide theoretical support for healthy protection against PS-MPs and their environmental risk assessment.

Distinct immune profiles and clinical outcomes in sepsis subphenotypes based on temperature trajectories.

Sepsis is a heterogeneous syndrome. Identification of sepsis subphenotypes with distinct immune profiles could lead to targeted therapies. This study investigates the immune profiles of patients with sepsis following distinct body temperature patterns (i.e., temperature trajectory subphenotypes). Hospitalized patients from four hospitals between 2018 and 2022 with suspicion of infection were included. A previously validated temperature trajectory algorithm was used to classify study patients into temperature trajectory subphenotypes. Microbiological profiles, clinical outcomes, and levels of 31 biomarkers were compared between these subphenotypes. The 3576 study patients were classified into four temperature trajectory subphenotypes: hyperthermic slow resolvers (N = 563, 16%), hyperthermic fast resolvers (N = 805, 23%), normothermic (N = 1693, 47%), hypothermic (N = 515, 14%). The mortality rate was significantly different between subphenotypes, with the highest rate in hypothermics (14.2%), followed by hyperthermic slow resolvers 6%, normothermic 5.5%, and lowest in hyperthermic fast resolvers 3.6% (p < 0.001). After multiple testing correction for the 31 biomarkers tested, 20 biomarkers remained significantly different between temperature trajectories: angiopoietin-1 (Ang-1), C-reactive protein (CRP), feline McDonough sarcoma-like tyrosine kinase 3 ligand (Flt-3l), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-15, IL-1 receptor antagonist (RA), IL-2, IL-6, IL-7, interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), human macrophage inflammatory protein 3 alpha (MIP-3a), neutrophil gelatinase-associated lipocalin (NGAL), pentraxin-3, thrombomodulin, tissue factor, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), and vascular cellular adhesion molecule-1 (vCAM-1).The hyperthermic fast and slow resolvers had the highest levels of most pro- and anti-inflammatory cytokines. Hypothermics had suppressed levels of most cytokines but the highest levels of several coagulation markers (Ang-1, thrombomodulin, tissue factor). Sepsis subphenotypes identified using the universally available measurement of body temperature had distinct immune profiles. Hypothermic patients, who had the highest mortality rate, also had the lowest levels of most pro- and anti-inflammatory cytokines.

Effect of Preoperative Glucocorticoid Application on Vitreous Parthanatos-Related Protein Expression in Patients with Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment

Purpose The protein concentrations of apoptosis inducing factor (AIF), macrophage migration inhibitory factor (MIF), interleukin-1β (IL-1β), poly ADP ribose polymerase-1 (PARP-1), poly (ADP-ribose) (PAR), α-synuclein (α-SYN), monocyte chemotactic protein‑1 (MCP-1) and tumor necrosis factor-α (TNF-α) in the vitreous of eyes with rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) were observed and analyzed. Methods A total of 57 patients’ samples were included. 30 patients with RRD were set as the control group, 27 patients with RRDCD were set as the experimental group (16 patients with preoperative glucocorticosteroid (GC+) and 11 patients without preoperative glucocorticosteroid (GC−)). The levels of AIF, MIF, IL-1β, PARP-1, PAR, α-SYN, MCP-1 and TNF-α in vitreous of patients in the control and experimental groups were detected by enzyme-linked immunosorbent assay (ELISA). Results The concentration of AIF in the vitreous was higher in the RRD group (9.96 ± 2.78 ng/ml) than in the RRDCD (GC+) group (7.65 ± 2.13 ng/ml, p = 0.006),the RRDCD (GC+) group was lower than the RRDCD (GC−) group (10.28 ± 2.81 ng/ml) (p = 0.013). The concentration of MIF in vitreous fluid was lower in the RRDCD (GC+) group (61.21 ± 17.56 ng/ml) than in the RRDCD (GC−) group (74.30 ± 9.66 ng/ml, p = 0.039). In the experimental group, the protein concentration of MCP-1 in the RRDCD (GC+) group was higher in the preoperative PVR grading C (284.93 ± 54.96 ng/ml) grade than in the D grade (225.94 ± 24.05 ng/ml) (p = 0.050); The protein concentration of MIF was lower in the RRDCD (GC+) group of patients with an ocular axis of <26 mm (56.19 ± 6.99 ng/ml) than in those with an ocular axis of ≥26 mm (76.26 ± 26.60 ng/ml, p = 0.043). Conclusion Low expression of Parthanatos-related proteins is present in the vitreous of patients with RRDCD (GC+), and preoperative treatment with glucocorticoids may reduce the expression of Parthanatos-related proteins.

Exploring Causal Correlations Between Inflammatory Cytokines and Kawasaki Disease: A Mendelian Randomization

Background The role of inflammatory cytokines in Kawasaki disease (KD) pathogenesis is known, but causal relationships are unclear. This study investigates these connections using Mendelian randomization (MR). Methods Genetic variations associated with KD were obtained from a GWAS including 119 cases and 6071 controls of European ancestry. Genetic data on inflammatory cytokines were sourced from a GWAS of 8,293 healthy participants. Results The study identified significant associations between higher levels of macrophage colony stimulating factor (M-CSF), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and increased risk of KD. The odds ratios (OR) were 1.04 (95% CI: 1.01–1.08, p = 0.010) for M-CSF, 1.03 (95% CI: 1.01–1.05, p = 0.026) for MCP-1, and 1.02 (95% CI: 1.01–1.04, p = 0.027) for TRAIL. Conclusion This study suggests that M-CSF, MCP-1, and TRAIL are potentially involved in the etiology of KD.

The Causal Relationship between Inflammatory Cytokines and Liver Cirrhosis in European Descent: A Bidirectional Two-Sample Mendelian Randomization Study and the First Conclusions.

Observational studies have highlighted the pivotal role of inflammatory cytokines in cirrhosis progression. However, the existence of a causal link between inflammatory cytokines and cirrhosis remains uncertain. In this study, we conducted a bidirectional Mendelian randomization (MR) analysis at a summarized level to illuminate the potential causal relationship between the two variables. This study utilized genetic variance in cirrhosis and inflammatory cytokines from a genome-wide association study (GWAS) of European descent. The MR-PRESSO outlier test, Cochran's Q test, and MR-Egger regression were applied to assess outliers, heterogeneity, and pleiotropy. The inverse variance weighted method and multiple sensitivity analyses were used to evaluate causalities. Furthermore, the validation set was used for simultaneous data validation. The inflammatory cytokine monocyte chemoattractant protein 3 (MCP-3) was supposedly associated with a greater risk of cirrhosis. And cirrhosis was significantly correlated with increased levels of hepatocyte growth factor (HGF). This study suggests that MCP-3 might be associated with the etiology of cirrhosis, while several inflammatory cytokines could potentially play a role in its downstream development. Additionally, the progression of cirrhosis was associated with elevated levels of HGF, suggesting a possible role for liver repair functions.

Botanical oleander extract and oleandrin have superior effects on innate immune functions pertaining to dermal allergic reactions in canine cells when compared to oclacitinib.

To perform testing for cytokines involved in dermal inflammatory reactions and to document and compare the effects of an oleander extract (OE), oleandrin, and oclacitinib on biomarkers relevant to allergic reactions. The effects of these compounds under inflamed culture conditions are of direct importance to the treatment of canine atopic dermatitis. Testing involved primary canine dermal fibroblasts and the canine DH82 macrophage cell line; both cell types are important for initiating, regulating, and resolving dermal allergic reactions via cytokine communication. Under inflamed conditions, OE and oleandrin downregulated key cytokines secreted by canine dermal fibroblasts and the DH82 macrophage cell line; all of which are treatment targets in dermatitis. In the DH82 macrophage cultures, the most noteworthy reductions involved IL-6, IL-12/IL-23p40, interferon-γ, tumor necrosis factor-α, VEGF, and nerve growth factor-β. Oclacitinib triggered reductions of some cytokines involved in allergic reactions, including TGF-β1, IL-12/IL-23p40, and tumor necrosis factor-α; however, these reductions were less robust than the reductions triggered by OE and oleandrin and accompanied by increases in other cytokines involved in dermal inflammation, including IL-6, interferon-γ, and nerve growth factor-β. In cultures of primary dermal fibroblasts, OE and oleandrin reduced the levels of IL-8 and monocyte chemoattractant protein-1, whereas oclacitinib had little or no effect. Oleander extract and oleandrin directly modulate immune responses under inflamed conditions. Moreover, OE and oleandrin appear to provide a more beneficial overall cytokine regulation than oclacitinib under inflamed culture conditions. These results suggest that OE and oleandrin are efficacious agents to treat canine atopic dermatitis. Future studies should evaluate the efficacy of these compounds in dogs affected by atopic dermatitis.

Parathyroidectomy Reduces Inflammatory Cytokines and Increases Vitamin D Metabolites in Patients With Primary Hyperparathyroidism

ContextPrimary hyperparathyroidism (PHPT) is accompanied by a decreased 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (DBP). High parathyroid hormone (PTH) is associated with elevated interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), yet the effect of parathyroidectomy (PTX) on DBP and cytokines is not clear. ObjectiveTo prospectively evaluate the effect of PTX on inflammatory profiles, total and free 25OHD, and DBP in patients with PHPT. MethodsNewly diagnosed patients with PHPT were recruited for the study (n = 70). Twenty-eight patients returned after PTX, 3 months later. Biochemical markers were measured before and after PTX. A group of age and body mass index-matched healthy subjects were included as controls (n = 70). ResultsBefore PTX, patients had lower serum DBP (37.5 ± 6.0 vs 41.5 ± 6.1 mg/dL, P < .001) and total 25OHD (30.1 ± 9.5 vs 33.3 ± 7.9 ng/mL, P < .05) but similar free 25OHD when compared to controls. Serum IL-6, C-reactive protein, and MCP-1 were higher in patients with PHPT (P < .05), whereas interleukin-10 was similar to that in controls. PTX increased total and free 25OHD and DBP (P < .001) and decreased serum IL-6 and MCP-1 (P < .05), but not C-reactive protein and interleukin-10. Multiple regression analysis indicated that the preoperative PTH explained a significant portion of the variance of IL-6 and MCP-1 (P < .05). ConclusionThese findings suggest that PTH may upregulate the production of MCP-1 and IL-6 and downregulate circulating DBP in patients with PHPT that are normalized by PTX. The exact mechanism of IL-6 and MCP-1 on DBP, vitamin D metabolites, and clinical outcomes in patients with PHPT is an area requiring further study.

Long-Term Prognostic Value of Adipocytokines in Patients with Acute Coronary Syndrome: An 8-Year Clinical Prospective Cohort Study.

To elucidate the predictive values of adipocytokines in patients with acute coronary syndrome (ACS). Overall, 297 patients with ACS were consecutively enrolled in this prospective cohort study between June 2015 and July 2017 and completed follow-up with a median follow-up time of 6.5 years. For consistency, the last visit date was June 20, 2023. Serum levels of retinol-binding protein-4 (RBP4), interleukin-1β (IL-1β), monocyte chemoattractant protein 1(MCP-1), adrenomedullin (ADM), netrin 1 (NTN 1), and omentin were measured using enzyme-linked immunosorbent assay. Follow-up data were collected during clinical visits or through telephone interviews at 1, 3, 6, 12 months, and annually. The primary endpoint was defined as major adverse cardiovascular events (MACEs), including all-cause mortality, rehospitalization for percutaneous coronary intervention, and severe angina requiring rehospitalization. All biomarkers displayed a good diagnostic ability of MACEs. The Kaplan-Meier curve showed that the cumulative survival rates of high level of RBP4, IL-1β, and MCP-1 and low level of the ADM, NTN1, and omentin had lower cumulative survival rates (Log rank tests: all p<0.05). After adjustment in the Cox hazard proportional model, the results were RBP4 ≥ 6.87 ng/mL, hazard ratio (HR)=2.512, p=0.003; IL-1β≥ 58.95 pg/mL, HR=3.809, p<0.001; MCP-1 ≥ 401.75 pg/mL, HR=4.047, p<0.001; ADM≤120.01 ng/mL, HR=3.930, p=0.008; NTN1 ≤63.7 pg/mL, HR=3.345, p=0.007; omentin ≤ 4.54 ng/mL, HR=2.830, p=0.004. P-values for interaction were > 0.05 in the sex, age, and dyslipidemia subgroups. Pro-inflammation adipocytokines RBP4, IL-1β, and MCP-1 increased and anti-inflammation biomarkers ADM, NTN1, and omentin decreased were independently associated with a higher risk of MACEs in patients with ACS.

Association of Monocyte Chemoattractant Protein-1 (MCP-1) 2518 A/G Polymorphism with Obesity in Korean Type 2 Diabetes Mellitus.

Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family, and the MCP-1 2518 A/G gene polymorphism is reported to be correlated with chronic inflammatory diseases, including insulin resistance and metabolic syndrome. However, few studies have investigated the association between MCP-1 gene polymorphisms and obesity in patients with type 2 diabetes mellitus (T2DM). We conducted a retrospective case-control study and evaluated the association between the MCP-1 2518 A/G polymorphism and obesity in Korean patients with T2DM. This single-center, retrospective, case-control study enrolled 526 Korean patients with T2DM. Obesity was defined using the body mass index (BMI) with a cutoff level of 25 kg/m2. Polymerase chain reaction-restriction fragment length polymorphism was used to analyze MCP-1 2518 A/G polymorphism; the genotypes was presented as GG, AG, or AA. We compared the MCP-1 2518 A/G polymorphism with the prevalence of diabetic complications, as well as clinical and biochemical characteristics. The obese group had a higher number of females and higher C-peptide, insulin, triglycerides, aspartate transaminase (AST), and alanine transaminase (ALT) levels. The obese group also had a higher prevalence of cardiovascular disease than the non-obese group. The obese group had a higher frequency of the MCP-1 2518 AA genotype and the A allele than the non-obese group. The results of multiple logistic regression analysis showed that the non-G allele of MCP-1 was significantly associated with obesity (odds ratio (OR), 1.888; P=0.016). This study demonstrates that the MCP-1 2518 A/G polymorphism is associated with obesity in Korean patients with T2DM. Further studies involving various ethnic groups are required to validate our results.

Investigation on the in vitro effects of resveratrol on peripheral blood mononuclear cells harvested from healthy and atopic dogs

Canine atopic dermatitis (AD) is a common skin disease. Many therapeutic options are available to decrease inflammation and ameliorate pruritus. However, those treatments are associated with side effects, a long lag phase for efficacy, or high expense. Natural plant extracts have been identified as possible, safer alternatives to traditional anti-inflammatory and antipruritic drugs. Resveratrol has been revisited as a new, possible alternative for its numerous beneficial properties. The purpose of this study was to evaluate the in vitro effects of resveratrol on peripheral blood mononuclear cells (PBMC) harvested from healthy and atopic privately-owned dogs.The PBMC harvested from nine healthy and 11 atopic dogs were isolated and exposed to four concentrations (1.5-9 μg/mL) of resveratrol both with or without phytohemagglutinin stimulation. After 24 h cytotoxicity, host defense peptides (HDPs), as well as oxidative stress (catalase and superoxide dismutase), and pro-inflammatory cytokines were assessed. Cytotoxicity was not observed in either group under any experimental conditions. An increase in catalase was only seen in healthy PBMC after exposure to low concentrations of resveratrol (p ≤ 0.03). Resveratrol did not show any effect on canine HDPs. Compared to baseline, there was a significant reduction in monocyte chemotactic protein-1 and interleukin-6 after exposure to 9 μg/mL of resveratrol in unstimulated healthy (p = 0.029) and stimulated atopic (p = 0.0075) PBMC. In conclusion, these data confirm the overall lack of cytotoxicity of resveratrol on healthy and atopic PBMC at the tested concentrations. However, at the concentrations tested, there was only a minimal effect of resveratrol on the secretion of HDPs and pro-inflammatory cytokines.

Tangeretin inhibits airway inflammatory responses by reducing early growth response 1 (EGR1) expression in mice exposed to cigarette smoke and lipopolysaccharide

BackgroundTangeretin, a natural polymethoxyflavone compound, possesses potent anti-inflammatory activity that improves respiratory inflammation in chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying the anti-COPD effects of tangeretin remain unclear. In this study, we aimed to investigate the key molecular mechanisms by which tangeretin suppresses COPD-related inflammatory responses. MethodsWe conducted the investigation in phorbol-12-myristate-13-acetate (PMA)-stimulated human airway epithelial cells (in vitro) and cigarette smoke (CS)/lipopolysaccharide (LPS)-exposed mice (in vivo). ResultsTangeretin decreased the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and mucin 5AC (MUC5AC), by suppressing early growth response 1 (EGR1) expression in vitro. Tangeretin and EGR1 small interfering ribonucleic acid (siRNA) combination showed a synergistic reduction in MUC5AC and TNF-α secretion. Tangeretin administration significantly inhibited the levels of reactive oxygen species (ROS) production, elastase activity, TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1) secretion, and macrophage and neutrophil numbers in the bronchoalveolar lavage fluid of CS/LPS-exposed mice. Tangeretin also prevented CS/LPS-induced abnormal pathological changes and excessive MUC5AC and EGR1 expression in lung tissue. ConclusionComprehensively, tangeretin inhibits the lung inflammatory response associated with COPD by reducing EGR1 expression in PMA-induced human epithelial cells and in a CS/LPS-stimulated mouse model. This study shows that tangeretin has anti-COPD properties and can be a promising alternative (or complementary) treatment for inflammatory lung disease.

Direct Effects of Inflammatory Cytokines on Mouse Uterine Contraction.

Uterine contractions signal labor onset, with elevated pro-inflammatory cytokines playing a pivotal role. Prior studies have explored their effects on prostaglandins, oxytocin, and signaling pathways, but have overlooked their direct effects on uterine contractions. Here, we aim to investigate the direct effects of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) on contractions to ascertain if they have immediate observable effects like those reported for lipopolysaccharide (LPS) and other effects. Tension recordings were used to assess the direct effects of cytokines and/or LPS on mouse uterine contractions. Calcium imaging was employed to observe calcium oscillations in cytokine-pretreated myometrial smooth muscle cells (MSMCs) in response to oxytocin. The release of inflammatory cytokines and chemokines from uterine explants after LPS and/or cytokines application was investigated using Luminex. IL-1β, IL-6, and TNF-α rapidly enhanced contractions of term pregnant mouse uterus. LPS combined with TNF-α intensified contractions compared to LPS alone, although this effect was not statistically significant in our results (p > 0.050). Pretreatment of MSMCs with IL-1β, IL-6, or TNF-α increased calcium oscillations in response to oxytocin. LPS and/or cytokine significantly stimulated the release of IL-1β, IL-6, TNF-α, Chemokine (C-X-C motif) ligand 1 (CXCL1), and monocyte chemoattractant protein-1 (MCP1) from uterine explants in vitro. Inflammatory cytokines have short-term and long-term effects on mouse uterine contractions, which together contribute to progressively stronger contractions during labor.

Dietary Protein in a Challenge Meal Does Not Alleviate Postprandial Impairments in Vascular Endothelial Function in Healthy Older Adults with Cardiometabolic Risk: A Randomized Crossover-Controlled Trial

BackgroundPostprandial vascular endothelial dysfunction is an early marker of atherosclerosis. Meal protein has been reported to reduce endothelial dysfunction in adults, and the effect could be mediated by the amino acid content. ObjectivesThis trial aims to assess the effect of a specifically designed plant-protein blend that contains high leucine, arginine, and cysteine on postprandial endothelial function in the elderly. MethodsIn a randomized, double-blind, 3-period crossover (2-wk washout), controlled trial, we compared the vascular effects of 3 high-saturated-fat high-sucrose (HFHS) meals based on either our specific plant-protein blend, milk protein, or without added protein. The trial was conducted on 29 healthy adults aged >65 y presenting ≥2 cardiometabolic risk factors. Postprandial vascular function was evaluated at fasting, 3 h, and 5 h postprandially, using brachial flow-mediated dilation (FMD), hand microvascular reactivity (using Flowmetry Laser Doppler, FLD), and finger reactive hyperemia index (using Peripheral Arterial Tonometry, RHI). Immune cell count and gene expression in peripheral blood mononuclear cells (PBMCs) were also assessed postprandially. Data were analyzed using mixed linear models with repeated measurements on participants for meal composition and time of sampling. This trial was registered at clinicaltrials.gov as NCT04923555. ResultsFMD incremental AUC value decreased after meals (time effect P < 0.01), with no significant differences between meals. RHI also decreased with time (P < 0.01). PBMC count and monocyte chemoattractant protein-1, IL-1b, and IL-6 expression increased after meals showing postprandial endothelial activation (P < 0.05). Overall, meal composition had no effect on any of the postprandial changes (Ps>0.10). ConclusionsIn healthy adults aged >65 y presenting cardiometabolic risk, adding protein to an HFHS challenge meal does not mitigate postprandial impairments in vascular endothelial function and inflammatory activation. Further studies are needed to explore the potential differences with younger adults.

Preparation and characterization of cysteine-rich collagen peptide and its antagonistic effect on microplastic induced damage to HK-2 cells

Cysteine (Cys) plays a significant role in the stability and antioxidant capacity of peptide. This study was to prepare Cys-rich collagen peptide and evaluate its preventive effect on microparticle (MPs)-induced HK-2 cell damage. The results showed that the Cys-rich peptides (AMP-C) were successfully prepared from collagen hydrolysate by plastein reaction in the presence of exogenous Cys. The scavenging activities of 2,2-Diphenyl-1-picrylhydrazyl and hydroxyl radical of AMP-C were significantly higher than those of original peptides without Cys. The fraction with molecular weight < 3 kDa (AMP-CA) significantly improved MPs-induced damage and apoptosis of HK-2 cells. Compared with the same fractions lacking Cys (AMP-A), AMP-CA showed better performance in reducing reactive oxygen species and increasing the total superoxide dismutase and glutathione peroxidase levels, which may be related to its down-regulation of Kelch-like ECH-associated protein 1 (Keap1) expression. In addition, AMP-CA showed strong effects on inhibiting interleukin-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, kidney injury molecule-1, and nuclear factor kappa-B levels. Finally, 330 Cys-containing peptides were isolated from AMP-CA, among which Leucine-Glycine-Asparagine-Glycine-Cysteine-Proline (LGNGCP) showed the lowest binding energy with Keap1 protein. In conclusion, the Cys-rich collagen peptide with higher antioxidant activity was successfully prepared by plastein reaction, which alleviated the HK-2 cells damage induced by MPs through antioxidant and anti-inflammatory. Our findings suggested that Cys-rich collagen peptide might be used as a functional food to mitigate health hazards associated with MPs accumulation.