Elevated Levels Of Inflammation Research Articles

Cilostazol attenuates mirabegron-induced hepatic and renal toxicity in rats: regulation of metabolic, oxidative, and inflammatory pathways

Background Mirabegron (MIRG) is a type of β3 adrenoceptor agonist that is considered an alternative therapy for the treatment of overactive bladder (OAB) symptoms. Cilostazol (CITZ) is a selective inhibitor of phosphodiesterase (III) that has various pharmacological effects. Objectve The current study aimed to highlight the regulatory effects of CITZ on MIRG-induced toxicity. Materials and Methods Male rats were divided into six groups. Blood samples were collected to determine different hepatic and kidney function levels along with serum protein electrophoresis and inflammatory factor levels. Histopathological studies and oxidative stress (OS) were also assessed. Kidney and hepatic damage were detected following the administration of MIRG, especially at high doses, due to elevated OS, inflammation, and apoptotic marker levels. Results Rats receiving CITZ exhibited significant improvements in both hepatic and kidney functions, with decreased inflammation and OS. Conclusion CITZ administration plays a beneficial role in alleviating hepatic and nephrotoxicity induced by MIRG by inhibiting OS and inflammation.

Red blood cell distribution width (RDW) and adverse outcomes in acute coronary syndrome patients

Background and objectives. Red blood cell distribution width (RDW) is an early biomarker indicative of the inflammatory process. Elevated levels of systemic and local inflammation are integral to the pathophysiology of acute coronary syndromes (ACS). This study aims to examine the correlation between increased RDW and various severe prognostic factors associated with ACS. Materials and methods. This cross-sectional descriptive study was conducted on a cohort of 60 patients diagnosed with acute coronary syndromes (ACS). The diagnostic threshold for elevated RDW-CV was established at 15%. Accordingly, the study population was stratified into two groups: group 1 (RDW-CV≤15%), and group 2 (RDW-CV15%). Results. The range of RDW-CV (%) distribution is from 11.2% to 16.9%, with a mean value of 14.2±1.3. A negative correlation exists between RDW-CV (%) and ejection fraction (EF%) (r=-0.4, p<0.01). Univariate linear regression analysis indicates that a 1% increase in RDW-CV (%) corresponds to a 3.3% decrease in EF (%) (Coefficient=-3.3, p<0.01). Furthermore, univariate logistic regression analysis reveals that patients with RDW >15% have a 9.3-fold increased risk of heart failure with reduced EF (OR=9.3, p<0.01) and a 4.5-fold increased risk of having damage to 2-3 coronary vessels (OR=4.5, p<0.05) compared to those with RDW≤15%. ROC curves demonstrate that RDW has a good predictive ability for reduced EF (AUC=0.779, 95% CI 0.626-0.932, p=0.006). Conclusions. There is a significant relationship between elevated RDW and severe prognostic factors in acute coronary syndromes (ACS), including reduced ejection fraction (EF) and the extent of coronary vessel damage. Monitoring this straightforward hematological marker can enhance prognostic accuracy and inform appropriate treatment strategies.

A molecular subtyping associated with the cGAS-STING pathway provides novel perspectives on the treatment of ulcerative colitis

Ulcerative colitis (UC) is characterized by an abnormal immune response, and the pathogenesis lacks clear understanding. The cGAS-STING pathway is an innate immune signaling pathway that plays a significant role in various pathophysiological processes. However, the role of the cGAS-STING pathway in UC remains largely unclear. In this study, we obtained transcriptome sequencing data from multiple publicly available databases. cGAS-STING related genes were obtained through literature search, and differentially expressed genes (DEGs) were analyzed using R package limma. Hub genes were identified through protein–protein interaction (PPI) network analysis and module construction. The ConsensuClusterPlus package was utilized to identify molecular subtypes based on hub genes. The therapeutic response, immune microenvironment, and biological pathways of subtypes were further investigated. A total of 18 DEGs were found in UC patients. We further identified IFI16, MB21D1 (CGAS), TMEM173 (STING) and TBK1 as the hub genes. These genes are highly expressed in UC. IFI16 exhibited the highest diagnostic value and predictive value for response to anti-TNF therapy. The expression level of IFI16 was higher in non-responders to anti-TNF therapy. Furthermore, a cluster analysis based on genes related to the cGAS-STING pathway revealed that patients with higher gene expression exhibited elevated immune burden and inflammation levels. This study is a pioneering analysis of cGAS-STING pathway-related genes in UC. These findings provide new insights for the diagnosis of UC and the prediction of therapeutic response.

Histological Features of Uterine Myometrial Dysfunction: Possible Involvement of Localized Inflammation.

The latest perspective suggests that elevated levels of inflammation and cytokines are implicated in atonic postpartum hemorrhage. Lipopolysaccharide (LPS) has been widely used to induce inflammation in animal models. Therefore, this study aimed to induce uterine inflammation using LPS to investigate whether local inflammation triggers dysfunction and atrophy in the myometrium, as well as the potential underlying molecular mechanisms involved. In vivo, an animal model was established by intraperitoneal injection of 300 μg/ kg LPS in rats on gestational day 21. Hematoxylin-eosin (H&E) staining and Masson staining were employed to determine morphological changes in the rat uterine smooth muscle. Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory cytokines. Immunohistochemistry, tissue fluorescence, and Western blotting were conducted to assess the expression levels of the uterine contraction-related proteins Toll-like receptor 4 (TLR4) and the nuclear factor kappa-B (NF-κB) signaling pathway. In vitro, human uterine smooth muscle cells (HUtSMCs) were exposed to 2 μg/mL LPS to further elucidate the involvement of the TLR4/NF-κB signaling pathway in LPS-mediated inflammation. In this study, LPS induced uterine myometrial dysfunction in rats, leading to a disorganized arrangement, a significant increase in collagen fiber deposition, and widespread infiltration of inflammatory cells. In both in vivo animal models and in vitro HUtSMCs, LPS elevated IL-6, IL-1β, and TNF-α levels while concurrently suppressing the expression of connexin 43 (Cx43) and oxytocin receptor (OXTR). Mechanistically, the LPS-treated group exhibited TLR4 activation, and the phosphorylation levels of p65 and IκBα were notably increased. LPS triggered the TLR4/NF-κB signaling pathway, inducing an inflammatory response in the myometrium and leading to uterine myometrial dysfunction and uterine atony.

Neuroinflammation in dementia: A meta-analysis of PET imaging studies.

Dementia is a major public health challenge for aging societies worldwide. Neuroinflammation is thought to be a key factor in dementia development. The aim of this study was to comprehensively assess translocator protein (TSPO) expression by positron emission tomography (PET) imaging to reveal the characteristics of neuroinflammation in dementia. We used a meta-analysis to retrieve literature on TSPO expression in dementia using PET imaging technology, including but not limited to the quality of the study design, sample size, and the type of TSPO ligand used in the study. For the included studies, we extracted key data, including TSPO expression levels, clinical characteristics of the study participants, and specific information on brain regions. Meta-analysis was performed using R software to assess the relationship between TSPO expression and dementia. After screening, 12 studies that met the criteria were included. The results of the meta-analysis showed that the expression level of TSPO was significantly elevated in patients with dementia, especially in the hippocampal region. The OR in the hippocampus was 1.50 with a 95% CI of 1.09 to 1.25, indicating a significant increase in the expression of TSPO in this region compared to controls. Elevated levels of inflammation in the prefrontal lobe and cingulate gyrus are associated with cognitive impairment in patients. This was despite an OR of 1.00 in the anterior cingulate gyrus, indicating that TSPO expression in this region did not correlate significantly with the findings. The overall heterogeneity test showed I² = 51%, indicating moderate heterogeneity. This study summarizes the existing literature on TSPO expression in specific regions of the brain in patients with dementia, and also provides some preliminary evidence on the possible association between neuroinflammation and dementia. However, the heterogeneity of results and limitations of the study suggest that we need to interpret these findings with caution. Future studies need to adopt a more rigorous and consistent methodological design to more accurately assess the role of neuroinflammation in dementia, thereby providing a more reliable evidence base for understanding pathological mechanisms and developing potential therapeutic strategies.

Dysregulated serum lipid profile is associated with inflammation and disease activity in primary Sjögren's syndrome: a retrospective study in China

PurposeTo investigate the relationship between the lipid profiles of patients with primary Sjögren's syndrome (pSS) and other clinical characteristics, laboratory examination, disease activity, and inflammatory factors. In addition, the risk factors for hyperlipidemia-related complications of pSS and the effect of hydroxychloroquine (HCQ) usage on the lipid profile were incorporated into this study. MethodsThis is a single-center, retrospective study that included 367 patients who were diagnosed with pSS at Tongji Hospital, School of Medicine, Tongji University, China from January 2010 to March 2022. Initially, demographic information, clinical characteristics, medication records, and complications of the patients were gathered. A case-control analysis compared the 12 systems involvement (ESSDAI domain), clinical symptoms, and laboratory tests between pSS patients with and without dyslipidemia. A simple linear regression model was employed to investigate the relationship between serum lipid profile and inflammatory factors. Logistics regression analysis was performed to assess variables for hyperlipidemia-related complications of pSS. The paired t-test was then used to evaluate the improvement in lipid profile among pSS patients. Results48.7 % of all pSS patients had dyslipidemia, and alterations in lipid levels were related to gender, age, and smoking status but not body mass index (BMI). Dyslipidemia is more prevalent in pSS patients who exhibit heightened autoimmunity and elevated levels of inflammation. Higher concentrations of multiple highly inflammatory factors correlate with a more severe form of dyslipidemia. Non-traditional cardiovascular risk factors may contribute to hyperlipidemia-related complications of pSS, such as increased, low complement 3 (C3) and low C4. According to our study, HCQ usage may protect against lipid-related disease in pSS. ConclusionAttention should be paid to the dyslipidemia of pSS. This research aims to clarify the population portrait of pSS patients with abnormal lipid profiles and provides insights into the correlation between metabolism and inflammation in individuals with pSS and the potential role they play in the advancement of the disease. These findings provide novel avenues for further understanding the underlying mechanisms of pSS pathogenesis.

Multifunctional Drug- and AuNRs-Loaded ROS-Responsive Selenium-Containing Polyurethane Nanofibers for Smart Wound Healing.

Elevated levels of ROS, bacterial infection, inflammation, and improper regeneration are the factors that need to be addressed simultaneously for achieving effective wound healing without scar formation. This study focuses on the fabrication of electrospun ROS-responsive selenium-containing polyurethane nanofibers incorporating deferoxamine mesylate (Def), indomethacin (Indo), and gold nanorods (AuNRs) as proangiogenesis, anti-inflammatory, and antibacterial agents for synchronized delivery to a full-thickness wound in vivo. The structure of the fabricated nanofibers was analyzed by various techniques. Toxicity was checked by CCK-8 and hemolytic assays. The efficiency of wound healing in vitro was verified by a transwell assay and cell scratch assay. The wound healing efficiency of the nanofibers was assayed in full-thickness wounds in a rat model. The multifunctional nanofibers had a porous structure, enhanced antioxidation, antibacterial activity, and promoted wound healing. They eradicated TNF-α and IL-6, increased IL-10 expression, and revealed the angiogenic potential by increased expression of HIF-1α, VEGF, and CD31.

Associations of Systematic Inflammatory Markers with Diet Quality, Blood Pressure, and Obesity in the AIRWAVE Health Monitoring Study.

Chronic low-grade inflammation is a characteristic feature of obesity, and elevated levels of inflammation are associated with pathophysiologic consequences and a constellation of metabolic disturbances, such as hypertension. The relationships of inflammation with diet, obesity, and hypertension are complex, hence, this study aimed to assess cross-sectional relationships between inflammatory scores, diet quality, obesity, high blood pressure (BP), and hypertension in the Airwave Health Monitoring Study cohort, a large cohort of police officers and police staff in the United Kingdom. Data from 5198 men and 3347 women who completed health screening measurements and dietary assessment between 2007 and 2012 were included (n=8545 adults). Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and the systemic immune-inflammation index (SII) were calculated. Diet quality was evaluated using the Nutrient-Rich Food 9.3 (NRF9.3) index score. Results show that a 1SD higher diet quality score, waist circumference, and systolic/diastolic BP were significantly associated with SII differences of -33.3 (95% confidence interval (CI): -49.0, -17.6), 8.2 (95% CI: 0.2, 16.6), 17.9 (95% CI: 10.1, 25.8), and 18.3 (95% CI: 10.8, 25.7) (Model 2; P<0.0001), respectively. A 1SD higher diet quality score, waist circumference, and BMI were also significantly associated with PLR (P<0.0001). The odds of elevated PLR were higher in those with higher systolic and diastolic BP (P<0.0001, P=0.0006, respectively). In conclusion, the findings of this analysis add to the existing knowledge indicating a link between inflammation and conditions such as obesity, hypertension, and behavioral factors including diet quality. Of the various inflammatory scores evaluated, SII and PLR were consistently significantly associated with diet quality and these conditions.

A panel study of exposure to fine particulate matter and modeled respiratory deposition on biomarkers of inflammation, blood coagulation, and oxidative stress in healthy young adults in Hefei, China

Evidence is scarce on the acute cardiovascular health effects of fine particulate matter (PM2.5) and its respiratory tract depositions. We performed a panel study in Hefei, China to explore the relations of PM2.5 and its depositions in 3 respiratory tract regions over different lag times with a range of cardiovascular biomarkers among 40 college students and the potential mediating effects of inflammation. We found significant effects of PM2.5 exposure on the alterations of biomarkers at specific lag days, in a concentration-response manner, even at PM2.5 level below Chinese Ambient Air Quality Standard (CAAQS) Grade I (35 μg/m3). For example, per 10 μg/m3 increase in PM2.5 concentration was associated with −9.33% increase in ADAMTS13 on lag 0-1d. The corresponding increases in D-Dimer, GM-CSF, and MCP-1 for the same change in PM2.5 concentration on lag 5-6d were 30.51%, 11.43%, and 20.05%. Besides, tracheobronchial region (TB) deposition presented more evident effects on these biomarkers than that in PM2.5. Additionally, we observed greater associations of PM2.5-biomarkers among females, those with abnormal body mass index (BMI), and those with physical activity. The results indicated that short-term PM2.5 exposure and its respiratory tract depositions were concentration-responsive associated with damaged cardiovascular health via inducing blood coagulation, oxidative stress and inflammation among healthy young adults even at concentration below CAAQS Grade I. Elevated serum levels of systemic inflammation may be partly responsible for the effects of PM2.5 and its respiratory tract depositions on coagulation function.

Abstract 6885: Investigating a novel role of DCLK1 isoforms in colitis and colitis associated colon cancer

Abstract Chronic intestinal inflammation in patients diagnosed with inflammatory bowel disease (IBD) significantly increases their risk of colorectal cancer (CRC). Despite the rising global frequency of IBD, the precise mechanisms that regulate the transition from IBD to colon cancer are poorly understood. Doublecortin-like kinase 1 (DCLK1) is a protein with two major isoforms, DCLK1-L and DCLK1-S. Previous studies have shown that hypermethylation of the DCLK-1α promoter encoding DCLK1-L, particularly in colorectal cancer, allows switching to the DCLK1-S isoform that confers an invasive tumor phenotype. The DCLK1-L is a tuft cell marker that protects against colitis by sensing and eliminating gut pathogenic infection through various mechanisms. On the contrary, the role of DCLK1-S in colitis and colitis-associated cancer has not been thoroughly investigated. Studies from our lab have identified a marked elevation of DCLK1-S in tissue samples of IBD patients. We also recently discovered that DCLK1-S is predominantly expressed in Ly6G+; MHCII- neutrophils, which coincide with elevated levels of inflammation and tissue damage in the colon. To further understand the role of DCLK1 isoforms in driving the progression of colitis to colon cancer, we bred Dclk1fl/fl mice with MRP8-Cre-ires/GFP mice to generate Dclk1fl/fl;MRP8-Cre+/- that eliminates DCLK1-L upon tamoxifen injection resulting in sustained expression of DCLK1-S in the granulocytes especially neutrophils. When infected with Citrobacter rodentium (CR), MRP8;Dclk1−/− mice compared to MRP8;Dclk1+/− or WT mice developed more severe colitis. We have also discovered a novel interaction between DCLK1-S and MMP13 in an unbiased docking study that correlated with significant co-localization of DCLK1-S with MMP13 in the colons of CR-infected mice. Employing a knock-in mice over-expressing the DCLK1-S +19 under the CAG promoter, the DCLK1-MMP13 co-localization correlated with severe ulceration and colitis with loss of crypts and immune cell infiltration including Ly6G+ neutrophils. Studies are underway to see if the severity of colitis in MRP8;Dclk1−/− mice translates into enhanced tumorigenesis and to see if potential interaction between DCLK1-S and MMP13 could provide a plausible mechanism of colitis progression to colon cancer through ECM remodeling and tissue damage. Citation Format: Kafayat Aderonke Yusuf, Badal C. Roy, Shrikant Anant, Shahid Umar. Investigating a novel role of DCLK1 isoforms in colitis and colitis associated colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6885.

Abstract P187: Associations of Body Composition, Inflammation, and Lipids: The Multi-Ethnic Study of Atherosclerosis

Background: Prior evidence has linked inflammation with myopenic obesity (MO), a high cardiometabolic risk body composition phenotype characterized by low muscle and high fat mass. Inflammation may also alter lipid metabolism. This study aimed to examine the association between MO and lipids and whether inflammation is one potential mediator of their complex relationship. Methods: We conducted a cross-sectional analysis of 1,421 Multi-Ethnic Study of Atherosclerosis participants with abdominal computed tomography body composition, lipid, and inflammatory marker measurements. The ratio of total skeletal muscle area to total adipose tissue area (SM/AT) at L3-4 was used to identify MO (lowest sex-stratified tertiles of &lt;0.52 in men and &lt;0.44 in women). Principal component analysis was used to reduce six inflammatory markers by patterns of covariation. Parallel mediation analysis was conducted to examine whether the inflammatory components mediated the relationship between SM/AT and lipids, acknowledging the limitations of cross-sectional data. Results: The sample’s mean age was 64±10 years, 52.4% were female, and 42.1% were Caucasian. Participants with MO (n=474), compared to those without (n=947), had lower high-density lipoprotein cholesterol (HDL-C; 49±13 vs. 54±16, p&lt;0.001), higher remnant cholesterol (RC; 28±13 vs. 24±13, p&lt;0.001), and similar low-density lipoprotein cholesterol (LDL-C; 110±32 vs. 113±30, p=0.073). All inflammatory markers were higher in MO (p≤0.002). Parallel mediation analysis showed significant direct effects between SM/AT and both HDL-C and RC, which were mediated by component 1 but not component 2. There was no significant direct or indirect effect between SM/AT and LDL-C (Table 1). Conclusion: Participants with MO exhibited elevated levels of inflammation and unfavorable lipid profiles. Two inflammatory components were identified, one of which (IL-6, CRP, fibrinogen, and leptin) partially mediated the relationship of SM/AT with HDL-C and RC.

Role of the Fungus Pneumocystis in IL1β Pathway Activation and Airways Collagen Deposition in Elastase-Induced COPD Animals.

Inflammation and mucus production are prevalent characteristics of chronic respiratory conditions, such as asthma and chronic chronic obstructive pulmonary disease (COPD). Biological co-factors, including bacteria, viruses, and fungi, may exacerbate these diseases by activating various pathways associated with airway diseases. An example is the fungus Pneumocystis, which is linked to severe COPD in human patients. Recent evidence has demonstrated that Pneumocystis significantly enhanced inflammation and mucus hypersecretion in a rat model of elastase-induced COPD. The present study specifically aims to investigate two additional aspects associated with the pathology induced by Pneumocystis infection: inflammation and collagen deposition around airways. To this end, the focus was to investigate the role of the IL-1β pro-inflammatory pathway during Pneumocystis infection in COPD rats. Several airway pathology-related features, such as inflammation, mucus hypersecretion, and fibrosis, were evaluated using histological and molecular techniques. COPD animals infected with Pneumocystis exhibited elevated inflammation levels, including a synergistic increase in IL-1β and Cox-2. Furthermore, protein levels of the IL-1β-dependent transcription factor cAMP response element-binding (CREB) showed a synergistic elevation of their phosphorylated version in the lungs of COPD animals infected with Pneumocystis, while mucus levels were notably higher in the airways of COPD-infected animals. Interestingly, a CREB responsive element (CRE) was identified in the Muc5b promoter. The presence of CREB in the Muc5b promoter was synergistically increased in COPD animals infected with Pneumocystis compared to other experimental groups. Finally, an increment of deposited collagen was identified surrounding the airways of COPD animals infected with Pneumocystis compared with the other experimental animal groups and correlated with the increase of Tgfβ1 mRNA levels. These findings emphasize the role of Pneumocystis as a potential biological co-factor in chronic respiratory diseases like COPD or asthma, warranting new perspectives in the treatment of chronic respiratory diseases.

Characterization of preclinical Alzheimer’s disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology

BackgroundThe key to the prevention and treatment of Alzheimer’s disease (AD) is to be able to predict and diagnose AD at the preclinical or early stage, but the lack of a preclinical model of AD is the critical factor that causes this problem to remain unresolved.MethodsWe assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG < 100 mg/dL). Levels of pro-inflammatory cytokines and AD pathological biomarkers was measured by ELISA and Simoa Technology, respectively. 9 monkeys evaluated ex vivo for AD-like pathology (n = 6 / T2DM group, age 22.17, FPG ≥ 126 mg/dL, and n = 3 / NC group, age 14.67, FPG < 100 mg/dL). To evaluate the pathological features of AD in the brains of T2DM monkeys, we assessed the levels of Aβ, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Aβ plaques by Bielschowsky’s silver, Congo red, and Thioflavin S staining. Synaptic damage and neurodegeneration were assessed by immunofluorescence.ResultsWe found not only increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased β-amyloid (Aβ) 42 and Aβ40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Aβ plaque deposition, p-tau from neuropil thread to pre-neurofibrillary tangles (NFTs), and even the appearance of extracellular NFT. Microglia were activated from a resting state to an amoeboid. Astrocytes showed marked hypertrophy and an increased number of cell bodies and protrusions. Finally, we observed impairment of the postsynaptic membrane but no neurodegeneration or neuronal death.ConclusionsOverall, T2DM monkeys showed elevated levels of peripheral and intracerebral inflammation, positive AD biomarkers in body fluids, and developing AD-like pathology in the brain, including Aβ and tau pathology, glial cell activation, and partial synaptic damage, but no neuronal degeneration or death as compared to the healthy normal group. Hereby, we consider the T2DM monkeys with elevation of the peripheral pro-inflammatory factors and positive AD biomarkers can be potentially regarded as a preclinical AD model.

Advantages of Chinese herbal medicine in treating rheumatoid arthritis: a focus on its anti-inflammatory and anti-oxidative effects.

Oxidative stress is a condition characterized by an imbalance between the oxidative and antioxidant processes within the human body. Rheumatoid arthritis (RA) is significantly influenced by the presence of oxidative stress, which acts as a pivotal factor in its pathogenesis. Elevated levels of mitochondrial reactive oxygen species (ROS) and inflammation have been found to be closely associated in the plasma of patients with RA. The clinical treatment strategies for this disease are mainly chemical drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids (GCs) and biological agents, but it is difficult for patients to accept long-term drug treatment and its side effects. In the theory of traditional Chinese medicine (TCM), RA is thought to be caused by the attack of "wind, cold, damp humor," and herbs with the effect of removing wind and dampness are used to relieve pain. Chinese herbal medicine boasts a rich heritage in effectively attenuating the symptoms of RA, and its global recognition continues to ascend. In particular, RA-relevant anti-inflammatory/anti-oxidative effects of TCM herbs/herbal compounds. The main aim of this review is to make a valuable contribution to the expanding pool of evidence that advocates for the incorporation of Chinese herbal medicine in conventional treatment plans for RA.

Serum Neopterin, Biopterin, Tryptophan, and Kynurenine Levels in Patients with Fabry Disease

Fabry disease is characterized by the accumulation of globotriaosylceramide. Substrate accumulation in lysosomes is thought to trigger an inflammatory response and is responsible for progressive organ damage through the induction of autoimmunity. The levels of pteridine and kynurenine pathway metabolites increase when immune activation is observed and are employed to monitor several diseases and determine prognosis. To elucidate the effects of immune activation on the pathophysiology of Fabry disease and to investigate the potential utility of pteridine and kynurenine metabolites. A prospective case-control study. In this study, 33 patients with Fabry disease and 33 age-and sex-matched healthy controls were included. Blood pteridine and kynurenine metabolites were studied in both groups. Organ involvement in Fabry disease and its correlation with the pteridine and kynurenine pathways were also investigated. The patients’ neopterin and biopterin levels and the tryptophan/kynurenine ratio were statistically higher than those of the healthy control group (p < 0.05). A statistically significant association was found between neopterin levels and hypertrophic cardiomyopathy, cardiac arrhythmias, and GFR values (p = 0.044, p = 0.021, and p = 0.030, respectively), tryptophan and corneal verticillate, hearing loss and tinnitus (p = 0.010, p = 0.009 and p = 0.046, respectively), and kynurenine levels and valvular heart disease (p = 0.020). From the onset of the disease, patients with Fabry disease exhibited elevated levels of inflammation and immune activation. Furthermore, inflammation and immune activation markers can be used as early disease biomarkers.

RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway.

Hepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI. We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments. Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity

BackgroundAsialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity.MethodsASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration.ResultsASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function.ConclusionASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage.

P241 Systemic redox status associates with disease activity and clinical phenotypes in Inflammatory Bowel Disease

Abstract Background Oxidative stress is a key pathophysiological mechanism in inflammatory bowel diseases (IBD). Systemic levels of oxidative stress are reflected by reduced levels of free thiols (FT) in circulating proteins, especially those in albumin, which associates with disease activity in IBD. Yet, clinal value of circulating FT level as biomarkers of disease and therapy response remains largely unexplored. Here we investigated the association between plasma FT levels and clinical parameters, the plasma inflammatory proteome and medication use. Methods Plasma samples from 1,028 patients with IBD (567 Crohn's disease [CD] and 461 ulcerative colitis [UC]), and 500 healthy controls (HCs) participating in the 1000IBD and LifeLines projects were profiled for free thiols (FT), uric acid, bilirubin and 92 inflammation-related proteins (Olink Inflammation panelÒ). All biomarkers were associated with clinical phenotypes using general linear models adjusting for age, sex, body mass index, smoking and medication use. Results Plasma FT levels were significantly lower in IBD compared to HCs (p&amp;lt;0.05) (Figure 1A), with patients with UC showing even lower levels than patients with CD (p&amp;lt;0.05). Patients with UC on induction therapy had lower FT levels compared to patients on maintenance therapy (p&amp;lt;0.05). Furthermore, FT levels of patients with IBD were strongly associated with systemic inflammation (C-reactive protein [CRP], p&amp;lt;0.05) (Figure 1B). In both patients withCD and UC, reduced FT levels were associated with elevated levels of inflammation-, apoptosis-, and growth factor-related proteins, including C-X-C motif chemokine 9 (CXCL9) (Figure 1C-D), CUB domain-containing protein 1 (CDCP1) and caspase-8 (CASP8), proteins previous associated with preclinical IBD1-3. Furthermore, specifically for patients with UC, reduced FT levels were associated with elevated eotaxin-1 (CCL11) (Figure 1C), monocyte chemotactic protein-1 (MCP-1), and several cytokine biomarkers like Interleukine-6 (IL6) and Interleukin-17A (IL17A). Conclusion Systemic FT levels associate with inflammatory disease activity and clinical therapy and may offer potential utility in clinical assessments. This study highlights the intricate involvement of oxidative stress in various inflammatory pathways and components, particularly in innate/adaptive immune balance, cell damage, and apoptosis. These findings contribute to a deeper understanding of the interplay between oxidative stress, inflammation, and IBD. Funding: This study was supported by Janssen Research &amp; Development LLC.

The Impact of Nociception Monitor-Guided Multimodal General Anesthesia on Postoperative Outcomes in Patients Undergoing Laparoscopic Bowel Surgery: A Randomized Controlled Trial.

Excess surgical stress responses, caused by heightened nociception, can lead to elevated levels of postoperative inflammation, resulting in an increased incidence of complications after surgery. We hypothesized that utilizing nociception monitor-guided multimodal general anesthesia would exert effects on postoperative outcomes (e.g., serum concentrations of C-reactive protein (CRP) after surgery, postoperative complications). This single-center, double-blinded, randomized trial enrolled ASA class I/II adult patients with normal preoperative CRP levels, scheduled for laparoscopic bowel surgery. Patients were randomized to receive either standard care (control group) or nociception monitor-guided multimodal general anesthesia using the nociceptive response (NR) index (NR group), where NR index was kept below 0.85 as possible. The co-primary endpoint was serum concentrations of CRP after surgery or rates of 30-day postoperative complications (defined as Clavien-Dindo grades ≥ II). One hundred and four patients (control group, n = 52; NR group, n = 52) were enrolled for analysis. The serum CRP level on postoperative day (POD) 1 was significantly lower in the NR group (2.70 mg·dL-1 [95% confidence interval (CI), 2.19-3.20]) than in the control group (3.66 mg·dL-1 [95% CI, 2.98-4.34], p = 0.024). The postoperative complication rate was also significantly lower in the NR group (11.5% [95% CI, 5.4-23.0]) than in the control group (38.5% [95% CI, 26.5-52.0], p = 0.002). Nociception monitor-guided multimodal general anesthesia, which suppressed intraoperative nociception, mitigated serum concentrations of CRP level, and decreased postoperative complications after laparoscopic bowel surgery.

Prognostic potential of neutrophil-to-lymphocyte ratio, platelet to lymphocyte ratio, and monocyte to lymphocyte ratio in acute myocardial infarction patients combined with chronic obstructive pulmonary disease.

Inflammation is considered to play an important role in chronic obstructive pulmonary disease (COPD) and acute myocardial infarction (AMI), but the relationship between inflammation and poor prognosis in these patients has not yet been studied. We enrolled AMI patients combined with COPD and divided them into three groups according to the tertiles of neutrophil-to-lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and monocyte to lymphocyte ratio (MLR) respectively. Logistic regression analyses were used to identify risk factors for in-hospital all-cause death in these patients. Covariates were adjusted stepwise to determine the association between inflammatory markers and poor prognosis. Also, the receiver operating characteristic (ROC) curve was used to evaluate the greatest predictive indicator for all-cause death. A total of 281 AMI patients combined with COPD were enrolled, of which 31 experienced in-hospital mortality. The risk of all-cause death was significantly higher among those with higher NLR. The highest tertile of NLR was significantly associated with an increased risk of all-cause death (all P < 0.05). This association remained significant after adjusting for confounding factors [Odds Ratio (OR): 10.571, 95% confidence interval (CI): 2.307-48.442, P = 0.002]. Moreover, compared to MLR and PLR, NLR had the highest predictive value for all-cause death [area under the curve (AUC): 0.764, 95% CI: 0.681-0.847]. In AMI patients combined with COPD, elevated levels of inflammation were associated with increased all-cause mortality. Compared to other inflammatory indicators, NLR may provide a more superior predictive value.