Biomarkers of Inflammation and Longitudinal Evaluation of Lung Function, Physical Activity, and Grip Strength: A Secondary Analysis in the CASCADE Study.

Rationale: Physical activity, lung function, and grip strength are associated with exacerbations, hospitalizations, and mortality in people with chronic obstructive pulmonary disease (COPD). We tested whether baseline inflammatory biomarkers were associated with longitudinal outcomes of these physiologic measurements. Methods: The COPD Activity: Serotonin Transporter, Cytokines, and Depression (CASCADE) study was a prospective observational study of individuals with COPD. Fourteen inflammatory biomarkers were measured at baseline. Participants were followed for 2 years. We analyzed associations between baseline biomarkers and FEV1, physical activity, and grip strength. We used a hierarchical hypothesis testing procedure to reduce type I error. We used Pearson correlations to test associations between baseline biomarkers and longitudinal changes in the outcomes of interest. We used Fisher's linear discriminant analysis to test if linear combinations of baseline biomarkers predict rapid FEV1 decline. Finally, we used linear mixed modeling to test associations between baseline biomarkers and outcomes of interest at baseline, year 1, and year 2; models were adjusted for age, smoking status, baseline biomarkers, and FEV1. Results: 302 participants (age 67.5 ± 8.5 years, 19.5% female, 28.5% currently smoking) were included. Baseline biomarkers were not associated with longitudinal changes in grip strength, physical activity, or rapid FEV1 decline. Higher IL-6 and CRP were associated with lower physical activity at baseline and these relationships persisted at year 1 and year 2. Conclusion: Baseline inflammatory biomarkers did not predict changes in lung function or physical activity, but higher inflammatory biomarkers were associated with persistently low levels of physical activity.

Exploring the clinical transition of engineered exosomes designed for intracellular delivery of therapeutic proteins.

Extracellular vesicles, particularly exosomes, have emerged as promising drug delivery systems owing to their unique advantages, such as biocompatibility, immune tolerability, and target specificity. Various engineering strategies have been implemented to harness these innate qualities, with a focus on enhancing the pharmacokinetic and pharmacodynamic properties of exosomes via payload loading and surface engineering for active targeting. This concise review outlines the challenges in the development of exosomes as drug carriers and offers insights into strategies for their effective clinical translation. We also highlight preclinical studies that have successfully employed anti-inflammatory exosomes and suggest future directions for exosome therapeutics. These advancements underscore the potential for integrating exosome-based therapies into clinical practice, heralding promise for future medical interventions.

Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss.

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

Investigation of the efficacy of Dengzhan Shengmai capsule against heart failure with preserved ejection fraction.

ETHNOPHARMACOLOGICAL RELEVANCE: Heart failure with preserved ejection fraction (HFpEF) has emerged as a condition with high incidence and mortality rates in recent years. Dengzhan Shengmai capsule (DZSMC) is a Chinese patent medicine based on the classic recipe "Shengmai powder". The relevant Chinese medicine ratio of Erigeron breviscapus (Vaniot) Hand.-Mazz., Panax ginseng C.A.Mey., Schisandra chinensis (Turcz.) Baill., and Ophiopogon japonicus (Thunb.) Ker Gawl. is 30 : 6 : 6 : 11 . Traditional Chinese medicine (TCM) is being increasingly explored as a safe and effective treatment modality for HFpEF. Clinical studies have shown that DZSMCs can effectively treat heart failure, however, the mechanism of action of DZSMCs in the treatment of HFpEF are still not clear. AIM OF THE STUDY: To investigate the efficacy and underlying mechanisms of Dengzhan Shengmai capsule (DZSMC), in the treatment of HFpEF by focusing on its ability to treat microvascular inflammation. MATERIALS AND METHODS: First, the efficacy of DZSMCs against HFpEF was predicted by network pharmacology. After 3 days of adaptive feeding in SPF-grade polypropylene cages, the mice in the Model group, DZSMC group, and Captopli group underwent single kidney resection, and micropumps were implanted in their backs for continuous infusion of aldosterone at a rate of 0.3 µg/h for 4 weeks. Moreover, the mice were given DZSMCs or Captopli via oral gavage for four weeks. Overall, cardiac function was evaluated in mice, and cardiac ultrasound and blood biochemical indices were evaluated in HFpEF mice. RESULTS: DZSMCs can ameliorate myocardial hypertrophy and cardiomyocyte damage caused by excessive myocardial stress, ultimately mitigating long-term cardiac impairment; it aids in the restoration of myocardial fibre proliferation and enhances mitochondrial morphology and function. In a murine model of ventricular hypertrophy and left ventricular dysfunction, which are indicative of cardiac insufficiency, the administration of DZSMCs resulted in notable improvements. Echocardiographic and overall assessments of cardiac function revealed a reduction in cardiac dysfunction and ventricular hypertrophy post-DZSMC intervention. Moreover, intervention with DZSMCs led to a reduction in the serum levels of several markers associated with chronic systemic inflammation, such as sST2, IL1RL1, CRP, and IL-6. Simultaneously, the levels of indicators of microvascular inflammation, including VCAM and E-SELECTIN, also decreased following DZSMC intervention. These findings suggest the potential multifaceted impact of DZSMCs in alleviating cardiac abnormalities, mitigating systemic inflammation, and reducing microvascular inflammatory markers, highlighting their promising therapeutic role in managing myocardial health. CONCLUSIONS: These results provide novel evidence that DZSMCs improve HFpEF by regulating microvascular inflammation.

Gender and sex hormone effects on neonatal innate immune function.

OBJECTIVES: Scientific evidence provides a widened view of differences in immune response between male and female neonates. The X-chromosome codes for several genes important in the innate immune response and neonatal innate immune cells express receptors for, and are inhibited by, maternal sex hormones. We hypothesized that sex differences in innate immune responses may be present in the neonatal population which may contribute to the increased susceptibility of premature males to sepsis. We aimed to examine the in vitro effect of pro-inflammatory stimuli and hormones in neutrophils and monocytes of male and female neonates, to examine the expression of X-linked genes involved in innate immunity and the miRNA profiles in these populations. METHODS: Preterm infants (n = 21) and term control (n = 19) infants were recruited from the Coombe Women and Infants University Hospital Dublin with ethical approval and explicit consent. The preterm neonates (eight female, 13 male) were recruited with a mean gestation at birth (mean ± SD) of 28 ± 2 weeks and corrected gestation at the time of sampling was 30 + 2.6 weeks. The mean birth weight of preterm neonates was 1084 ± 246 g. Peripheral blood samples were used to analyze immune cell phenotypes, miRNA human panel, and RNA profiles for inflammasome and inflammatory genes. RESULTS: Dividing neutrophil results by sex showed no differences in baseline CD11b between sexes among either term or preterm neonates. Examining monocyte CD11b by sex shows, that at baseline, total and classical monocytes have higher CD11b in preterm females than preterm males. Neutrophil TLR2 did not differ between sexes at baseline or following lipopolysaccharide (LPS) exposure. CD11b expression was higher in preterm male non-classical monocytes following Pam3CSK treatment when compared to females, a finding which is unique to our study. Preterm neonates had higher TLR2 expression at baseline in total monocytes, classical monocytes and non-classical monocytes than term. A sex difference was evident between preterm females and term females in TLR2 expression only. Hormone treatment showed no sex differences and there was no detectable difference between males and females in X-linked gene expression. Two miRNAs, miR-212-3p and miR-218-2-3p had significantly higher expression in preterm female than preterm male neonates. CONCLUSIONS: This study examined immune cell phenotypes and x-linked gene expression in preterm neonates and stratified according to gender. Our findings suggest that the responses of females mature with advancing gestation, whereas male term and preterm neonates have very similar responses. Female preterm neonates have improved monocyte activation than males, which likely reflects improved innate immune function as reflected clinically by their lower risk of sepsis. Dividing results by sex showed changes in preterm and term infants at baseline and following LPS stimulation, a difference which is reflected clinically by infection susceptibility. The sex difference noted is novel and may be limited to the preterm or early neonatal population as TLR2 expression on monocytes of older children does not differ between males and females. The differences shown in female and male innate immune cells likely reflect a superior innate immune defense system in females with sex differences in immune cell maturation. Existing human studies on sex differences in miRNA expression do not include preterm patients, and most frequently use either adult blood or cord blood. Our findings suggest that miRNA profiles are similar in neonates of opposite sexes at term but require further investigation in the preterm population. Our findings, while novel, provide only very limited insights into sex differences in infection susceptibility in the preterm population leaving many areas that require further study. These represent important areas for ongoing clinical and laboratory study and our findings represent an important contribution to exiting literature.

A Comprehensive Pilot Study to Elucidate the Distinct Gut Microbial Composition and Its Functional Significance in Cardio-Metabolic Disease.

Cardio-metabolic disease is a significant global health challenge with increasing prevalence. Recent research underscores the disruption of gut microbial balance as a key factor in disease susceptibility. We aimed to characterize the gut microbiota composition and function in cardio-metabolic disease and healthy controls. For this purpose, we collected stool samples of 18 subjects (12 diseased, 6 healthy) and we performed metagenomics analysis and functional prediction using QIIME2 and PICRUSt. Furthermore, we carried out assessments of microbe-gene interactions, gene ontology, and microbe-disease associations. Our findings revealed distinct microbial patterns in the diseased group, particularly evident in lower taxonomic levels with significant variations in 14 microbial features. The diseased cohort exhibited an enrichment of Lachnospiraceae family, correlating with obesity, insulin resistance, and metabolic disturbances. Conversely, reduced levels of Clostridium, Gemmiger, and Ruminococcus genera indicated a potential inflammatory state, linked to compromised butyrate production and gut permeability. Functional analyses highlighted dysregulated pathways in amino acid metabolism and energy equilibrium, with perturbations correlating with elevated branch-chain amino acid levels-a known contributor to insulin resistance and type 2 diabetes. These findings were consistent across biomarker assessments, microbe-gene associations, and gene ontology analyses, emphasizing the intricate interplay between gut microbial dysbiosis and cardio-metabolic disease progression. In conclusion, our study unveils significant shifts in gut microbial composition and function in cardio-metabolic disease, emphasizing the broader implications of microbial dysregulation. Addressing gut microbial balance emerges as a crucial therapeutic target in managing cardio-metabolic disease burden.

DNA Methylation, Inflammation, and Neurobehavior in Preterm Infants.

Objectives: Inflammation contributes to disparate neurodevelopmental outcomes between preterm and term-born infants. In this context, DNA methylation may contribute to inflammation by affecting gene expression. Brain-derived neurotrophic factor (BDNF) and nuclear factor-kappa-B-inhibitor alpha (NFKBIA) are important genes for targeted DNA methylation analysis. The aims of this study were to (1) identify associations between inflammatory factors and BDNF and NFKBIA methylation, and (2) identify associations between BDNF and NFKBIA methylation and early neurobehavior in preterm infants. Methods: In a longitudinal cohort study of preterm infants born 28-31 weeks gestational age, blood samples were collected weekly for the quantification of inflammatory factors. We extracted DNA from saliva samples and quantified methylation of six BDNF cytosine-phosphate-guanine (CpG) sites and five NFKBIA CpG sites. Neurobehavior was assessed using the Neurobehavioral Assessment of the Preterm Infant. Results: Sixty-five infants were included in the analysis. In females, inflammatory factors were positively associated with BDNF methylation of most CpG sites. Interleukin-1 receptor antagonist was negatively associated with NFKBIA methylation at two CpG sites. In males, interleukin-6 was negatively associated with BDNF and NFKBIA methylation at most CpG sites. In females, BDNF methylation at two sites was inversely associated with motor performance. In males, NFKBIA methylation at one site was inversely associated with motor performance. Conclusion: This study provides evidence for the relationship between inflammation and neurobehavior in preterm infants, working mechanistically through DNA methylation. The finding of a difference between males and females suggests that female infants are potentially more vulnerable to inflammation and warrants future study.

Vernodalin Alleviates Cardiotoxicity and Inflammation in Isoproterenol-Mediated Myocardial Infarction through NF-κB/AMPK Signaling Pathways in Rats.

BACKGROUND: Myocardial infarction (MI) is the foremost cause of mortality in cardiovascular diseases. MI ultimately exacerbates cardiotoxicity due to the release of toxicity biomarkers and inflammatory infiltration. AIM: Vernodalin (VN) is a renowned cytotoxic sesquiterpene lactone that possesses antioxidant, anticancer, and anti-inflammatory properties. The cardioprotective mechanism of VN remains concealed. Hence, we explored the cardioprotective efficacy of VN on isoproterenol (ISO)- mediated MI and analyzed its underlying mechanism. METHODS: Wistar albino rats were injected ISO (85 mg/kg bw) subcutaneously to induce MI to evaluate the cardioprotective potential of VN (10 mg/kg bw) by assessing heart weight/ body weight index, hemodynamic, toxicity enzymes, histopathology, inflammatory mediators, and signaling pathway. ISO enhanced heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammation, and histopathological changes while reducing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways. RESULTS: Treatment with VN could significantly (p<0.05) mitigate the heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammatory cytokines, and histopathological changes while enhancing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways. Collectively, our findings revealed that the VN ameliorated defensive action against MI and averted myocardial injury by reducing the NF-κB-mediated inflammatory pathways in rats. CONCLUSION: These findings established that VN expressively preserves the myocardium and employs anti-inflammatory actions by regulating NF-κB, VEGF-B, AMPK, and eNOS signaling pathways.

Revealing the Curative Possibilities: A Comprehensive Exploration of Caffeic Acid.

Caffeic acid, a phenolic compound of the hydroxycinnamic acid family, is abundant in various plant-based foods, such as fruits, vegetables, and coffee, alongside other biologically active compounds. Recognizing its potential to address various health issues and its widespread presence in commonly consumed foods underscores the importance of comprehending and harnessing the benefits of caffeic acid for human nutrition and well-being. This versatile substance, characterized by acrylic and phenolic functional groups, plays a pivotal role in the food and pharmaceutical industries. Furthermore, a detailed exploration of its pharmacokinetic properties, absorption, distribution, metabolism, and excretion enhances our understanding of how the human body processes it. Functioning as a precursor for essential compounds, caffeic acid contributes to formulations with notable anti-inflammatory, antiviral, anti-cancer, anti-diabetic, antibacterial, neuroprotective, and hepatoprotective qualities. Its current applications in treating Parkinson's and Alzheimer's disease underscore its therapeutic significance. This comprehensive analysis sheds light on caffeic acid's importance, showcasing its diverse applications across various domains and paving the way for further research and development to fully unlock its therapeutic potential. In conclusion, caffeic acid emerges as a bioactive substance with a broad spectrum of pharmacological properties, suggesting its potential utility in diverse therapeutic contexts. The comprehensive information provided in this article serves as a foundation for further research and learning regarding the various ways that caffeic acid supports human health.

Bioactive sulforaphane from cruciferous vegetables: advances in biosynthesis, metabolism, bioavailability, delivery, health benefits, and applications.

Chronic inflammation-induced diseases (CID) are the dominant cause of death worldwide, contributing to over half of all global deaths. Sulforaphane (SFN) derived from cruciferous vegetables has been extensively studied for its multiple functional benefits in alleviating CID. This work comprehensively reviewed the biosynthesis, metabolism, bioavailability, delivery, health benefits, and applications of SFN and its potential mechanisms against CID (e.g., cancer, obesity, type 2 diabetes, et al.), and neurological disorders based on a decade of research. SFN exerts its biological functions through the hydrolysis of glucosinolates by gut microbiota, and exhibits rapid metabolism and excretion characteristics via metabolization of mercapturic acid pathway. Microencapsulation is an important way to improve the stability and targeted delivery of SFN. The health benefits of SNF against CID are attributed to the multiple regulatory mechanisms including modulating oxidative stress, inflammation, apoptosis, immune response, and intestinal homeostasis. The clinical applications of SFN and related formulations show promising potential; however, further exploration is required regarding the sources, dosages, toxicity profiles, and stability of SFN. Together, SFN is a natural product with great potential for development and application, which is crucial for the development of functional food and pharmaceutical industries.

IL-1R-Mediated Activation of Renal Sensory Nerves in DOCA-Salt Hypertension.

BACKGROUND: Clinical trials of renal denervation for the treatment of hypertension have shown a variety of off-target improvements in conditions associated with sympathetic overactivity. This may be due to the ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. Renal IL (interleukin)-1ß is elevated in the deoxycorticosterone acetate-salt model of hypertension, and its activity may be responsible for the elevation in afferent renal nerve activity and arterial pressure. METHODS: Continuous blood pressure recording of deoxycorticosterone acetate-salt mice with IL-1R (IL-1 receptor) knockout or antagonism was used individually and combined with afferent renal denervation (ARDN) to assess mechanistic overlap. Protein quantification and histological analysis of kidneys were performed to characterize renal inflammation. RESULTS: ARDN attenuated deoxycorticosterone acetate-salt hypertension (-20±2-Δmm Hg mean arterial pressure [MAP] relative to control at study end) to a similar degree as total renal denervation (-21±2-Δmm Hg MAP), IL-1R knockout (-16±4-Δmm Hg MAP), or IL-1R antagonism (-20±3-Δmm Hg MAP). The combination of ARDN with knockout (-18±2-Δmm Hg MAP) or antagonism (-19±4-Δmm Hg MAP) did not attenuate hypertension any further than ARDN alone. IL-1R antagonism was found to have an acute depressor effect (-15±3-Δmm Hg MAP, day 10) in animals with intact renal nerves but not those with ARDN. CONCLUSIONS: These findings suggest that IL-1R signaling is partially responsible for the elevated afferent renal nerve activity, which stimulates central sympathetic outflow to drive deoxycorticosterone acetate-salt hypertension.

One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial.

BACKGROUND: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. AIM: To investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. METHODS: Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. RESULTS: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. On the other hand, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an EPA-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. CONCLUSIONS: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.

Pongamol Alleviates Neuroinflammation and Promotes Autophagy in Alzheimer's Disease by Regulating the Akt/mTOR Signaling Pathway.

Alzheimer's disease (AD), one of the neurodegenerative disorders, is highly correlated with the abnormal hyperphosphorylation of Tau and aggregation of ß-amyloid (Aß). Oxidative stress, neuroinflammation, and abnormal autophagy are key drivers of AD and how they contribute to neuropathology remains largely unknown. The flavonoid compound pongamol is reported to possess a variety of pharmacological activities, such as antioxidant, antibacterial, and anti-inflammatory. This study investigated the neuroprotective effect and its mechanisms of pongamol in lipopolysaccharide (LPS)-induced BV2 cells, d-galactose/sodium nitrite/aluminum chloride (d-gal/NaNO2/AlCl3)-induced AD mice, and Caenorhabditis elegans models. Our research revealed that pongamol reduced the release of inflammatory factors IL-1ß, TNF-α, COX-2, and iNOS in LPS-induced BV2 cells. Pongamol also protected neurons and significantly restored memory function, inhibited Tau phosphorylation, downregulated Aß aggregation, and increased oxidoreductase activity in the hippocampus of AD mice. In addition, pongamol reversed the nuclear transfer of NF-κB and increased the levels of Beclin 1 and LC3 II/LC3 I. Most importantly, the anti-inflammatory and promoter autophagy effects of pongamol may be related to the regulation of the Akt/mTOR signaling pathway. In summary, these results showed that pongamol has a potential neuroprotective effect, which greatly enriched the research on the pharmacological activity of pongamol for improving AD.

Macrophage-derived FGFR1 drives atherosclerosis through PLCγ-mediated activation of NF-κB inflammatory signaling pathway.

BACKGROUND: Atherosclerosis is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signaling in atherosclerosis are not known. In the present study, we investigated FGFR1 signaling in atherosclerosis development and progression. METHODS AND RESULTS: Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. CONCLUSION: Our study provides evidence of a new FGFR1-PLCγ- NF-κB axis in macrophages in inflammatory atherosclerosis, supporting FGFR1 as a potentially therapeutic target for atherosclerosis-related diseases.

Apigenin attenuates indomethacin-induced gastric ulcer in rats: emphasis on antioxidant, anti-inflammatory, anti-apoptotic, and TGF-ß1 enhancing activities.

Gastric ulcer disease is associated with significant morbidity and mortality rates. The most two common causes of the ulcer are Helicobacter pylori infection and non-steroidal anti-inflammatory drugs. In the past few decades, a significant decrease in the morbidity and mortality rate has been observed probably due to the discovery of proton pump inhibitors. However, the medications used to treat gastric ulcers impose several nauseous side effects. Therefore, recent studies focus on the use of natural products to treat gastric ulcers. In the current study, gastric ulcer was effectively induced using indomethacin, and the protective effect of apigenin, a potent antioxidant flavonoid, was assessed in comparison to omeprazole. The administration of a single oral indomethacin (50 mg/kg) induced gastric ulcer as manifested by hemorrhagic lesions in the gastric mucosa, increased ulcer index, and histopathological alterations. Indomethacin also increased lipid peroxidation, decreased the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase, increased the immunoreactivity of the inflammatory markers cyclo-oxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB), increased the transcription of the apoptotic marker, Bax, and decreased that of the antiapoptotic Bcl-2. Indomethacin also decreased the immunoreactivity of transforming growth factor-beta 1 (TGF-ß1). On the other hand, pretreatment with apigenin (10 and 20 mg/kg) resulted in a dose-dependent improvement in the macroscopic and microscopic features of the gastric mucosa in a manner comparable to that of omeprazole. The gastroprotective effects of apigenin may be attributed to its anti-inflammatory, anti-antioxidant, and anti-apoptotic activities as well as enhancing the expression of TGF-ß1. Further experimental and clinical research is required to confirm activity of apigenin as anti-ulcer agent.

Effects of Probiotics on Inflammatory Biomarkers and Its Associations With Cardiac Autonomic Function in Women With Arterial Hypertension: A Secondary Analysis of a Randomized Clinical Trial.

Preclinical evidence suggests that probiotic administration may exert an anti-inflammatory effect and reduce autonomic dysfunction and blood pressure. This study evaluated the effects of probiotic therapy on inflammatory biomarkers and characterized the correlations between inflammation and cardiac autonomic function in women with arterial hypertension. Women were randomized into probiotics (n = 20) or placebo (n = 20). The probiotic group received 109 CFU/day of Lactobacillus (L.) paracasei LPC-37, L. rhamnosus HN001, L. acidophilus NCFM, and Bifidobacterium lactis HN019, and the placebo group received polydextrose. Clinical, electrocardiogram, heart rate variability (HRV) analysis, and cytokine levels were assessed at baseline and after 8 weeks. Women who received probiotics for 8 weeks had increased serum levels of IL-17A (p = 0.02) and decreased INF-γ (p = 0.02) compared to baseline. Probiotic supplementation increased serum levels of IL-10 compared to the placebo group (p = 0.03). Probiotic or placebo administration did not change serum levels of TNFα and IL-6. Serum levels of IL-2 (p = 0.001, and p = 0.001) and IL-4 (p = 0.001, and p = 0.001) were reduced in women receiving placebo or probiotics, respectively. Correlations between HRV indices and inflammatory variables showed that INF-γ was positively correlated with heart rate (HR) and sympathetic HRV indices and negatively correlated with vagal HRV indices. IL-10 was negatively correlated with HR and sympathetic HRV indices. IL-6 was negatively correlated with parasympathetic HRV indices and positively correlated with SD2/SD1 ratio. Probiotic therapy has a discreet anti-inflammatory effect in hypertensive women, and pro-inflammatory cytokines were negatively correlated with vagal modulation and positively correlated with sympathetic modulation of HRV. The clinical trial was registered in the Brazilian Registry of Clinical Trials (ReBEC) with the identification RBR-9mj2dt.

The higher dietary inflammation is associated with a higher burden of multimorbidity of cardio-metabolic and mental health disorders in an urbanizing community of southern India: A cross-sectional analysis for the APCAPS cohort.

Background & aims: Habitual dietary pattern has been shown to be a major modulator of systemic inflammation and is considered a modifiable risk factor for cardio-metabolic diseases (CMDs) and mental health disorders. We examined whether dietary-inflammation is associated with the multimorbidity of CMDs and mental health disorders in urbanizing-villages in southern India. We hypothesized that the participants with higher dietary-inflammation would have a higher burden of multimorbidity. Materials & methods: We conducted a cross-sectional analysis of 5984 adults (53% male) participating in the Andhra Pradesh Children and Parents' Study. We assessed dietary-inflammation using dietary inflammatory index (DII®) based on intake of 27 micro- and macro-nutrients which were measured using a validated food-frequency-questionnaires. The CMDs and mental health disorders were assessed using standardized clinical procedures and validated questionnaires. 'Multimorbidity' was defined as a co-existence of one or more CMDs (hypertension, diabetes, myocardial infarction, heart failure, angina and stroke) and one or more mental health disorders (depression and anxiety). The association of multimorbidity with dietary-inflammation was examined using robust Poisson regression. Results: The prevalence of multimorbidity was 3.5% and ∼75% of participants were consuming a pro-inflammatory diet (DII >0.0). As compared to the 1st DII-quartile (least dietary-inflammatory group), the adjusted prevalence ratio (95% confidence interval) for the presence of multimorbidity was 1.46(0.87, 2.46) for 2nd, 1.75(1.05, 2.89) for 3rd, and 1.77(1.06, 2.96) for 4th DII-quartile (p-trend = 0.021). There was no evidence of an interaction between DII and sex on multimorbidity. Conclusions: Dietary-inflammation had a positive linear association with the multimorbidity, which suggest that even modest reduction in dietary-inflammation may reduce the multimorbidity burden.

Relationship of postprandial fibroblast growth factor 21 with lipids, inflammation and metabolic dysfunction-associated fatty liver disease during oral fat tolerance test.

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with serum fibroblast growth factor (FGF) 21; however, previous studies have typically focused on the static fasting state, and the relationships between postprandial FGF21 levels, postprandial metabolic status, and MAFLD remain unclear. Therefore, we measured postprandial lipids, inflammatory factors, and FGF21 levels in MAFLD and further analyzed their relationship using an oral fat tolerance test (OFTT). Patients and methods: In total, 103 non-diabetic adult volunteers, including 46 patients with MAFLD, were included in this study. All participants underwent the OFTT. Venous blood samples were collected at 0, 2, 4, and 6 h. Circulating total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), hypersensitive-C reactive protein(hs-CRP) and FGF21 were assessed. Results: Serum FGF21 significantly increased in the fasting state (P < 0.05) and showed a biphasic change of first decreasing and then increasing in MAFLD during the OFTT. The postprandial levels of TG, TC, LDL-C, FFA, IL-6, TNF-α and hs-CRP were significantly increased in MAFLD (P < 0.05). After adjusting for multiple factors, the FGF21 incremental area under the curve (iAUC) was linearly correlated with the FFA iAUC, TG iAUC, and IL-6 iAUC (P < 0.05) and was an independent factor for MAFLD (P < 0.05, OR=1.403). Conclusion: Dyslipidemia and excessive inflammation in MAFLD are associated to FGF21 levels in the postprandial period. An abnormal postprandial FGF21 response may be an important mechanism of MAFLD.

Repeated epidural delivery of Shinbaro2: effects on neural recovery, inflammation, and pain modulation in a rat model of lumbar spinal stenosis.

The choice of treatment for lumbar spinal stenosis (LSS) depends on symptom severity. When severe motor issues with urinary dysfunction are not present, conservative treatment is often considered to be the priority. One such conservative treatment is epidural injection, which is effective in alleviating inflammation and the pain caused by LSS-affected nerves. In this study, Shinbaro2 (Sh2), pharmacopuncture using natural herbal medicines for patients with disc diseases, is introduced as an epidural to treat LSS in a rat model. The treatment of primary sensory neurons from the rats' dorsal root ganglion (DRG) neurons with Sh2 at various concentrations (0.5, 1, and 2 mg/mL) was found to be safe and non-toxic. Furthermore, it remarkably stimulated axonal outgrowth even under H2O2-treated conditions, indicating its potential for stimulating nerve regeneration. When LSS rats received epidural injections of two different concentrations of Sh2 (1 and 2 mg/kg) once daily for 4 weeks, a significant reduction was seen in ED1+ macrophages surrounding the silicone block used for LSS induction. Moreover, epidural injection of Sh2 in the DRG led to a significant suppression of pain-related factors. Notably, Sh2 treatment resulted in improved locomotor recovery, as evaluated by the Basso, Beattie, and Bresnahan scale and the horizontal ladder test. Additionally, hind paw hypersensitivity, assessed using the Von Frey test, was reduced, and normal gait was restored. Our findings demonstrate that epidural Sh2 injection not only reduced inflammation but also improved locomotor function and pain in LSS model rats. Thus, Sh2 delivery via epidural injection has potential as an effective treatment option for LSS.