Inflammation-related Proteins Research Articles

High cumulative glucocorticoid dose is associated with increased levels of inflammation-related mediators in active rheumatoid arthritis

IntroductionGlucocorticoids (GCs) are widely used as a treatment for rheumatoid arthritis (RA), leading to high cumulative doses in long-term treated patients. The impact of a high cumulative GC dose on the systemic inflammatory response in RA remains poorly understood.MethodsWe investigated long-treated patients with RA (n = 72, median disease duration 14 years) through blood counts and the serum levels of 92 inflammation-related proteins, and disease activity was assessed using the Simple Disease Activity Index (SDAI). Patients were grouped based on the cumulative GC dose, with a cut-off value of 20 g (low/high, n = 49/23).Results and discussionPatients with a high cumulative GC dose within the active RA group had elevated serum levels in 23 inflammation-related proteins compared with patients with a low dose (cytokines/soluble receptors: CCL3, CCL20, CCL25, IL-8, CXCL9, IL-17A, IL-17C, IL-18, sIL-18R1, IL-10, sIL-10RB, OSM and sOPG; growth factors: sTGFα and sHGF; other inflammatory mediators: caspase 8, STAMBP, sCDCP1, sirtuin 2, 4E-BP1, sCD40, uPA and axin-1; pcorr < 0.05). In non-active RA, the high and low GC groups did not differ in analysed serum protein levels. Moreover, patients with active RA with a high GC dose had an increased white blood cell count, increased neutrophil–lymphocyte and platelet–lymphocyte ratios and a decreased lymphocyte–monocyte ratio compared with the low dose group (p < 0.05). This is the first study to report elevated serum levels in inflammation-related proteins and deregulated blood counts in patients with active RA with a high cumulative GC dose. The elevated systemic inflammation highlights the importance of improving care for patients receiving high cumulative GC doses.

Lung dECM matrikine-based hydrogel reverses bleomycin-induced pulmonary fibrosis by suppressing M2 macrophage polarization.

Recent studies have shown promising results using decellularized extracellular matrix (dECM) matrikines-based hydrogel as attractive strategies for preventing and alleviating fibrosis.
Methods & Results: Porcine lung decellularization and pepsin digestion were used to prepare the lung dECM hydrogel. Proteomic analysis revealed that the lung dECM hydrogel was enriched in glycoproteins, collagens, laminins, fibrinogen, held receptors, and bound growth factors. With porous structures and good mechanical properties and stability, the lung dECM hydrogel showed low cytotoxicity and good biocompatibility both in vitro and in vivo. The lung dECM hydrogel was further administered to verify the safety and effectiveness of reversing pulmonary fibrosis in a bleomycin induced rat model. The results revealed a relatively complete alveolar structure with less inflammatory infiltration and a reduced amount of collagen fiber deposition. TMT quantification proteomic analyses revealed significant downregulation of proteins, pathways, and interactions involved in the regulation of ECM components, tissue remodeling, inflammation, and the cytoskeleton and indicated that fibrosis-related proteins were obviously downregulated and inflammation-related proteins were significantly changed, particularly in macrophages, after administration of the lung dECM hydrogel. Multiplex immunohistochemical (mIHC) staining of lung tissue revealed that the inflammatory response was regulated by the lung dECM hydrogel, as indicated by a decrease in the number of CD3+ T cells and macrophages and the suppression of M2 macrophage polarization. Gene set enrichment analysis revealed that downregulated ficolin signaling was enriched in macrophages after lung dECM hydrogel administration, and the findings were verified in lung tissue by mIHC. Additionally, the effects of ficolin B proteins on macrophage polarization were proved in vitro.
Conclusion: This study suggested that the lung dECM hydrogel can reverse pulmonary fibrosis by suppressing M2 macrophage polarization through downregulation of the ficolin signaling pathway. Thus, the dECM hydrogel represent a promising class of biological materials for use in regenerative medicine.

Association between mitophagy and NLRP3 inflammasome in uric acid nephropathy

Objective This study was recruited to investigate the role of mitophagy in activating NLRP3 inflammasome in the kidney of uric acid (UA) nephropathy (UAN) rats. Methods This study developed a uric acid nephropathy (UAN) rat model divided into five groups: Negative control (NC), UAN model (M), UAN + autophagy inhibitor (3-MA), UAN + lysosome inhibitor (CQ), and ROS scavenger (N-acetylcysteine, N). H&E staining assessed renal structure, ROS levels were measured with 2, 7-dichlorofluorescin diacetate, and ELISA measured serum markers (creatinine, UA, cystatin C, NGAL, IL-1β, IL-18). Western blot and qRT-PCR evaluated autophagy and inflammation-related protein (LC3 II/I, p62, Pink1, Parkin, NLRP3, Caspase1, IL-1β) expression. NRK-52E cells treated with uric acid and shRNA were analyzed by western blot. Results Renal injury in UAN rats was aggravated by ROS accumulation, which promoted mitophagy and activated the NLRP3 inflammasome. Eliminating ROS reduced mitophagy, inhibited NLRP3 activation, lowered IL-1β and IL-18 levels, and alleviated renal injury. Notably, inhibiting mitophagy increased ROS accumulation, up-regulated NLRP3, Caspase1, and IL-1β expression, further worsening renal injury. In vitro, uric acid treatment of NRK-52E cells altered autophagy-related protein and pro-inflammatory cytokine levels, highlighting the interplay between mitophagy and inflammation in uric acid nephropathy. Conclusion Mitophagy influences renal injury in uric acid nephropathy (UAN) by regulating ROS accumulation and NLRP3 inflammasome activation, suggesting that mitophagy may serve as a potential therapeutic target for UAN.

Causal effects of circulating inflammatory proteins on knee and hip osteoarthritis: A two sample Mendelian randomization study.

Numerous circulating proteins are linked to the presence or severity of joint inflammation. However, traditional studies could not explain whether these protein biomarkers are proximate to disease progression. We conducted a study to explore the causal effects of 91 circulating inflammation-related proteins (CIPs) on knee osteoarthritis (KOA) and hip osteoarthritis (HOA), using two-sample Mendelian randomization (MR). The primary analysis utilized the inverse variance weighted (IVW) method, augmented by complementary approaches including weighted median, weighted mode, simple median, MR-Egger, and MR-PRESSO analysis. Sensitivity analysis validated the robustness of the results and ensured the absence of heterogeneity and horizontal pleiotropy. We identified 2 CIPs with a causal effect on KOA, including CXCL9 (OR = 1.249, 95% CI = 1.046-1.492, P = 0.014) and TNF-β (OR = 1.105, 95% CI = 1.014-1.204, P = 0.023). Additionally, 3 CIPs were found to have a causal effect on HOA, including CXCL6 (OR = 1.058, 95% CI = 1.004-1.116, P = 0.035), RANKL (OR = 1.067, 95% CI = 1.002-1.137, P = 0.044), and VEGFA (OR = 1.072, 95% CI = 1.008-1.140, P = 0.027). In the current study, our findings indicated that CXCL9 and TNF-β had the potential to influence the risk of KOA, while CXCL6, RANKL, and VEGFA could impact the risk of HOA. These discoveries underscored the significance of these proteins as potential targets for intervention in the prevention and treatment of KOA and HOA. Key Points •We presented genetic evidence supporting a causal link between circulating inflammatory proteins associated with joint inflammation using MR methods. •5 CIPs have demonstrated promotive effects on the occurrence of KOA and HOA.

Circulating FGF21 is lower in South Asians compared to Europids with type 2 diabetes mellitus.

Inflammation contributes to the development of type 2 diabetes mellitus (T2DM). While South Asians are more prone to develop T2DM than Europids, the inflammatory phenotype of the South Asian population remains relatively unknown. Therefore, we aimed to investigate potential differences in circulating levels of inflammation-related proteins in South Asians compared to Europids with T2DM. In this secondary analysis of three randomized controlled trials, relative plasma levels of 73 inflammation-related proteins were measured using the Olink Target Inflammation panel and serum FGF21 concentration using an ELISA kit in Dutch South Asians (n=47) and Dutch Europids (n=49) with T2DM. Of the 73 inflammation-related proteins, the relative plasma levels of 6 proteins were higher (SCF, CASP-8, CCL28, IFN-gamma, ST1A1, CST5; q-value<0.05), while relative levels of 6 proteins were lower (FGF21, MMP-1, IL8, CCL4, CXCL6, MCP-1; q-value<0.05) in South Asians compared to Europids. Of these, the effect size of FGF21 was the largest, particularly in females. We validated this finding by assessing FGF21 concentration in serum. FGF21 concentration was indeed lower in South Asians compared to Europids with T2DM in both males (-42.2%; P<0.05) and females (-58.5%; P<0.001). Relative plasma levels of 12 inflammation-related proteins differed between South Asians and Europids with T2DM, with a significantly pronounced reduction in FGF21. In addition, serum FGF21 concentration was significantly lower in South Asian males and females compared to Europids. Whether low FGF21 is an underlying cause or consequence of T2DM in South Asians remains to be determined.

Lily extract ameliorate mouse pneumonia by modulating ciliary function

This study explores the biological effects and mechanisms of Lily extract on LPS-induced pneumonia mice. Research has found that after 48 h of treatment with low-dose and high-dose lily extract (100 mg/kg, 200 mg/kg), there was a significant reduction in inflammatory cell infiltration, mRNA expression levels of pro-inflammatory factors (IL-6, IL-1β, TNF-α), protein levels of inflammation-related proteins (IL-6, NF-κB P65) in the lung tissue. In addition, lily extract significantly improved the function of cilia assembly and movement. The expression levels of cilia-related genes (Ttc21a, Cfap45, etc.) and proteins were significantly upregulated. Among them, the high-dose treatment group had tightly arranged cilia and good growth conditions, which was significantly better than the LPS pneumonia model and low-dose treatment group. This found providing novel insights into the pathogenesis and progression of pneumonia. This has important implications for the prevention and treatment of pneumonia, as well as the development of natural agents.

Exploring the gut-inflammation connection: A Mendelian randomization study on gut microbiota, inflammatory factors, and uterine fibroids risk

This study employs Mendelian randomization (MR) approach to investigate the potential causal association between genetic variants associated with gut microbiota, inflammatory factors, and the risk of uterine fibroids development. We extracted data on 211 types of gut microbiota, 91 inflammatory factors, and uterine fibroids occurrence from genome-wide association studies and applied the inverse-variance weighted (IVW) method for analysis. To further assess the robustness of our MR analysis, we conducted sensitivity tests including Cochrane’s Q test, the MR-Egger intercept test, the MR-PRESSO global test, and a leave-one-out analysis. IVW analysis identified a potential causal association between 14 types of gut microbiota and 8 inflammatory factors with the risk of uterine fibroids. When using 91 inflammation-related proteins as the outcome variable, 13 proteins demonstrated a potential causal association with uterine fibroids risk (IVW, all P &lt; .05). Additionally, the MR-Egger intercept and MR-PRESSO global tests indicated no evidence of horizontal pleiotropy (P &gt; .05), and the leave-one-out analysis confirmed the robustness of the results. This MR approach suggests that specific gut microbiota and inflammatory factors may have a causal association with the development of uterine fibroids, shedding light on the pathogenesis of uterine fibroids and potentially identifying targets for future therapeutic interventions.

Ceftiofur induced intestinal flora disorder exacerbates liver toxicity via microbiota-gut-liver axis

As a common antibiotic, ceftiofur was widely used in animal husbandry. It is estimated that the consumption of ceftiofur (CEF) in animal production will continue to increase due to the role of promoting growth. Accumulating evidences showed that excessive supplementation of ceftiofur in feed disrupted the intestinal flora. However, the mechanism of liver injury caused by excessive supplementation of ceftiofur induced intestinal flora disturbance remains unclear. In this study, our finding indicated that excessive ceftiofur uptake significantly disrupted intestinal flora, which lead to serious liver injury through the gut-liver axis. Our results showed that CEF exposure causes significantly decreased the expression of jejunum tight junction proteins (ZO-1, Claudin, and Occludin); and reduced the number of intestinal goblet cells. In addition, excessive CEF uptake significantly promoted the expression of inflammatory-related proteins in jejunum. Meanwhile, 16s rDNA analysis found that CEF exposure disrupted the abundance of Lactobacillus, HT002, Escherichia-Shigella, Klebaiella, Enterococcus, and Citrobacter, thereby affecting metal iron binding, molecular function, and mitochondrial function in the liver. Furthermore, CEF exposure caused ferroptosis in hepatocytes, as shown by increased the expression of TFR1, FACL4, FLC, COX2, HMGB1, and TXNIP protein, and reduced the expression of GPX4, XCT, and Ferritin protein. These results suggest that the significant adverse impacts of excessive CEF supplementation on gut-liver axis in mice may increase the long-term risks related to liver diseases.

Identifying Herbal Candidates and Active Ingredients Against Postmenopausal Osteoporosis Using Biased Random Walk on a Multiscale Network.

Postmenopausal osteoporosis is a major global health concern, particularly affecting aging women, and necessitates innovative treatment options. Herbal medicine, with its multi-compound, multi-target characteristics, offers a promising approach for complex diseases. In this study, we applied multiscale network and random walk-based analyses to identify candidate herbs and their active ingredients for postmenopausal osteoporosis, focusing on their underlying mechanisms. A dataset of medicinal herbs, their active ingredients, and protein targets was compiled, and diffusion profiles were calculated to assess the propagation effects. Through correlation analysis, we prioritized herbs based on their relevance to osteoporosis, identifying the top candidates like Benincasae Semen, Glehniae Radix, Corydalis Tuber, and Houttuyniae Herba. Gene Set Enrichment Analysis (GSEA) revealed that the 49 core protein targets of these herbs were significantly associated with pathways related to inflammation, osteoclast differentiation, and estrogen metabolism. Notably, compounds such as falcarindiol from Glehniae Radix and tetrahydrocoptisine from Corydalis Tuber-previously unstudied for osteoporosis-were predicted to interact with inflammation-related proteins, including IL6, IL1B, and TNF, affecting key biological processes like apoptosis and cell proliferation. This study advances the understanding of herbal therapies for osteoporosis and offers a framework for discovering novel therapeutic agents.

Sodium Danshensu Inhibits Macrophage Inflammation in Atherosclerosis via the miR-200a-3p/MEKK3/NF-κB Signaling Pathway.

Macrophages are fundamental cellular components of atherosclerotic plaques, and inhibition of macrophage inflammation can delay the development of atherosclerotic plaques. Sodium danshensu (SDSS) can inhibit inflammatory responses and thus delay atherosclerosis, but the specific mechanism remains unclear.The effect of SDSS in inhibiting atherosclerosis was confirmed by observing and detecting atherosclerotic plaque area, morphology and lipid levels in the aorta. The mechanism by which SDSS attenuated atherosclerotic plaques was elucidated by in vivo and in vitro detection of inflammation-related mRNA and protein expression. In addition, bioinformatics analysis, RT-qPCR and dual-luciferase assays were used to predict and validate the potential miRNAs of SDSS to attenuate atherosclerosis. miR-200a-2p mimic and inhibitor were then compared for their effects on the efficacy of SDSS.SDSS inhibited atherosclerotic plaque formation and suppressed the expression of MEKK3, TNF-α, and IL-1β as well as nuclear factor-κB (NF-κB) phosphorylation and nuclear translocation to attenuate inflammatory responses. Bioinformatic predictions combined with RT-qPCR results and dual-luciferase assays indicated that miR-200a-3p negatively regulated MEKK3 expression by directly targeting the 3'UTR region of MEKK3, thereby blocking MEKK3. Further studies showed that miR-200a-3p inhibitor, but not miR-200a-3p mimic, reversed the beneficial effects of SDSS on inflammation.SDSS inhibited macrophage inflammation by modulating the miR-200a-3p/MEKK3/NF-κB signaling pathway.

Acute physical exercise and ambulatory blood pressure in resistant hypertension

Objectives: The effects of acute physical exercise in patients with resistant hypertension remain largely unexplored compared with hypertensive patients in general. We assessed the short-term effects of acute moderate-intensity (MICE) and high-intensity interval exercise (HIIE) on the clinic (BP) and 24-h ambulatory blood pressure (ABP) of patients with resistant hypertension. Methods: Using a crossover randomized controlled design, 10 participants (56 ± 7 years) with resistant hypertension performed three experimental sessions: MICE, HIIE, and control. MICE consisted of continuous treadmill exercise at an intensity of 3–4 metabolic equivalents of energy (METs) until completing 3 kcal/kg and was energy-matched to HIIE (which included six to eight intervals of 3 min duration at 6–7 METs interspersed with 1.5-min rests at 3 METs). In the control session, participants remained seated for 50 min. Flow-mediated vasodilation, autonomic nervous system balance (heart rate variability), exerkines [interleukin (IL)-6, IL-8, IL-15, vascular endothelial growth factor A, irisin, adiponectin, and angiopoietin] and 71 inflammatory-related proteins were also measured. Results: Compared with baseline, HIIE and MICE reduced clinic SBP immediately (P &lt; 0.001 for both) and 90 min (P = 0.001 and P = 0.041, respectively) postexercise. HIIE and MICE also reduced clinic DBP immediately postexercise (P = 0.003 and P = 0.025). By contrast, no changes were found in the control session. On the other hand, no significant effects were noted for 24 h ABP measures or for the rest of variables. Conclusion: Although in patients with resistant hypertension, acute aerobic exercise induces short-term reductions in clinic BP, this stimulus does not suffice to reduce 24 h ABP or to impact on potential biological mechanisms.

Causal correlations between inflammatory proteins and heart failure: A two-sample Mendelian randomization analysis.

Inflammation plays a critical role in both the development and progression of heart failure (HF), which is a leading cause of morbidity and mortality worldwide. However, the causality between specific inflammation-related proteins and HF risk remains unclear. This study aims to investigate the genetically supported causality between inflammatory proteins and HF using a two-sample Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data of 91 inflammation-related proteins as exposures from the SCALLOP Consortium (14,824 participants), alongside outcome GWAS summary statistics from FinnGen (29,218 cases/381,838 controls) and HERMES (47,309 cases/930,014 controls) for HF, to conduct a two-sample MR analysis. For each inflammatory protein, instrumental variables (IVs) were chosen following the three foundational assumptions of the MR analysis, requiring a minimum of three qualifying single nucleotide polymorphisms (SNPs) each with a P<5e-8. Associations between inflammatory proteins and HF were assessed through inverse-variance weighted (IVW), MR-Egger regression, weighted median and weighted mode analysis. The reliability and validity of the results were evaluated by examining heterogeneity, horizontal pleiotropy, leave-one-out analysis, meta-analysis and reverse MR analysis. Heterogeneity refers to the variation in results across different genetic variants. Horizontal pleiotropy occurs when a genetic variant influences multiple traits through different biological pathways. Addressing both heterogeneity and horizontal pleiotropy is crucial for ensuring the reliability and interpretability of MR results. Our analysis identified associations between three inflammatory proteins and HF risk. Matrix metalloproteinase-1 (MMP-1) (OR, 1.09; 95% CI, 1.00-1.18; P=0.04) and TNF-beta (OR, 1.05; 95% CI, 1.01-1.09; P=0.01) were positively associated with HF risk in FinnGen. In contrast, urokinase-type plasminogen activator (uPA) was inversely associated with HF risk in both FinnGen (OR, 0.85; 95% CI, 0.78-0.92; P=3.27e-5) and HERMES (OR, 0.93; 95% CI, 0.87-0.99; P=0.03). No evidence of heterogeneity and horizontal pleiotropy was observed in the MR analysis, indicating the robustness of our findings. A meta-analysis further supported this association, indicating a reduced risk (OR, 0.89; 95% CI, 0.81-0.98; P=0.02). No reverse causality was found between HF and these three inflammatory proteins (P>0.05 for all). This study provides genetically supported evidence of the causal association of specific inflammatory proteins with HF risk. The positive association of MMP-1 and TNF-beta with HF suggests their roles in disease pathogenesis, whereas the inverse association of the uPA indicates its potential protective effect. Our findings highlight the potential of targeting specific inflammatory pathways as a therapeutic strategy for HF.

BMI trajectories from birth to young adulthood associate with distinct cardiometabolic profiles.

Numerous studies have investigated links between body mass index (BMI) trajectories and cardiovascular risk, yet discrepancies in BMI measurement duration and timing of the cardiovascular-related outcome evaluation have led to inconsistent findings. We included participants from the Swedish birth cohort (BAMSE) and applied latent class mixture modeling to identify BMI trajectories using data of multiple BMI measures (≥ 4 times) from birth until 24-year follow-up (n = 3204). Subsequently, we analyzed the associations of BMI trajectories with lipids (n = 1974), blood pressure (n = 2022), HbA1c (n = 941), and blood leukocytes (n = 1973) using linear regression. We also investigated the circulating levels of 92 inflammation-related proteins (n = 1866) across BMI trajectories. Six distinct BMI groups were identified, denoted as increasing-persistent high (n = 74; 2.3%), high-accelerated increasing (n = 209; 6.5%), increasing-accelerated resolving (n = 142; 4.4%), normal-above normal (n = 721; 22.5%), stable normal (n = 1608; 50.2%), and decreasing-persistent low (n = 450; 14.1%) BMI groups. The increasing-persistent high and high-accelerated increasing BMI groups had higher levels of total cholesterol [mean difference (95% confidence intervals): 0.30 (0.04-0.56) and 0.16 (0.02-0.31) mmol/L], triglyceride, low-density lipoprotein, hemoglobin A1C [3.61 (2.17-5.54) and 1.18 (0.40-1.98) mmol/mol], and low-density lipoprotein/high-density lipoprotein ratios, but a lower level of high-density lipoprotein than the stable normal BMI group. These two groups also had higher leukocyte cell counts and higher circulating levels of 28 inflammation-related proteins. No increased cardiometabolic markers were observed in the increasing-accelerated resolving BMI group. Participants with persistently high or accelerated increasing BMI trajectories from birth to young adulthood have elevated levels of cardiometabolic risk markers at young adulthood than those with stable normal BMI. However, a raised BMI in childhood may not be inherently harmful to cardiometabolic health, provided it does not persist into adulthood.

Characterisation of IBD heterogeneity using serum proteomics: A multicentre study.

Recent genetic and transcriptomic data highlight the need for improved molecular characterisation of inflammatory bowel disease (IBD). Proteomics may advance the delineation of IBD phenotypes since it accounts for post-transcriptional modifications. We aimed to assess the IBD spectrum based on inflammatory serum proteins and identify discriminative patterns of underlying biological subtypes across multiple European cohorts. Using proximity extension methodology, we measured 86 inflammation-related serum proteins in 1551 IBD patients and 312 healthy controls (HC). We screened for proteins exhibiting significantly different levels among IBD subtypes and between IBD and HC. Classification models for differentiating between Crohn's disease (CD) and ulcerative colitis (UC) were employed to explore the IBD spectrum based on estimated probability scores. Levels of multiple proteins, such as IL-17A, MMP-10, and FGF-19, differed (fold-change>1.2; FDR<0.05) between ileal vs colonic IBD. Using multivariable models, a protein signature reflecting the IBD spectrum was identified, positioning colonic CD between UC and ileal CD, which were at opposite ends of the spectrum. Based on area under the curve (AUC) estimates, classification models more accurately differentiated UC from ileal CD (median AUCs>0.73) than colonic CD (median AUCs<0.62). Models differentiating colonic CD from ileal CD demonstrated intermediate performance (median AUCs 0.67-0.69). Our findings in serum proteins support the presence of a continuous IBD spectrum rather than a clear separation of CD and UC. Within the spectrum, disease location may reflect a more similar disease than CD vs UC, as colonic CD resembled UC more closely than ileal CD.

Synergistic effects of ginsenoside Rb1 and peroxiredoxin 6 in enhancing myocardial injury treatment through anti-inflammatory, anti-oxidative, and anti-apoptotic mechanisms

AimGinsenosides have notable bioactivity in treating cardiovascular diseases, but the mechanisms of their combined use with Peroxiredoxin 6 (PRDX6) in myocardial injury remain unclear. This study explores the synergistic effects of Ginsenoside Rb1 (Gs-Rb1) and PRDX6, aiming to provide a theoretical foundation for their therapeutic potential. MethodsWe established a rat model of isoproterenol (ISO)-induced myocardial injury and observed that combination therapy was more effective than single-drug treatments, as shown by ECG monitoring and Masson staining. We performed RNA sequencing (RNA-Seq) on the combination therapy group and the ISO group. The results indicated that, compared to the ISO group, the combination therapy alleviated myocardial injury by reducing inflammation, oxidative stress, and apoptosis. Further analyses, including cell morphology, apoptosis rates, HE staining, ROS fluorescence intensity, and inflammation-related proteins, confirmed that the combination therapy successfully inhibited apoptosis, managed oxidative stress, and lessened inflammation. ResultsCombined treatment with Gs-Rb1 and PRDX6 significantly inhibited cardiac tissue fibrosis in rats, leading to a marked decrease in serum CK and LDH levels. RNA-seq analysis revealed upregulated genes related to lipid metabolism and small molecule biosynthesis, while downregulated genes were associated with oxidative stress, inflammation, and apoptosis. Validation experiments confirmed the combined treatment's significant inhibition of apoptosis, ROS activity, and inflammation. These results support the effectiveness of the two-drug combination in suppressing key biological processes in cardiac tissue, suggesting potential mechanisms for combating cardiac fibrosis. ConclusionThis study clarifies how Gs-Rb1 and PRDX6 work together to protect against myocardial damage, demonstrating that their combined therapy reduces inflammation, apoptosis, and oxidative stress. This highlights a new avenue for developing ginseng-based treatments.

Carboxymethyl chitosan oligosaccharide enzymatic hydroxylates with reactive oxygen species scavenging and anti-inflammatory activity for topical treatment of skin photodamage

Skin photodamage caused by ultraviolet (UV) radiation is a major public health concern. UVB rays penetrate the epidermis, inducing oxidative stress and compromising essential cellular components. The demand for natural ingredients with properties such as moisturization, anti-inflammatory effects, antioxidant protection, and compatibility is increasing to combat the impact of photodamage on the skin. Herein, the carboxymethyl chitosan oligosaccharide (CM-COS) enzymatic hydroxylates were used on the topical application of skin photodamage for the first time. CM-COS, the degradation product of carboxymethyl chitosan, has high water solubility and multiple biological activities. Results showed that CM-COS promoted human epidermal cell (HaCaT) migration without causing cytotoxicity. In photodamaged HaCaT cells, CM-COS maintained cell viability and cytoskeletal integrity while inhibiting reactive oxygen species accumulation, apoptosis, and cell cycle arrest. CM-COS regulates gene expression related to cell cycle, oxidative stress, and inflammation in UVB-radiated HaCaT based on transcriptomic and qPCR data. In UVB-exposed mice, topical treatment of CM-COS significantly alleviated redness and scab formation and increased the moisture content of photodamaged skin. Histological analyses revealed reduced epidermal thickness and increased collagen I and collagen III deposition in photodamaged skin following CM-COS treatment. Additionally, gene expression related to the cell cycle, extracellular matrix, and inflammation were significantly activated by CM-COS based on transcriptomic and qPCR data. CM-COS modulated the levels of collagen and inflammation-related proteins. Collectively, the data confirm the therapeutic effect of CM-COS against skin photodamage and highlight the potential of natural marine oligosaccharides for treating skin diseases such as aging, wounds, and burns.

Comparison of the Cecum Ligation and Puncture Method and the Intraperitoneal Lipopolysaccharide Injection Method for the Construction of a New-Onset Atrial Fibrillation Model of Sepsis.

New-onset atrial fibrillation (AF) in sepsis significantly impacted patient morbidity and mortality, yet the optimal animal model for studying this condition remains undetermined. This study aimed to establish a stable animal model for new-onset AF in sepsis and to explore the molecular mechanisms involved. Forty-seven Sprague-Dawley rats were utilized, with the cecal ligation and puncture (CLP) group divided into 0.6 mm and 1.0 mm needle outer diameter subgroups, and the lipopolysaccharide (LPS) group into 5 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg dosage subgroups. The incidence of new-onset AF and five-day mortality rates were compared to identify the most stable modeling conditions. Selected subgroups underwent further analysis, including cardiac ultrasound, electrophysiology, and pathological examinations. Inflammation-related molecular levels in the atrium were assessed using ELISA and Western blotting (WB). The intraperitoneal injection of 10 mg/kg LPS was identified as the most stable model for new-onset AF in sepsis, with significant findings including increased left atrial area and fibrosis, left ventricular pump dysfunction, uncoordinated ventricular wall motion, and impaired electrical impulse conduction. The effective atrial refractory period was markedly shorter, and susceptibility to AF was higher in the LPS group compared to the CLP group. Molecular analysis revealed elevated levels of NOD-like receptor protein 3(NLRP3) inflammasomes, apoptosis-associated speck-like protein containing a CARD(ASC), Caspase-1 p20 Elevated levels of three inflammation-related proteins and increased activity of the Sphingosine 1-phosphate/Sphingosine 1-phosphate Receptor 2(S1P/S1P2) signaling axis. Intraperitoneal injection of 10 mg/kg of LPS can successfully construct a new-onset AF model in sepsis, and NLRP3 inflammatory vesicles mediated by the S1P/S1P2 signaling axis may promote new-onset AF in sepsis.

Lactobacillus plantarum LP104 improved intestinal and brain inflammation by modulating TLR4 pathway and gut flora in alcohol liver injury mice

In this study, Lactobacillus plantarum LP104 (LP104) originating from kimchi was treated to C57BL/6N mice fed a chronic-plus-single-binge ethanol diet for ten days, aiming to evaluate the effects of the probiotics on intestinal and brain inflammation in the alcohol-induced liver injury model. Dietary supplementation with LP104 significantly reduced the concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) in alcoholic hepatic injury mice. The 16S rDNA sequencing results inferred that LP104 modulated the intestinal microbiota by depleting inflammation-related bacterial genera Proteobacteria and enriching Lactobacillus and Roseburia. Furthermore, LP104 intervention attenuated alcohol-induced gut inflammation by the TLR4 signaling pathway, which regulated the expressions of intestinal tight junction proteins such as ZO-1, Claudin-1 and Occludin. Subsequently, LP104 intake exerted neuroprotection by restoring neurotrophic factor levels and the blood-brain barrier (BBB) function to decrease lipopolysaccharide (LPS) levels in the serum. The western blotting results suggested LP104 ameliorated alcohol-induced brain inflammation by inhibiting the LPS/TLR4 signaling pathway in mice. Spearman's correlation analysis demonstrated that differential intestinal bacterial taxa were connected with the expressions of inflammation-related proteins in both gut and brain of alcohol liver injury mice.

Intermittent preventive treatment for malaria in pregnancy and infant growth: a mediation analysis of a randomised trial

Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses. We analysed data from 633 infants born to mothers enrolled in a randomised trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs. sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0 to 12 months of age. Using generalised linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anaemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrolment, maternal age, maternal parasitaemia at enrolment, education, and wealth. SP increased mean LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased mean WLZ by 0.11-0.28 Z from 2 to 8 months compared to SP among infants of multigravidae; at these ages, confidence intervals for mean differences excluded 0. We did not observe differences among primigravida. Mediators of SP included birth weight, birth length, maternal stem cell factor, and DNER. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery. In high malaria transmission settings, this exploratory study suggests different IPTp regimens may influence infant growth among multigravidae, potentially through distinct pathways, in the exclusive breastfeeding period, when few other interventions are available. Stanford Center for Innovation in Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation.

Plasma metabolites as mediators in the relationship between inflammation-related proteins and benign prostatic hyperplasia: insights from mendelian randomization

Benign prostatic hyperplasia (BPH) is a condition commonly observed in aging males. Inflammatory and metabolic factors are pivotal in the development and progression of BPH. The degree to which the effects of 91 inflammation-related proteins on BPH are mediated by 1400 plasma metabolites remains ambiguous. Our research analyzed the impact of these traits utilizing genetic evidence.Two-sample Mendelian randomization (MR) and multivariable MR (MVMR) were utilized in our study to infer the genetic causal effect of inflammation-related proteins on BPH, with metabolites serving as mediators. Increased levels of IL-2 were linked to a heightened incidence of BPH (β = 0.071, OR:1.074, 95% CI [1.002–1.152], p = 0.045), whereas lower concentrations of N6,N6-dimethyllysine were associated with decreased risk (β1=-0.127, p = 0.02; β2=-0.039, p = 0.008). The mediation effect was 0.005 (95% CI [0.0004, 0.012], OR: 1.005, 95% CI [1.000, 1.012]), accounting for 7.04% of the total effect. subsequently, we examined the phenotypic co-localization of the two pairings independently, revealing that the posterior probability of rs145516501 associated with IL-2 and BPH was 80.7%, whereas the posterior likelihood of rs4917820 linked to N6,N6-dimethyllysine levels and BPH was 95.9%. The research indicated that N6,N6-dimethyllysine levels seem to influence the causative relationship between IL-2 and BPH. These results elucidate the complex interplay between inflammation-related proteins and metabolism in the context of BPH, offering novel diagnostic and therapeutic avenues and enhancing our comprehension of the disease’s etiology for prospective research.