Reduction Of Inflammatory Markers Research Articles

Preclinical Safety Assessment of Deferoxamine-preconditioned Canine Adipose Tissue-derived Mesenchymal Stem Cells.

In the pursuit of translating stem cell therapy technology into clinical practice, ensuring the safety and efficacy of treatments is paramount. Despite advancements, the effectiveness of stem cell applications often falls short of clinical requirements. This study aimed to address the challenge of limited efficacy by investigating the safety and effectiveness of canine adipose tissue-derived mesenchymal stem cells (cATMSCs) preconditioned with deferoxamine (DFO). Different concentrations of DFO were used to evaluate its impact on cATMSC activity. The therapeutic potential of these preconditioned cells was validated using a mouse model of systemic inflammation. Comprehensive evaluations, including clinical hematological and radiological assessments before and after intravenous injection of preconditioned cells were conducted. The study showed a notable reduction in inflammatory markers and an overall decrease in the inflammatory response in the mouse model. The data collected from the clinical hematological and radiological assessments provided essential insights. This study lays the groundwork for the future clinical deployment of DFO-preconditioned cATMSCs, demonstrating their potential to improve the efficacy and safety of stem cell therapies.

Efficacy of pitavastatin in patients with HIV: a systematic review and meta-analysis of randomized controlled trials

Abstract Background People with HIV (PWH) experience elevated cardiovascular disease (CVD) risk, exacerbated by antiretroviral therapy-induced dyslipidemia. Managing CVD risks in PWH presents significant challenges, notably due to the potential drug interactions. Pitavastatin is a statin with minimal interactions with antiretrovirals. Methods A systematic literature search of PubMed, Cochrane Library, and Embase databases was conducted up to March 1st, 2024, for studies comparing pitavastatin in PWH. Statistical software RStudio version 4.1.2 was used. Results Three studies with a total of 8045 participants were included in this analysis. Of these 4026 (50.04%) received pitavastatin. The mean age was 49.98 years and 69.38% were male. In the pooled analysis of studies, pitavastatin significantly reduced LDL cholesterol (MD -25.47; 95% CI -35.26 to -15.69; p<0.01; I² = 91%; Figure 1A) and non-HDL cholesterol (MD -27.53; 95% CI -41.19 to -13.87; p<0.01; I² = 91%; Figure 1B). Recently, the randomized trial to prevent vascular events in HIV study showed a reduction in adverse cardiovascular events and noncalcified plaque volume, as well as a reduction in inflammatory markers including oxidized LDL. Conclusions Pitavastatin offers a promising strategy for managing dyslipidemia and reducing CVD risk in PWH by reducing cholesterol, improving coronary plaque characteristics and inflammatory markers.

The impact of intravenous metoprolol tartrate on mortality rates in patients with septic shock due to ventilator-associated pneumonia: A randomized clinical trial

Background: Septic shock, particularly due to ventilator-associated pneumonia (VAP), is a significant cause of mortality in critically ill patients. Traditional treatments include antimicrobial therapy, fluid resuscitation, and vasopressors. However, recent interest has emerged in using β-blockers to modulate the hyperadrenergic state seen in sepsis. β-blockers, like metoprolol, may improve cardiac efficiency, reduce myocardial oxygen demand, and ultimately enhance patient outcomes. Objective: This study aimed to assess the impact of administering intravenous metoprolol tartrate on the mortality rates of patients with septic shock due to VAP. Methods: This study employed a randomized clinical trial design within the Intensive Care Units of Alexandria Main University Hospital. A cohort of 100 patients diagnosed with septic shock due to ventilator-associated pneumonia (VAP) participated in the trial. Upon achieving hemodynamic stabilization, participants were randomly assigned to either receive standard care alone or standard care supplemented with intravenous metoprolol. Variables of interest included assessing 28-day mortality rates, duration of ICU stay and mechanical ventilation, reliance on intravenous fluids and vasopressors, acid-base balance, lactate levels, inflammatory markers, and mean arterial pressure (MAP). This comprehensive approach aimed to evaluate the impact of metoprolol on critical outcomes in this patient population. Results: The administration of intravenous metoprolol tartrate resulted in significant clinical benefits, including lower 28-day mortality rates (P = 0.013), shortened durations of ICU stay (P < 0.001), and reduced mechanical ventilation periods (P < 0.001). These outcomes were explained by the observed decreased reliance on intravenous fluids and vasopressors (P < 0.001), improved acid-base balance and lactate levels. The rapid reduction of inflammatory markers (P < 0.001) and the sustained improvement of MAP in the metoprolol group compared to the control group further contributed to the explication of these findings. Conclusion: Intravenous metoprolol tartrate effectively controlled inflammation, optimized hemodynamics, and improved patient outcomes compared to standard care, suggesting it as a beneficial adjunct in the management of septic shock. Trial registration: PACTR202404531355476. Keywords: Metoprolol; septic shock; ventilator-associated pneumonia; beta-blockers; mortality.

The Impact of RNA Interference on Atherosclerotic Plaque Progression: A Meta-Analysis of Preclinical Studies

Background: Atherosclerosis, a chronic inflammatory disease characterized by the buildup of plaque within arteries, remains a leading cause of cardiovascular morbidity and mortality. RNA interference (RNAi) has emerged as a promising therapeutic strategy for atherosclerosis by targeting genes involved in plaque formation and progression. This meta-analysis aimed to evaluate the efficacy of RNAi in preclinical models of atherosclerosis. Methods: A systematic search of PubMed, Embase, and Web of Science databases was conducted from January 2013 to December 2023 to identify preclinical studies investigating the impact of RNAi on atherosclerotic plaque progression. Studies utilizing various RNAi modalities (siRNA, miRNA mimics/inhibitors, shRNA) targeting different genes involved in atherosclerosis were included. The primary outcome was plaque size reduction. Secondary outcomes included changes in plaque composition, lipid profiles, and inflammatory markers. A random-effects model was used to pool data and calculate standardized mean differences (SMD) with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic. Results: Seven preclinical studies met the inclusion criteria, encompassing a total of 210 animals. RNAi interventions significantly reduced atherosclerotic plaque size compared to controls (SMD -1.51; 95% CI -2.36 to -0.66; p<0.00001; I²=12%). Analysis of secondary outcomes revealed favorable effects of RNAi on plaque composition, with a significant decrease in lipid content and an increase in collagen content. Furthermore, RNAi significantly improved lipid profiles by reducing total cholesterol and LDL-cholesterol levels. A significant reduction in inflammatory markers, such as TNF-α and IL-6, was also observed. Conclusion: This meta-analysis provides compelling evidence supporting the therapeutic potential of RNAi in attenuating atherosclerotic plaque progression in preclinical models. RNAi effectively reduced plaque size, improved plaque stability, and modulated lipid metabolism and inflammation.

The Protective Effect against Lung Injury of Phytosome Containing the Extract of Purple Waxy Corn Tassel in an Animal Model of PM2.5-Induced Lung Inflammation.

Lung inflammation caused by fine particulate matter (PM), particularly PM2.5, poses a significant public health challenge, with oxidative stress and inflammation playing central roles in its pathophysiology. This study evaluates the protective effects of phytosome-encapsulated extract of purple waxy corn tassel (PPT) against PM2.5-induced lung inflammation. Male Wistar rats received PPT at doses of 100, 200, and 400 mg/kg BW for 21 days prior to exposure and continued to receive the same doses for 27 days during PM2.5 exposure. Significant reductions in inflammatory markers, including cyclooxygenase-2 (COX-II), various interleukins (IL-1β, IL-6, IL-8), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB), were observed, indicating that PPT effectively regulates the inflammatory response. Additionally, PPT improved oxidative stress markers by reducing malondialdehyde (MDA) levels and enhancing antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), thereby restoring lung antioxidant defenses. Notably, the study revealed that PPT modulates epigenetic mechanisms, as evidenced by decreased histone deacetylase (HDAC) activity and upregulation of sirtuins in lung tissue. These epigenetic modifications likely contribute to the reduction in inflammation and oxidative stress, suggesting a multifaceted protective role of PPT that involves both direct biochemical pathways and epigenetic regulation. The interplay between reduced inflammatory signaling, enhanced antioxidant capacity, and epigenetic modulation underscores PPT's potential as a therapeutic agent for managing respiratory inflammation-related diseases and its promise for the development of future functional food products.

Effects of sulphur thermal water inhalations in long-COVID syndrome: Spa-centred, double-blinded, randomised case–control pilot study

BackgroundThe long-COVID syndrome is characterised by a plethora of symptoms. Given its social and economic impact, many studies have stressed the urgency of proposing innovative strategies other than hospital settings. In this double-blinded, randomised, case–control trial, we investigate the effects of sulphur thermal water inhalations, rich in H2S, compared to distilled water inhalations on symptoms, inflammatory markers and nasal microbiome in long-COVID patients. MethodsAbout 30 outpatients aged 18–75 with positive diagnosis for long-COVID were randomised in two groups undergoing 12 consecutive days of inhalations. The active group (STW) received sulphur thermal water inhalations whereas the placebo group received inhalations of sterile distilled non-pyrogenic water (SDW). Each participant was tested prior treatment at day 1 (T0), after the inhalations at day 14 (T1) and at 3 months follow-up (T2). At each time point, blood tests, nasal swabs for microbiome sampling, pulmonary functionality tests (PFTs) and pro-inflammatory marker measure were performed. ResultsThe scores obtained in the administered tests (6MWT, Borg score and SGRQ) at T0 showed a significant variation in the STW group, at T1 and T2. Serum cytokine levels and other inflammatory biomarkers reported a statistically significant decrease. Some specific parameters of PFTs showed ameliorations in the STW group only. Changes in the STW nasopharyngeal microbiota composition were noticed, especially from T0 to T2. ConclusionsInhalations of sulphur thermal water exerted objective and subjective improvements on participants affected by long-COVID. Significant reduction of inflammatory markers, dyspnoea scores and quantitative and qualitative changes in the nasopharyngeal microbiome were also assessed.

MSC–extracellular vesicle microRNAs target host cell-entry receptors in COVID-19: in silico modeling for in vivo validation

BackgroundCoronavirus disease 2019 (COVID-19) has created a global pandemic with significant morbidity and mortality. SARS-CoV-2 primarily infects the lungs and is associated with various organ complications. Therapeutic approaches to combat COVID-19, including convalescent plasma and vaccination, have been developed. However, the high mutation rate of SARS-CoV-2 and its ability to inhibit host T-cell activity pose challenges for effective treatment. Mesenchymal stem cells (MSCs) and their extracellular vesicles (MSCs–EVs) have shown promise in COVID-19 therapy because of their immunomodulatory and regenerative properties. MicroRNAs (miRNAs) play crucial regulatory roles in various biological processes and can be manipulated for therapeutic purposes.ObjectiveWe aimed to investigate the role of lyophilized MSC–EVs and their microRNAs in targeting the receptors involved in SARS-CoV-2 entry into host cells as a strategy to limit infection. In silico microRNA prediction, structural predictions of the microRNA–mRNA duplex, and molecular docking with the Argonaut protein were performed.MethodsMale Syrian hamsters infected with SARS-CoV-2 were treated with human Wharton’s jelly-derived Mesenchymal Stem cell-derived lyophilized exosomes (Bioluga Company)via intraperitoneal injection, and viral shedding was assessed. The potential therapeutic effects of MSCs–EVs were measured via histopathology of lung tissues and PCR for microRNAs.ResultsThe results revealed strong binding potential between miRNA‒mRNA duplexes and the AGO protein via molecular docking. MSCs–EVs reduced inflammation markers and normalized blood indices via the suppression of viral entry by regulating ACE2 and TMPRSS2 expression. MSCs–EVs alleviated histopathological aberrations. They improved lung histology and reduced collagen fiber deposition in infected lungs.ConclusionWe demonstrated that MSCs–EVs are a potential therapeutic option for treating COVID-19 by preventing viral entry into host cells.

Colchicine in acutely decompensated heart failure: the COLICA trial.

Acute heart failure (AHF) promotes inflammatory activation, which is associated with worse outcomes. Colchicine has proven effective in other cardiovascular conditions characterized by inflammatory activation, but has never been evaluated in the setting of AHF. This multicenter, randomized, double-blind and placebo-controlled trial included patients with AHF, requiring ≥40 mg of intravenous furosemide, regardless of their left ventricular ejection fraction (LVEF) and inpatient or outpatient setting. Patients were randomized within the first 24 hours of presentation to receive either colchicine or placebo, with loading dose of 2 mg followed by 0.5 mg every 12 hours for 8 weeks. A total of 278 patients (median age 75 years, LVEF 40%, baseline N-terminal pro-B-type natriuretic peptide [NT-proBNP] 4390 pg/mL) were randomized to colchicine (n=141) or placebo (n=137). The primary endpoint, the time-averaged reduction in NT-proBNP levels at 8 weeks, did not differ between the colchicine group (-62.2%, 95% confidence interval [CI] -68.9% to -54.2%) and the placebo group (-62.1%, 95% CI -68.6% to -54.3%) (ratio of change 1.0). The reduction in inflammatory markers was significantly greater with colchicine: ratio of change 0.60 (p<0.001) for C-reactive protein and 0.72 (p=0.019) for interleukin-6. No differences were found in new worsening heart failure episodes (14.9% with colchicine vs. 16.8% with placebo, p=0.698); however, the need for intravenous furosemide during follow-up was lower with colchicine (p=0.043). Diarrhea was slightly more common with colchicine, but it did not result in differences in medication withdrawal (8.5% vs. 8.8%). Colchicine was safe and effective in reducing inflammation in patients with AHF, however colchicine and placebo exhibited comparable effects on reducing NT-proBNP and preventing new worsening heart failure events.

Analysis of effectiveness of Fecal Microbiota Transplantation in Multiple Sclerosis

Multiple Sclerosis is a chronic, autoimmune disorder characterized by demyelination and neuroinflammation affecting 2.3 million people around the world. MS have different types, relapsing and remitting MS being the most prevalent type with unpredicted flare ups with complete or incomplete recovery of the patient. Research suggests the emerging impact of alterations in gut microbiome on various diseases. The dysbiosis of gut flora has been linked to various diseases one of many is central nervous system autoimmune disorders. The study aims to evaluate the potential role and effectiveness of FMT in treating MS. The literature and clinical trials focused on gut microbiota, efficacy, Safety, and mechanisms of FMT were analyzed. The major focus of the study is assessing the impact of FMT on MS symptoms and gut microbiota composition and results of the study were concluded based on outcomes. Primary outcomes noted improvement in MS symptoms both subjectively and objectively including enhanced motor symptoms and improved disability scores like EDSS. Secondary outcomes showed significant improvement in gut microbiota and 55-65% reduction in inflammatory markers like IL 6 and TNF alpha. FMT shows promising outcomes to be considered as a therapeutic intervention in MS by offering symptom relief and halting disease progression.

Eco-friendly nanotechnology in rheumatoid arthritis: ANFIS-XGBoost enhanced layered nanomaterials

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and pain in the joints, which can lead to joint damage and disability over time. Nanotechnology in RA treatment involves using nano-scale materials to improve drug delivery efficiency, specifically targeting inflamed tissues and minimizing side effects. The study aims to develop and optimize a new class of eco-friendly and highly effective layered nanomaterials for targeted drug delivery in the treatment of RA. The study's primary objective is to develop and optimize a new class of layered nanomaterials that are both eco-friendly and highly effective in the targeted delivery of medications for treating RA. Also, by employing a combination of Adaptive Neuron-Fuzzy Inference System (ANFIS) and Extreme Gradient Boosting (XGBoost) machine learning models, the study aims to precisely control nanomaterials synthesis, structural characteristics, and release mechanisms, ensuring delivery of anti-inflammatory drugs directly to the affected joints with minimal side effects. The in vitro evaluations demonstrated a sustained and controlled drug release, with an Encapsulation Efficiency (EE) of 85% and a Loading Capacity (LC) of 10%. In vivo studies in a murine arthritis model showed a 60% reduction in inflammation markers and a 50% improvement in mobility, with no significant toxicity observed in major organs. The machine learning models exhibited high predictive accuracy with a Root Mean Square Error (RMSE) of 0.667, a correlation coefficient (r) of 0.867, and an R2 value of 0.934. The nanomaterials also demonstrated a specificity rate of 87.443%, effectively targeting inflamed tissues with minimal off-target effects. These findings highlight the potential of this novel approach to significantly enhance RA treatment by improving drug delivery precision and minimizing systemic side effects.

The influence of CLEC5A on early macrophage-mediated inflammation in COPD progression

Chronic obstructive pulmonary disease (COPD) is a complex syndrome with poorly understood mechanisms driving its early progression (GOLD stages 1–2). Elucidating the genetic factors that influence early-stage COPD, particularly those related to airway inflammation and remodeling, is crucial. This study analyzed lung tissue sequencing data from patients with early-stage COPD (GSE47460) and smoke-exposed mice. We employed Weighted Gene Co-Expression Network Analysis (WGCNA) and machine learning to identify potentially pathogenic genes. Further analyses included single-cell sequencing from both mice and COPD patients to pinpoint gene expression in specific cell types. Cell–cell communication and pseudotemporal analyses were conducted, with findings validated in smoke-exposed mice. Additionally, Mendelian randomization (MR) was used to confirm the association between candidate genes and lung function/COPD. Finally, functional validation was performed in vitro using cell cultures. Machine learning analysis of 30 differentially expressed genes identified 8 key genes, with CLEC5A emerging as a potential pathogenic factor in early-stage COPD. Bioinformatics analyses suggested a role for CLEC5A in macrophage-mediated inflammation during COPD. Two-sample Mendelian randomization linked CLEC5A single nucleotide polymorphisms (SNPs) with Forced Expiratory Volume in One Second (FEV1), FEV1/Forced Vital Capacity (FVC) and early/later on COPD. In vitro, the knockdown of CLEC5A led to a reduction in inflammatory markers within macrophages. Our study identifies CLEC5A as a critical gene in early-stage COPD, contributing to its pathogenesis through pro-inflammatory mechanisms. This discovery offers valuable insights for developing early diagnosis and treatment strategies for COPD and highlights CLEC5A as a promising target for further investigation.

Mirikizumab: A promising breakthrough in Crohn's disease treatment.

Crohn's disease (CD) is a chronic, progressive inflammatory bowel disorder characterized by persistent inflammation and noncontiguous "skip lesions" throughout the gastrointestinal tract. With a prevalence of 100-300 cases per 100,000 individuals, CD is most common in Western Europe and North America. Symptoms include abdominal pain, diarrhea, fever, weight loss, and anemia, with severe cases leading to complications such as perianal abscesses and cutaneous fistulas. Treatment involves pharmaceutical interventions, bowel rest, and sometimes surgery, with biological therapies like ustekinumab and mirikizumab gaining prominence. The VIVID-1 trial assessed mirikizumab in patients with moderately to severely active CD. By Week 12, mirikizumab significantly outperformed placebo in clinical response (45.4% vs. 19.6%, p < 0.000001). By Week 52, it showed higher clinical remission rates (54.1% vs. 19.6%) and demonstrated non-inferiority to ustekinumab in clinical remission (p = 0.51). The SEQUENCE study compared risankizumab to ustekinumab, with risankizumab showing superior reductions in inflammatory markers and higher biologic remission rates at Weeks 8, 24, and 48. Both treatments had similar safety profiles, with common adverse events including COVID-19, anemia, and headache. Mirikizumab, based on the VIVID-1 trial outcomes, is a promising addition to CD therapy. It demonstrated significant clinical responses and remission rates, warranting further research on its long-term efficacy and safety. Updating professional guidelines and addressing affordability will ensure broader access and improved management of CD.

Impact of Immunoglobulin M-enriched Immunoglobulins on the Outcomes of Severe Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) led to a major global health crisis, leading to a worldwide pandemic. Several therapeutic interventions have been tried with varied results. The purpose of this academic work was to assess the efficacy of immunoglobulin M (IgM)-enriched Ig in the management of patients with severe COVID-19 pneumonia. In this retrospective cohort study, severe COVID-19 pneumonia patients who received IgM-enriched immunoglobulin, in addition to standard-of-care treatment, were retrospectively enrolled. Levels of inflammatory biomarkers, oxygenation status, and organ dysfunction were evaluated, and differences were noted after giving IgM-supplemented IgM. Data from 32 consecutive severe COVID-19 patients admitted to medical intensive care units (ICUs) were analyzed. After giving IgM-enriched Ig, there was an improvement in oxygenation indices as shown by saturation of oxygen/fraction of inspired oxygen (SpO2/FiO2) on days 3 and 7, but it was not statistically significant. Oxygen support could be de-escalated in 13 (40.6%) patients on day 3 and in 8 (25%) patients on day 7, after giving IgM-enriched Ig. After giving IgM-enriched Ig, there was a reduction in the levels of all the studied inflammatory markers [interleukin-6 (IL-6), D-dimer, and ferritin) on days 3 and 7, but it was statistically significant only for IL-6. The overall ICU mortality was 53.1%. Outcomes of patients with severe COVID-19 requiring ICU care remain dismal. IgM-enriched Ig may be helpful in improving oxygenation and combating cytokine storm in these patients. However, in the present study, the improvement in oxygenation indices (SpO2/FiO2) and reduction in inflammatory markers like D-dimer and ferritin were not statistically significant. Hence, larger randomized controlled trials are required to get more definitive evidence to support this therapy and show significant clinical and mortality benefits.

Investigating the anti-inflammatory effects of icariin: A combined meta-analysis and machine learning study

ObjectiveThe objectives of this study were to define the superiority of icariin and its derivatives' anti-inflammatory activities and to create a reference framework for evaluating preclinical evidence. This method combines machine learning and meta-analysis to identify underlying biological pathways. MethodsData came from PubMed, Embase, Web of Science, and the Cochrane Library. SYRCLE was used to evaluate the risk of bias in a subset of research. Meta-analysis and detailed subgroup analyses, categorized by species, genders, disease type, dosage, and treatment duration, were performed using R and STATA 15.0 software to derive nuanced insights. Employing R software (version 4.2.3) and the tidymodels package, the analysis focused on constructing a model and selecting features, with TNF-α as the dependent variable. This approach aims to identify significant predictors of drug efficacy. An in-depth literature facilitated the synthesis of anti-inflammatory mechanisms attributed to icariin and its constituent compounds. ResultsFollowing a meticulous search and selection process, 19 studies, involving 370 and 260 animals were included in the meta-analysis and machine-learning assessment, respectively. The findings revealed that icariin and its derivatives markedly reduced inflammation markers, including TNF-α and IL-1β. Additionally, machine-learning outcomes, with TNF-α as the target variable, indicated enhanced anti-inflammatory effects of icariin across respiratory, urological, neurological, and digestive disease types. These effects were more pronounced at doses exceeding 27.52 mg/kg/day and treatment durations beyond 31.22 days. ConclusionStrong anti-inflammatory effects are exhibited by icariiin and its derivatives, which are especially beneficial in the management of digestive, neurological, pulmonary, and urinary conditions. Effective for periods longer than 31.22 days and at dosages more than 27.52 mg/kg/day. Subsequent research will involve more targeted animal experiments and safety assessments to obtain more comprehensive preclinical evidence.

A randomised controlled trial of plasma exchange compared to standard of care in the treatment of severe COVID-19 infection (COVIPLEX)

COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. Our primary objective was to assess the change in inflammatory and thrombotic markers associated with PEX, and secondary objectives were to assess the effects of PEX on progression of respiratory failure and incidence of acute thrombotic events. We conducted a prospective, phase II, non-blinded randomised control trial of plasma exchange compared to standard of care in critically ill adults with severe COVID-19 associated respiratory failure, requiring supplemental oxygen or ventilatory support and elevated thrombo-inflammatory markers (LDH, CRP, ferritin, and D-Dimer). Patients randomised to receive PEX were treated with a daily single volume plasma exchange for a minimum of five days. Twenty-two patients were randomised of who 11 received PEX. Demographic and clinical characteristics were similar between groups at presentation. PEX was associated with a significant reduction in pro-thrombotic markers FVIII, VWF and VWF Ag: ADAMTS 13 ratio (p < 0.001). There were no differences in the reduction of inflammatory markers, severity of respiratory failure (p = 0.7), thrombotic events (p = 0.67), or mortality (p > 0.99) at 28 days. PEX successfully reduced pro-thrombotic markers, although was not associated with reduction in inflammatory markers, respiratory failure, or thrombotic events.Trial registration: (NCT04623255); first posted on 10/11/2020.

Christensenella minuta Alleviates Acetaminophen-Induced Hepatotoxicity by Regulating Phenylalanine Metabolism.

Acetaminophen (APAP)-induced liver injury (AILI), even liver failure, is a significant challenge due to the limited availability of therapeutic medicine. Christensenella minuta (C. minuta), as a probiotic therapy, has shown promising prospects in metabolism and inflammatory diseases. Our research aimed to examine the influence of C. minuta on AILI and explore the molecular pathways underlying it. We found that administration of C. minuta remarkably alleviated AILI in a mouse model, as evidenced by decreased levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) and improvements in the histopathological features of liver sections. Additionally, there was a notable decrease in malondialdehyde (MDA), accompanied by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, and superoxide dismutase (SOD) activity. Furthermore, there was a significant reduction in inflammatory markers (IL6, IL1β, TNF-α). C. minuta regulated phenylalanine metabolism. No significant difference in intestinal permeability was observed in either the model group or the treatment group. High levels of phenylalanine aggravated liver damage, which may be linked to phenylalanine-induced dysbiosis and dysregulation in cytochrome P450 metabolism, sphingolipid metabolism, the PI3K-AKT pathway, and the Integrin pathway. Furthermore, C. minuta restored the diversity of the microbiota, modulated metabolic pathways and MAPK pathway. Overall, this research demonstrates that supplementing with C. minuta offers both preventive and remedial benefits against AILI by modulating the gut microbiota, phenylalanine metabolism, oxidative stress, and the MAPK pathway, with high phenylalanine supplementation being identified as a risk factor exacerbating liver injury.

Impact of silymarin-supplemented cookies on liver enzyme and inflammatory markers in non-alcoholic fatty liver disease patients.

Nonalcoholic fatty liver disease (NAFLD) is a growing public health concern characterized by fat accumulation and severe disorders like nonalcoholic steatohepatitis (NASH), which are influenced by obesity, inflammatory processes, and metabolic pathways. This research investigates the potential of silymarin-supplemented cookies in managing NAFLD by evaluating their impact on liver enzyme activity, inflammatory markers, and lipid profiles. A clinical trial in Lahore, Pakistan, involved 64 NAFLD patients. Participants were divided into placebo and three treatment groups, with the latter receiving silymarin-supplemented cookies for 3 months. The study assessed liver enzyme levels and inflammatory markers, at baseline and after the intervention, utilizing statistical analyses to evaluate differences. The lipid profile and renal function test (RFT) were also measured at baseline and after 3 months in each group for safety assessment. After 3 months, the treatment groups indicated more significant decreases in liver enzymes compared to the placebo group (p ≤ .05). Treatment 3 showed significant reductions in alanine aminotransferase (ALT) (64.39-49.38 U/L) and aspartate aminotransferase (AST) (61.53-45.38 U/L). Treatment 3 also showed improvements in alkaline phosphatase (ALP) levels and the AST/ALT ratio. Additionally, the treatment group demonstrated a significant reduction in inflammatory markers. Treatment 3 showed a significant decrease in C-reactive protein (CRP) (6.32-3.39 mg/L) and erythrocyte sedimentation rate (ESR) (38.72-23.86 mm/h), indicating that individuals with NAFLD may benefit from the intervention's potential benefits in lowering inflammation. The study revealed that an intervention significantly improved the inflammatory markers, liver enzymes, and lipid profiles of NAFLD participants, suggesting potential benefits for liver health.

Dapagliflozin, inflammation and left ventricular remodelling in patients with type 2 diabetes and left ventricular hypertrophy

Background and AimsSodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation.MethodsWe measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation.ResultsFollowing 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months.ConclusionsDapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin.Trial registrationClinicaltrials.gov NCT02956811 (06/11/2016).

Effects of acetylcysteine on micro-inflammation and pulmonary ventilation in chronic obstructive pulmonary disease exacerbation

BACKGROUND Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a serious complication of chronic obstructive pulmonary disease, often characterized by increased morbidity and mortality. In traditional Chinese medicine, AECOPD is linked to phlegm-heat and blood-stasis, presenting symptoms like thick sputum, fever, and chest pain. It has been shown that acetylcysteine inhalation in conjunction with conventional therapy significantly reduced inflammatory markers and improved lung function parameters in patients with AECOPD, suggesting that acetylcysteine may be an important adjunctive therapy for patients with phlegm-heat-blood stasis type AECOPD. AIM To investigate the effect of acetylcysteine on microinflammation and lung ventilation in patients with phlegm-heat and blood-stasis-type AECOPD. METHODS One hundred patients with phlegm-heat and blood-stasis-type AECOPD were randomly assigned to two groups. The treatment group received acetylcysteine inhalation (10% solution, 5 mL, twice daily) along with conventional therapy, whereas the control group received only conventional therapy. The treatment duration was 14 d. Inflammatory markers (C-reactive protein, interleukin-6, and tumor necrosis factor-alpha) in the serum and sputum as well as lung function parameters (forced expiratory volume in one second, forced vital capacity, and peak expiratory flow) were assessed pre- and post-treatment. Acetylcysteine inhalation led to significant reductions in inflammatory markers and improvements in lung function parameters compared to those in the control group (P &lt; 0.05). This suggests that acetylcysteine could serve as an effective adjunct therapy for patients with phlegm-heat and blood-stasis-type AECOPD. RESULTS Acetylcysteine inhalation significantly reduced inflammatory markers in the serum and sputum and improved lung ventilation function parameters in patients with phlegm-heat and blood-stasis type AECOPD compared with the control group. These differences were statistically significant (P &lt; 0.05). The study concluded that acetylcysteine inhalation had a positive effect on microinflammation and lung ventilation function in patients with this type of AECOPD, suggesting its potential as an adjuvant therapy for such cases. CONCLUSION Acetylcysteine inhalation demonstrated significant improvements in reducing inflammatory markers in the serum and sputum, as well as enhancing lung ventilation function parameters in patients with phlegm-heat and blood-stasis type AECOPD. These findings suggest that acetylcysteine could serve as a valuable adjuvant therapy for individuals with this specific type of AECOPD, offering benefits for managing microinflammation and optimizing lung function.

Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.