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It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor a (PPARa), here, we established that oral administration of gemfibrozil preserved the integrity of blood--brain barrier (BBB) and blood--spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα-/- mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARb (formerly PPARd), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα-/- EAE mice, but not PPARβ-/- EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα. [ABSTRACT FROM AUTHOR]

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease affecting lipoprotein metabolism. FCS is estimated to occur in 1 in 1–2 million individuals and can be diagnosed at any age, equally affecting all genders, races, and ethnicities. The condition is characterized by hypertriglyceridemia, which may predispose patients to acute pancreatitis. In this report, we present the case of a now 6-year-old girl with FCS on gemfibrozil and dietary restrictions. The patient initially presented at 40 days of age with bloody diarrhea. Serum samples revealed lipemia, with markedly elevated triglyceride levels. The patient was diagnosed with FCS, confirmed by genetic testing showing the homozygous variant c.833C>T(p,Ser278Phe) for the LPL gene. Despite being on a low-fat diet with medium chain triglyceride (MCT) based milk formulas, the patient developed acute pancreatitis 2 months later with continued elevated triglyceride levels. She was placed on gemfibrozil and fat-soluble vitamins at 2 months of age, with marked improvements subsequently noted. Currently, the patient is doing well, with normal growth parameters and no other episodes of acute pancreatitis. Her triglyceride levels have been maintained within normal levels. FCS is a rare, inherited lipid disorder that often goes underdiagnosed and unmanaged. It is worth considering the fibric acid derivative (gemfibrozil) to be one of the lines of management early on after diagnosis.

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease affecting lipoprotein metabolism. FCS is estimated to occur in 1 in 1–2 million individuals and can be diagnosed at any age, equally affecting all genders, races, and ethnicities. The condition is characterized by hypertriglyceridemia, which may predispose patients to acute pancreatitis. In this report, we present the case of a now 6-year-old girl with FCS on gemfibrozil and dietary restrictions. The patient initially presented at 40 days of age with vomiting. Serum samples revealed lipemia, with markedly elevated triglyceride levels. The patient was diagnosed with FCS, confirmed by genetic testing showing the homozygous variant c.833C>T(p,Ser278Phe) for the LPL gene. Despite being on a low-fat diet with medium chain triglyceride (MCT) based milk formulas, the patient developed acute pancreatitis 2 months later with continued elevated triglyceride levels. She was placed on gemfibrozil and fat-soluble vitamins at 2 months of age, with marked improvements subsequently noted. Currently, the patient is doing well, with normal growth parameters and no other episodes of acute pancreatitis. Her triglyceride levels have been maintained within normal levels. FCS is a rare, inherited lipid disorder that often goes underdiagnosed and unmanaged. It is worth considering the fibric acid derivative (gemfibrozil) to be one of the lines of management early on after diagnosis. [ABSTRACT FROM AUTHOR]

Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57 kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and − 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder. [ABSTRACT FROM AUTHOR]

Background: Gemfibrozil (Gem) is a drug that has been shown to activate PPAR‐α, a nuclear receptor that plays a key role in regulating lipid metabolism. Gem is used to lower the levels of triglycerides and reduce the risk of coronary heart disease in patients. Experimental studies in vitro and in vivo have shown that Gem can prevent or slow the progression of neurological disorders (NDs), including cerebral ischemia (CI), Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Neuroinflammation is known to play a significant role in these disorders. Method: The literature review for this study was conducted by searching Scopus, Science Direct, PubMed, and Google Scholar databases. Result: The results of this study show that Gem has neuroprotective effects through several cellular and molecular mechanisms such as: (1) Gem has the ability to upregulate pro‐survival factors (PGC‐1α and TFAM), promoting the survival and function of mitochondria in the brain, (2) Gem strongly inhibits the activation of NF‐κB, AP‐1, and C/EBPβ in cytokine‐stimulated astroglial cells, which are known to increase the expression of iNOS and the production of NO in response to proinflammatory cytokines, (3) Gem protects dopamine neurons in the MPTP mouse model of PD by increasing the expression of PPARα, which in turn stimulates the production of GDNF in astrocytes, (4) Gem reduces amyloid plaque pathology, reduces the activity of glial cells, and improves memory, (5) Gem increases myelin genes expression (MBP and CNPase) via PPAR‐β, and (6) Gem increases hippocampal BDNF to counteract depression. Conclusion: According to the study, Gem was investigated for its potential therapeutic effect in NDs. Further research is needed to fully understand the therapeutic potential of Gem in NDs. [ABSTRACT FROM AUTHOR]

This article presents a comparative study on the benefits of different treatments for rats with streptozotocin-induced diabetes. The study found that a combination therapy of insulin, rosiglitazone, and gemfibrozil was more effective in controlling blood sugar and lipid levels compared to individual treatments. The combination therapy also had a positive effect on lipid levels, reducing cholesterol and triglycerides while increasing HDL. The study suggests that this combination therapy may help prevent cardiovascular events associated with diabetes. [Extracted from the article]

Introduction: Increased blood lipids are an important factor in the occurrence of cardiovascular diseases and heart attacks in humans. The aim of this study is to compare the effect of the traditional medicine product Lipexan with placebo along with Gemfibrozil on blood lipid indicators. Material and methods: This study was conducted as a double-blind randomized clinical trial with a parallel design, on 109 patients with hyperlipidemia. After entering the study, patients were randomly divided into two groups receiving Lipexan herbal capsules (containing garlic, sumac, apple cider vinegar, fenugreek and dill) and placebo capsules. Both groups received Gemfibrozil capsules at the same time and were prescribed the same diet. The duration of treatment was 40 days. The lipid profile of the patients was checked before and after taking the drugs. Results: In the Lipexan drug treatment group, the average blood triglyceride before taking the drug was 362.2 mg/dl, which reached 243.1 mg/dl after taking the drug. Also, the average blood cholesterol before and after taking the drug was 201.4 and 187.7, respectively. Statistically, there was a significant decrease in triglyceride, total cholesterol, Low Density Lipoprotein, High Density Lipoprotein, fasting blood sugar and alkaline Phosphatase after taking Lipexan drug (P<0.05). Conclusion: The present study shows that Lipexan herbal capsule is effective in reducing blood fats and lipid profile in hyperlipidemia patients compared to placebo capsule. [ABSTRACT FROM AUTHOR]

Diabetes-associated cognitive dysfunction (DACD) is considered a significant complication of diabetes and manifests as cognitive impairment. Astrocytes are vital to the brain energy metabolism and cerebral antioxidant status. Ferroptosis has been implicated in cognitive impairment, but it is unclear whether the ferroptosis of astrocytes is involved in the progression of DACD. PPARA/PPARα (peroxisome proliferator-activated receptor alpha) is a transcription factor that regulates glucose and lipid metabolism in the brain. In this study, we demonstrated that high glucose promoted ferroptosis of astrocytes by disrupting iron metabolism and suppressing the xCT/GPX4-regulated pathway in diabetic mice and astrocytes cultured in high glucose. Administration of gemfibrozil, a known PPARα agonist, inhibited ferroptosis and improved memory impairment in db/db mice. Gemfibrozil also prevented the accumulation of lipid peroxidation products and lethal reactive oxygen species induced by iron deposition in astrocytes and substantially reduced neuronal and synaptic loss. Our findings demonstrated that ferroptosis of astrocytes is a novel mechanism in the development of DACD. Additionally, our study revealed the therapeutic effect of gemfibrozil in preventing and treating DACD by inhibiting ferroptosis. [ABSTRACT FROM AUTHOR]

Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO2)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO2 levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver. [ABSTRACT FROM AUTHOR]

It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor α (PPARα), here, we established that oral administration of gemfibrozil preserved the integrity of blood–brain barrier (BBB) and blood–spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα–/– mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARβ (formerly PPARδ), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα–/– EAE mice, but not PPARβ–/– EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα.

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Background: Severe community-acquired pneumonia is one of the most lethal forms of CAP with high mortality. For rapid and accurate decisions, we developed a mortality prediction model specifically tailored for elderly SCAP patients., Methods: The retrospective study included 2365 elderly patients. To construct and validate the nomogram, we randomly divided the patients into training and testing cohorts in a 70% versus 30% ratio. The primary outcome was in-hospital mortality. Univariate and multivariate logistic regression analyses were used in the training cohort to identify independent risk factors. The robustness of this model was assessed using the C index, ROC and AUC. DCA was employed to evaluate the predictive accuracy of the model., Results: Six factors were used as independent risk factors for in-hospital mortality to construct the prediction model, including age, the use of vasopressor, chronic renal disease, neutrophil, platelet, and BUN. The C index was 0.743 (95% CI 0.719-0.768) in the training cohort and 0.731 (95% CI 0.694-0.768) in the testing cohort. The ROC curves and AUC for the training cohort and testing cohort (AUC = 0.742 vs. 0.728) indicated a robust discrimination. And the calibration plots showed a consistency between the prediction model probabilities and observed probabilities. Then, the DCA demonstrated great clinical practicality., Conclusions: The nomogram incorporated six risk factors, including age, the use of vasopressor, chronic renal disease, neutrophil, platelet and BUN, which had great predictive accuracy and robustness, while also demonstrating clinical practicality at ICU admission., (© 2024. The Author(s).)

Background/aims: There may be many predictors of anticoagulation-related gastrointestinal bleeding (GIB), but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify all risk factors for anticoagulant-associated GIB to inform risk prediction in the management of anticoagulation- related GIB., Methods: A systematic review and meta-analysis were conducted to search PubMed, EMBASE, Web of Science, and Cochrane Library databases (from inception through January 21, 2022) using the following search terms: anticoagulants, heparin, warfarin, dabigatran, rivaroxaban, apixaban, DOACs, gastrointestinal hemorrhage, risk factors. According to inclusion and exclusion criteria, studies of risk factors for anticoagulation-related GIB were identified. Risk factors for anticoagulant-associated GIB were used as the outcome index of this review., Results: We included 34 studies in our analysis. For anticoagulant-associated GIB, moderate-certainty evidence showed a probable association with older age, kidney disease, concomitant use of aspirin, concomitant use of the antiplatelet agent, heart failure, myocardial infarction, hematochezia, renal failure, coronary artery disease, helicobacter pylori infection, social risk factors, alcohol use, smoking, anemia, history of sleep apnea, chronic obstructive pulmonary disease, international normalized ratio (INR), obesity et al. Some of these factors are not included in current GIB risk prediction models. such as anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction, etc., Conclusion: The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.