ABSTRACT
Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.
Subject(s)
Lipoxins , Macrophages , Neutrophils , Spleen , Animals , Neutrophils/metabolism , Neutrophils/drug effects , Macrophages/metabolism , Mice , Humans , Lipoxins/metabolism , Lipoxins/pharmacology , Spleen/metabolism , Spleen/cytology , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/pharmacology , Eicosapentaenoic Acid/metabolism , Mice, Inbred C57BL , Phagocytosis , Male , Inflammation/metabolism , Heptanoic AcidsABSTRACT
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex gastrointestinal condition influenced by genetic, microbial, and environmental factors, among which the gut microbiota plays a crucial role and has emerged as a potential therapeutic target. Ganoderic acid A (GAA), which is a lanostane triterpenoid compound derived from edible mushroom Ganoderma lucidum, has demonstrated the ability to modulate gut dysbiosis. Thus, we investigated the impact of GAA on IBD using a dextran sodium sulfate (DSS)-induced colitis mouse model. GAA effectively prevented colitis, preserved epithelial and mucus layer integrity, and modulated the gut microbiota. In addition, GAA promoted tryptophan metabolism, especially 3-IAld generation, activated the aryl hydrocarbon receptor (AhR), and induced IL-22 production. Fecal microbiota transplantation validated the mediating role of the gut microbiota in the IBD protection conferred by GAA. Our study suggests that GAA holds potential as a nutritional intervention for ameliorating IBD by influencing the gut microbiota, thereby regulating tryptophan metabolism, enhancing AhR activity, and ultimately improving gut barrier function.
Subject(s)
Gastrointestinal Microbiome , Inflammatory Bowel Diseases , Lanosterol , Receptors, Aryl Hydrocarbon , Tryptophan , Animals , Humans , Male , Mice , Bacteria/classification , Bacteria/metabolism , Bacteria/genetics , Bacteria/isolation & purification , Bacteria/drug effects , Disease Models, Animal , Gastrointestinal Microbiome/drug effects , Heptanoic Acids , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/microbiology , Interleukin-22 , Lanosterol/analogs & derivatives , Lanosterol/pharmacology , Mice, Inbred C57BL , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Aryl Hydrocarbon/genetics , Tryptophan/metabolismABSTRACT
OBJECTIVE: Ganoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study aims to elucidate the underlying molecular mechanisms through proteomic analysis. METHODS: C57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels. RESULTS: Chronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment. CONCLUSION: GAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.
Subject(s)
Behavior, Animal , Depression , Disease Models, Animal , Lanosterol , Mice, Inbred C57BL , Prefrontal Cortex , Proteomics , Social Defeat , Stress, Psychological , Animals , Mice , Stress, Psychological/drug therapy , Stress, Psychological/metabolism , Depression/drug therapy , Depression/metabolism , Male , Prefrontal Cortex/metabolism , Prefrontal Cortex/drug effects , Behavior, Animal/drug effects , Lanosterol/analogs & derivatives , Lanosterol/pharmacology , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Imipramine/pharmacology , Doublecortin Protein , Heptanoic AcidsABSTRACT
Statin-induced immune-mediated necrotising myopathy (IMNM) is an inflammatory myopathy that can present as proximal muscle weakness and, in some cases, as dysphagia and respiratory distress. In this report, we present a case of statin-induced IMNM in a 78-year-old male. The patient had significantly high levels of creatinine kinase and myoglobinuria and experienced gradual weakness in the proximal muscles for 1 month after initiating a 20 mg dose of Atorvastatin 10 months before admission. Rapid clinical improvement was observed with the use of high-dose glucocorticoids in conjunction with methotrexate.
Subject(s)
Atorvastatin , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Myositis , Humans , Male , Aged , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Myositis/chemically induced , Myositis/drug therapy , Atorvastatin/therapeutic use , Atorvastatin/adverse effects , Methotrexate/therapeutic use , Methotrexate/adverse effects , Pyrroles/adverse effects , Pyrroles/therapeutic use , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Heptanoic Acids/adverse effects , Heptanoic Acids/therapeutic use , Necrosis/chemically induced , Glucocorticoids/therapeutic use , Muscular Diseases/chemically induced , Muscular Diseases/drug therapyABSTRACT
INTRODUCTION: Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects. METHODS: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range. RESULTS: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158-1.0089)/0.9965 (0.9550-1.0397) and 1.0033 (0.9800-1.0271)/1.0067 (0.9798-1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953-1.0294)/0.9851 (0.9368-1.0359) and 1.0198 (0.9950-1.0453)/1.0003 (0.9694-1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814-1.2797 and 0.7415-1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082-1.1003)/1.0252 (0.9841-1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418-1.1997)/0.9888 (0.8792-1.1120) in studies 1 and 2, respectively. CONCLUSION: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations. TRIAL REGISTRATION: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.
Subject(s)
Amlodipine , Atorvastatin , Benzimidazoles , Biphenyl Compounds , Cross-Over Studies , Drug Combinations , Tetrazoles , Humans , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/administration & dosage , Amlodipine/pharmacokinetics , Amlodipine/administration & dosage , Benzimidazoles/pharmacokinetics , Benzimidazoles/administration & dosage , Tetrazoles/pharmacokinetics , Tetrazoles/administration & dosage , Male , Adult , Female , Atorvastatin/pharmacokinetics , Atorvastatin/administration & dosage , Young Adult , Area Under Curve , Middle Aged , Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/administration & dosage , Therapeutic Equivalency , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/administration & dosage , Heptanoic Acids/pharmacokinetics , Heptanoic Acids/administration & dosage , Healthy VolunteersSubject(s)
Heptanoic Acids , Odorants , Perfume , Animals , Humans , Consumer Product Safety , Databases, Chemical , Endpoint Determination , No-Observed-Adverse-Effect Level , Pentanoic Acids/toxicity , Pentanoic Acids/chemistry , Perfume/toxicity , Perfume/chemistry , Risk Assessment , Toxicity Tests , Heptanoic Acids/chemistry , Heptanoic Acids/toxicityABSTRACT
BACKGROUND: Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages. METHODS AND RESULTS: Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90]). CONCLUSIONS: Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.
Subject(s)
Amlodipine , Atorvastatin , Drug Combinations , Heptanoic Acids , Hypercholesterolemia , Hypertension , Pyrroles , Humans , Amlodipine/administration & dosage , Amlodipine/adverse effects , Male , Hypercholesterolemia/drug therapy , Hypercholesterolemia/complications , Hypercholesterolemia/epidemiology , Hypertension/drug therapy , Hypertension/complications , Hypertension/epidemiology , Female , Middle Aged , Atorvastatin/administration & dosage , Aged , Taiwan/epidemiology , Treatment Outcome , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/adverse effects , Retrospective Studies , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/therapeutic use , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/adverse effects , Calcium Channel Blockers/therapeutic use , Blood Pressure/drug effectsABSTRACT
Breast cancer is one of the most common female malignant tumors, with triple-negative breast cancer (TNBC) being the most specific, highly invasive, metastatic and associated with a poor prognosis. Our previous study showed that the natural product ganoderic acid A (GAA) has a certain affinity for MDM2. In this study, two series of novel GAA PROTACs C1-C10 and V1-V10 were designed and synthesized for the treatment of breast cancer. The antitumor activity of these compounds was evaluated against four human tumor cell lines (MCF-7, MDA-MB-231, SJSA-1, and HepG2). Among them, V9 and V10 showed stronger anti-proliferative effects against breast cancer cells, and V10 showed the best selectivity in MDA-MB-231 cells (TNBC), which was 5-fold higher than that of the lead compound GAA. Preliminary structure-activity analysis revealed that V-series GAA PROTACs had better effects than C-series, and the introduction of 2O-4O PEG linkers could significantly improve the antitumor activity. Molecular docking, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and Western blot researches showed that both V9 and V10 could bind with MDM2, and degrade the protein through the ubiquitin-proteasome system. Molecular dynamics simulation (MD) revealed that V10 is a bifunctional molecule that can bind to von Hippel-Lindau (VHL) at one end and target MDM2 at the other. In addition, V10 promoted the upregulation of p21 in p53-mutant MDA-MB-231 cells, and induced apoptosis via down-regulation of the bcl-2/bax ratio and the expression of cyclin B1. Finally, in vivo experiments showed that, V10 also exhibited good tumor inhibitory activity in xenografted TNBC zebrafish models, with an inhibition rate of 27.2% at 50 µg/mL. In conclusion, our results suggested that V10 has anti-tumor effects on p53-mutant breast cancer in vitro and in vivo, and may be used as a novel lead compound for the future development of TNBC.
Subject(s)
Heptanoic Acids , Lanosterol/analogs & derivatives , Proto-Oncogene Proteins c-mdm2 , Triple Negative Breast Neoplasms , Animals , Female , Humans , Proto-Oncogene Proteins c-mdm2/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Tumor Suppressor Protein p53/metabolism , Molecular Docking Simulation , Zebrafish/metabolism , Cell Line, Tumor , Cell Proliferation , ApoptosisSubject(s)
Atorvastatin , Pulmonary Alveolar Proteinosis , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor , Humans , Pulmonary Alveolar Proteinosis/drug therapy , Atorvastatin/therapeutic use , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Male , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Heptanoic Acids/therapeutic use , Female , Pyrroles/therapeutic use , Treatment Outcome , ChildABSTRACT
Perfluorinated compounds (PFCs), organofluoride compounds comprising carbon-fluorine and carbon-carbon bonds, are used as water and oil repellents in textiles and pharmaceutical tablets; however, they are associated with potential neurotoxic effects. Moreover, the impact of PFCs on neuronal survival, activity, and regulation within the brain remains unclear. Additionally, the mechanisms through which PFCs induce neuronal toxicity are not well-understood because of the paucity of data. This study elucidates that perfluorooctanoic acid (PFOA) and perfluoroheptanoic acid (PFHpA) exert differential effects on the survival and activity of primary cortical neurons. Although PFOA triggers apoptosis in cortical neurons, PFHpA does not exhibit this effect. Instead, PFHpA modifies dendritic spine morphogenesis and synapse formation in primary cortical neuronal cultures, additionally enhancing neural activity and synaptic transmission. This research uncovers a novel mechanism through which PFCs (PFHpA and PFOA) cause distinct alterations in dendritic spine morphogenesis and synaptic activity, shedding light on the molecular basis for the atypical behaviors noted following PFC exposure. Understanding the distinct effects of PFHpA and PFOA could guide regulatory policies on PFC usage and inform clinical approaches to mitigate their neurotoxic effects, especially in vulnerable population.
Subject(s)
Fluorocarbons , Heptanoic Acids , Neurotoxicity Syndromes , Water Pollutants, Chemical , Humans , Water Pollutants, Chemical/analysis , Fluorocarbons/toxicity , Fluorocarbons/analysis , Caprylates/toxicity , Neurons/chemistry , CarbonABSTRACT
Ganoderic acid A (GAA) is one of the major triterpenoids in Ganoderma lucidum (GL). Accumulating evidence has indicated that GAA demonstrates multiple pharmacological effects and exhibits treatment potential for various neurological disorders. Here, the effects and mechanisms of GAA in the treatment of neurological disorders were evaluated and discussed through previous research results. By summarizing previous research results, we found that GAA may play a neuroprotective role through various mechanisms: anti-inflammatory, anti-oxidative stress, anti-apoptosis, protection of nerve cells, and regulation of nerve growth factor. Therefore, GAA is a promising natural neuroprotective agent and this review would contribute to the future development of GAA as a novel clinical candidate drug for treating neurological diseases.
Subject(s)
Heptanoic Acids , Lanosterol/analogs & derivatives , Nervous System Diseases , Neuroprotective Agents , Humans , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Lanosterol/pharmacology , Lanosterol/therapeutic use , Nervous System Diseases/drug therapyABSTRACT
OBJECTIVES: Reportedly, ganoderic acid A (GA-A) increases the sensitivity of hepatocellular carcinoma cells to cisplatin (DDP) chemotherapy. Therefore, this study aims to fathom the influence of GA-A on lung cancer cells. METHODS: After the construction of A549/DDP cells through exposure to DDP, the effects of GA-A on A549 and A549/DDP cells were revealed by cellular functional assays, western blot and quantitative reverse transcription PCR (qRT-PCR). The DDP-resistant lung cancer tumor was established in vivo, followed by further validation of the mechanism of GA-A. RESULTS: GA-A suppressed the viability, migration, and invasion while downregulating Beclin and autophagy marker LC3II/LC3I levels and upregulating P62 levels in A549 and A549/DDP cells. These effects were reversed by circFLNA overexpression. Also, GA-A reinforced the sensitivity of A549/DDP cells to DDP, elevated the apoptosis and regulated the circFLNA/miR-486-3p/cytochrome P450 family 1 subfamily A member 1 (CYP1A1)/X-ray repair cross-complementing 1 (XRCC1) axis. The reversal effects of circFLNA overexpression on GA-A-induced viability and apoptosis of A549/DDP cells could all be counteracted in the presence of 3MA. GA-A inhibited lung cancer tumor growth and blocked autophagy. CONCLUSION: GA-A suppresses autophagy by regulating the circFLNA/miR-486-3p/CYP1A1/XRCC1 axis to strengthen the sensitivity of lung cancer cells to DDP.
Subject(s)
Antineoplastic Agents , Autophagy , Carcinoma, Non-Small-Cell Lung , Heptanoic Acids , Lanosterol , Lung Neoplasms , MicroRNAs , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Autophagy/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Cell Proliferation , Cisplatin/pharmacology , Cytochrome P-450 CYP1A1/drug effects , Cytochrome P-450 CYP1A1/metabolism , Drug Resistance, Neoplasm , Heptanoic Acids/pharmacology , Heptanoic Acids/therapeutic use , Lanosterol/analogs & derivatives , Lanosterol/pharmacology , Lanosterol/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , MicroRNAs/drug effects , MicroRNAs/metabolism , RNA, Circular/drug effects , RNA, Circular/metabolism , X-ray Repair Cross Complementing Protein 1/drug effects , X-ray Repair Cross Complementing Protein 1/metabolismABSTRACT
Synthetic ester oils are widely used in many applications due to their ideal cleaning properties, lubricating performance and assured polarity. The majority of esters oils are more biodegradable. than any other base stock. For instance, oil soluble polyalkyleneglycols (PAGs) or polyalphaolephins (PAOs), are only biodegradable in the lower viscosity grades. The goal of this study is to create some synthetic base oils by two major protocols; the first is esterifying valeric acid with various glycols (ethylene glycol, propylene glycol, butylene glycol and poly (ethylene glycol 400). The second involves esterification of propanoic acid, heptanoic acid, or octanoic acid with ethylene glycol. The reaction yield varies between 85 and 94%. The chemical composition of the prepared esters was examined using various spectroscopic methods (Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The thermal properties investigation by thermo gravimetric analysis (TGA) showed pronounced thermal stability of the prepared esters. The biodegradability was verified versus two bacterial isolates (B1, B2). The results showed that percentage of degradation of the lube oil was in the range of 34% to 84% after 3 days of incubation. Moreover, the rheological study revealed that the prepared esters exhibited Newtonian rheological behaviours. Viscosity examination displayed that the esters based on ethylene glycol, such as (A), had the highest VI: 179 values when compared to those based on higher glycols. Viscosity and viscosity index results showed slight increase as the number of carbon atoms in the acid chain increases. At last, most of the synthesized esters possessed pour points ≤ - 32 °C: ≤ - 40 except in case of using higher acids like heptanoic acid and octanoic acid in preparation the pour point increases to - 9 °C and - 15 °C.
Subject(s)
Esters , Heptanoic Acids , Esters/chemistry , Caprylates , Spectroscopy, Fourier Transform Infrared , Polyethylene Glycols/chemistry , Plant Oils/chemistryABSTRACT
AIMS: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. METHODS AND RESULTS: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. CONCLUSION: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.
Subject(s)
Atorvastatin , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Medication Adherence , Atorvastatin/pharmacokinetics , Atorvastatin/therapeutic use , Atorvastatin/blood , Humans , Male , Female , Middle Aged , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Aged , Heptanoic Acids/pharmacokinetics , Heptanoic Acids/administration & dosage , Heptanoic Acids/blood , Heptanoic Acids/therapeutic use , Pyrroles/pharmacokinetics , Pyrroles/blood , Pyrroles/administration & dosage , Tandem Mass Spectrometry , Chromatography, Liquid , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/blood , Cardiovascular Diseases/prevention & control , Reproducibility of Results , Dose-Response Relationship, DrugABSTRACT
BACKGROUND AND OBJECTIVE: Per- and polyfluoroalkyl substances (PFASs) have been shown to be persistent and bioaccumulative. An elevated danger of pregnancy complications perhaps connected with exposure to PFASs, but the potential effects remain elusive. The objective of this study is to investigate the possible association between PFASs exposure and pregnancy complications, drawing upon existing evidence. METHODS: Electronic databases of PubMed, Qvid Medline, Embase, and Web of Science were searched thoroughly to identify eligible research published prior to November 28, 2023, examining the relationship between PFASs and pregnancy-related complications. To evaluate the quality of observational studies incorporated into the article, the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) tool was utilized. The main outcomes assessed in this study included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), gestational hypertension (GH), and preeclampsia (PE). RESULTS: Twenty-five relevant studies involving 30079 participants were finally selected from four databases. The combined estimates indicate that prenatal exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), and perfluoroenanthic acid (PFHpA) is associated with gestational diabetes mellitus (GDM) (PFOA: OR = 1.45, 95%CI: 1.07-1.94, P = 0.015; PFHxS: OR = 1.16, 95%CI: 1.00-1.36, P = 0.055; PFBS: OR = 1.44, 95%CI: 1.16-1.79, P = 0.001; PFHpA: OR = 1.41, 95%CI: 1.10-1.82, P = 0.008). The exposure to PFBS is positively associated with HDP (OR = 1.27, 95%CI: 1.14-1.41, P < 0.001), while both PFOA and PFHpA demonstrate statistically significant positive correlations with GH (PFOA: OR = 1.09, 95%CI: 1.00-1.19, P = 0.049; PFHpA: OR = 1.43, 95%CI: 1.15-1.78, P = 0.001). Negative correlations were observed for prenatal perfluorododecanoic acid (PFDoA) exposure and GH (OR = 0.71, 95%CI: 0.57-0.87, P = 0.001). However, no compelling evidence was identified to link PFASs exposure with the risk of PE. CONCLUSION: According to the meta-analysis findings, exposure to PFASs may be linked to GDM, HDP, and GH, but it does not significantly raise the risk of PE alone. Further research with larger sample size is required to verify this potential association and explore the biological mechanisms.
Subject(s)
Alkanesulfonic Acids , Caprylates , Diabetes, Gestational , Environmental Pollutants , Fluorocarbons , Heptanoic Acids , Hypertension, Pregnancy-Induced , Pre-Eclampsia , Sulfonic Acids , Pregnancy , Female , Humans , Diabetes, Gestational/chemically induced , Diabetes, Gestational/epidemiology , Environmental Pollutants/toxicity , Hypertension, Pregnancy-Induced/epidemiology , Pre-Eclampsia/chemically induced , Pre-Eclampsia/epidemiology , Fluorocarbons/toxicity , Alkanesulfonic Acids/toxicityABSTRACT
Osteoarthritis (OA) is a prevalent degenerative pathology, however, there exists a lack of cost-effective pharmacological interventions that efficaciously inhibit its progression. ganoderic acid A (GAA), a triterpenoid derived from Ganoderma lucidum, possesses antiapoptotic and -inflammatory effects. Our objective was to better understand the therapeutic effects of GAA on OA as well as to elucidate the underlying mechanisms of its action. To establish an OA cell model in vitro, chondrocytes (CHONs) were treated with interleukin (IL)-1ß. Subsequently, the investigation was conducted afterward according to the following indicators: cell viability, apoptosis, inflammation, and extracellular matrix (ECM) degradation. Western blotting analysis (WB) was employed to assess both endoplasmic reticulum (ER) stress and proteins associated with the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, based on molecular docking studies, GAA exhibits a significant binding competence to p65. OA mouse models were constructed by performing a destabilization medial meniscus (DMM) operation. Moreover, histopathology and immunohistochemistry were used to determine the GAA therapeutic effect in reducing OA in vivo. Our findings revealed that GAA has antiapoptotic, anti-inflammatory, and anti-ECM degradation effects by inhibiting the ER stress and NF-κB axis in CHONs in vitro. Furthermore, our findings suggest that GAA may attenuate the progression of osteoarthritis in vivo. GAA can protect CHONs by regulating apoptosis, ECM changes, and inflammation thereby preventing OA progression. These promising results indicate that GAA may be a therapeutic agent for OA treatment.
Subject(s)
Heptanoic Acids , Lanosterol/analogs & derivatives , NF-kappa B , Osteoarthritis , Mice , Animals , NF-kappa B/metabolism , Molecular Docking Simulation , Osteoarthritis/drug therapy , Osteoarthritis/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Chondrocytes/metabolism , Endoplasmic Reticulum Stress , Interleukin-1beta/metabolism , Cells, CulturedABSTRACT
Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation induced by BBB dysfunction and monocyte infiltration might be responsible for neuron damage and cognitive impairment. Atorvastatin is a lipid-lowering drug that is widely applied for the treatment of cardiovascular diseases. However, the potential function of Atorvastatin in hypercholesterolemia-induced MCI remains uncertain. Our research will explore the potential therapeutic function of Atorvastatin in memory deficits induced by chronic hypercholesterolemia. ApoE-/- mice were utilized to mimic the state of chronic hypercholesterolemia and were divided into four groups. Animals in the WT and ApoE-/-groups were orally administered with normal saline, while WT mice in the Atorvastatin group and ApoE-/- mice in the ApoE-/-+ Atorvastatin group were orally administered with 10 mg/kg/day Atorvastatin. Markedly increased plasma cholesterol levels reduced RI in the long-term memory test and the spatial short-term memory test, declined mobility in the open field test, and downregulated PSD-95 and BDNF were observed in ApoE-/- mice, all of which were signally reversed by Atorvastatin. Moreover, the percentages of brain Ly6Chi CD45+ cells and CD3+ CD45+ cells, as well as the blood Ly6Chi CD45+ cells, plasma IL-12/IL-23 levels and IL-17 level were found notably increased in ApoE-/- mice, all of which were largely repressed by Atorvastatin. Lastly, the increased BBB permeability, decreased ZO-1 and occludin levels, and reduced KLF2 level were markedly abolished by Atorvastatin. Collectively, Atorvastatin mitigated memory deficits and brain monocyte infiltration in ApoE-/- mice.
Subject(s)
Heptanoic Acids , Hypercholesterolemia , Hyperlipidemias , Humans , Mice , Animals , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Hypercholesterolemia/complications , Hypercholesterolemia/drug therapy , Monocytes/metabolism , Heptanoic Acids/pharmacology , Heptanoic Acids/therapeutic use , Pyrroles/pharmacology , Hyperlipidemias/drug therapy , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Brain/metabolismABSTRACT
OBJECTIVES: To compare the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in reducing blood lipid levels. METHODS: Patients with hyperlipidaemia admitted to the cardiac centre between January 2019 and December 2020 were included in the study. A total of 1063 patients with hyperlipidaemia took either Shanhuang Jiangzhi tablets (n = 372) or atorvastatin (n = 691) and met the inclusion and exclusion criteria. Clinical data, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, were retrospectively evaluated after propensity score matching (PSM) analysis. The adverse events were also recorded during the therapy process. RESULTS: Following PSM analysis, both groups were well matched across all parameters. Compared with the baseline, Shanhuang Jiangzhi tablets had greater effects on TC, TG and LDL-C, and the difference was statistically significant (p < 0.001). Furthermore, the results showed that Shanhuang Jiangzhi tablets are similar to atorvastatin in reducing TC and LDL-C, and all p-values were > 0.05. However, the decrease of TG was greater in the Shanhuang Jiangzhi group (p < 0.001). Clinical adverse reactions of Shanhuang Jiangzhi tablets are rare and have no statistical significance compared with atorvastatin (p = 0.682). CONCLUSIONS: Shanhuang Jiangzhi tablets have a higher hypotriglyceridaemic performance than atorvastatin and an equivalent ability to lower TC and LDL-C. In addition, Shanhuang Jiangzhi tablets are a low-risk option for lowering blood lipids.
Subject(s)
Anticholesteremic Agents , Heptanoic Acids , Hyperlipidemias , Humans , Atorvastatin/adverse effects , Hyperlipidemias/drug therapy , Hyperlipidemias/chemically induced , Cholesterol, LDL/therapeutic use , Anticholesteremic Agents/adverse effects , Retrospective Studies , Heptanoic Acids/adverse effects , Pyrroles/adverse effects , Lipids/therapeutic use , Triglycerides , Cholesterol, HDL/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy. METHODS: At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters. RESULTS: Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline. CONCLUSIONS: The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.
Subject(s)
Anticholesteremic Agents , Azetidines , Heptanoic Acids , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Humans , Atorvastatin/therapeutic use , Anticholesteremic Agents/therapeutic use , Cholesterol, LDL , Hypercholesterolemia/drug therapy , Azetidines/therapeutic use , Heptanoic Acids/adverse effects , Pyrroles/therapeutic use , Drug Therapy, Combination , Ezetimibe/therapeutic use , Cholesterol , Treatment Outcome , Double-Blind Method , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic useABSTRACT
PURPOSE: For many years, statins have been the most commonly used drugs in cholesterol-lowering therapy. In addition to these therapeutic effects, statins exhibit other, pleiotropic effects that can be beneficial, but also harmful to cells and tissues. The aim of this research was to determine and compare the pleiotropic effects of structurally different statins: atorvastatin, simvastatin and rosuvastatin at different concentrations on hepatocellular carcinoma (HepG2) cells. MATERIALS AND METHODS: The MTT assay was used to determine the cytotoxic effects of statins. The influence of statins on the production of reactive oxygen species (ROS) was determined by measuring fluorescent response of 2,7-dichlorofluorescein diacetate (DCFH-DA). The effect of statins on glucose production and excretion was determined with glucose production assay. RESULTS: The obtained results confirmed that all tested statins exhibit cytotoxic effects, increase the production of ROS as well as the production and excretion of glucose from HepG2 cells. It was observed that all the mentioned effects are more pronounced with lipophilic statins, atorvastatin and simvastatin compared to hydrophilic rosuvastatin. CONCLUSION: The less pronounced pleiotropic effects of rosuvastatin on HepG2 cells are probably due to differences in structure and solubility compared to atorvastatin and simvastatin. Transporter-dependent and a slower influx of rosuvastatin into cells compared to the tested lipophilic statins probably lead to a weaker accumulation of rosuvastatin in HepG2 cells, which results in less pronounced pleiotropic effects compared to lipophilic atorvastatin and simvastatin.