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BMC Musculoskeletal Disorders Jun 2024Ankylosing spondylitis (AS) with radiographic damage is more prevalent in men than in women. IL-17, which is mainly secreted from peripheral blood mononuclear cells...
BACKGROUND
Ankylosing spondylitis (AS) with radiographic damage is more prevalent in men than in women. IL-17, which is mainly secreted from peripheral blood mononuclear cells (PBMCs), plays an important role in the development of AS. Its expression is different between male and female. However, it is still unclear whether sex dimorphism of IL-17 contribute to sex differences in AS.
METHODS
GSE221786, GSE73754, GSE25101, GSE181364 and GSE205812 datasets were collected from the Gene Expression Omnibus (GEO) database. Differential expressed genes (DEGs) were analyzed with the Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods. CIBERSORTx and EcoTyper algorithms were used for immune infiltration analyses. Machine learning based on the XGBoost algorithm model was used to identify the impact of DEGs. The Connectivity Map (CMAP) database was used as a drug discovery tool for exploring potential drugs based on the DEGs.
RESULTS
According to immune infiltration analyses, T cells accounted for the largest proportion of IL-17-secreting PBMCs, and KEGG analyses suggested an enhanced activation of mast cells among male AS patients, whereas the expression of TNF was higher in female AS patients. Other signaling pathways, including those involving metastasis-associated 1 family member 3 (MAT3) or proteasome, were found to be more activated in male AS patients. Regarding metabolic patterns, oxidative phosphorylation pathways and lipid oxidation were significantly upregulated in male AS patients. In XGBoost algorithm model, DEGs including METRN and TMC4 played important roles in the disease process. we integrated the CMAP database for systematic analyses of polypharmacology and drug repurposing, which indicated that atorvastatin, famciclocir, ATN-161 and taselisib may be applicable to the treatment of AS.
CONCLUSIONS
We analyzed the sex dimorphism of IL-17-secreting PBMCs in AS. The results showed that mast cell activation was stronger in males, while the expression of TNF was higher in females. In addition, through machine learning and the CMAP database, we found that genes such as METRN and TMC4 may promote the development of AS, and drugs such as atorvastatin potentially could be used for AS treatment.
Topics: Humans; Female; Male; Interleukin-17; Spondylitis, Ankylosing; Machine Learning; Leukocytes, Mononuclear; Sex Characteristics; Computational Biology; Databases, Genetic; Gene Expression Profiling
PubMed: 38914997
DOI: 10.1186/s12891-024-07589-6 -
Cell Communication and Signaling : CCS Jun 2024Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating...
BACKGROUND
Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood.
METHODS
Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC.
RESULTS
TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin.
CONCLUSIONS
Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC.
Topics: Triple Negative Breast Neoplasms; Neutrophils; Humans; Animals; CD11b Antigen; Female; Intercellular Adhesion Molecule-1; Mice; Cell Adhesion; Cell Line, Tumor; Disease Progression; Cell Movement
PubMed: 38907234
DOI: 10.1186/s12964-024-01716-5 -
BMC Geriatrics Jun 2024Polypharmacy is a global public health concern. This study aimed to determine the prevalence of polypharmacy and trends in the use of commonly used and potentially...
BACKGROUND
Polypharmacy is a global public health concern. This study aimed to determine the prevalence of polypharmacy and trends in the use of commonly used and potentially inappropriate medications among older Korean patients.
METHODS
Individuals aged ≥ 65 years who were prescribed any medication between 2014 and 2018 were selected from the Korean National Health Information Database. Joinpoint regression analyses were used to determine trends in the age-adjusted polypharmacy rates by age group. The prescription rates of the most commonly used medications and the most commonly used potentially inappropriate medications were analysed by year or age group for patients with polypharmacy using the chi-square and proportion difference tests.
RESULTS
This study included 1,849,968 patients, 661,206 (35.7%) of whom had polypharmacy. Age-adjusted polypharmacy rates increased significantly between 2014 and 2018 (P = 0.046). Among patients with polypharmacy, the most commonly prescribed medications were aspirin (100 mg), atorvastatin, metformin, glimepiride, and rosuvastatin. The most commonly prescribed and potentially inappropriate medications were alprazolam, diazepam, amitriptyline, zolpidem, and dimenhydrinate. There was a significant decrease in the prescription rates for each of these drugs in 2018 compared with 2014 among patients with polypharmacy (all P < 0.001), whereas there was a significant increase in alprazolam prescription among patients aged ≥ 85 years when analysed by age group (P < 0.001).
CONCLUSIONS
This study revealed an increasing prevalence of polypharmacy among older adults. Additionally, it highlighted that the utilisation of commonly prescribed potentially inappropriate medications, such as benzodiazepines and tricyclic antidepressants, has remained persistent, particularly among patients aged ≥ 85 years who practiced polypharmacy. These findings provide evidence-based guidance for the development of robust polypharmacy management strategies to ensure medication safety among older adults.
Topics: Humans; Aged; Republic of Korea; Polypharmacy; Male; Female; Potentially Inappropriate Medication List; Aged, 80 and over; Inappropriate Prescribing
PubMed: 38907201
DOI: 10.1186/s12877-024-05141-8 -
Clinical Cardiology Jun 2024Statins are lipid-lowering drugs with favorable anti-inflammatory effects. This study aimed to explore different statin-based lipid-lowering strategies to reduce... (Comparative Study)
Comparative Study
BACKGROUND
Statins are lipid-lowering drugs with favorable anti-inflammatory effects. This study aimed to explore different statin-based lipid-lowering strategies to reduce high-sensitivity C-reactive protein (hs-CRP).
HYPOTHESIS
The hypothesis is that different statin-based lipid-lowering strategies might reduce hs-CRP.
METHODS
This retrospective study included 3653 patients who underwent percutaneous coronary intervention (PCI). Three statin-based lipid-lowering strategies were investigated, including different types of statins (atorvastatin vs. rosuvastatin), statin combined with ezetimibe therapy (vs. without), and intensive statin therapy (vs. regular). The hs-CRP levels and blood lipid indicators were measured at baseline and after 1-month lipid-lowering therapy. Multivariable linear regression analysis and structural equation mode analysis were conducted to verify the association between different lipid-lowering strategies, Δhs-CRP (%) and ΔLDL-C (%).
RESULTS
Totally, 3653 patients were enrolled with an average age of 63.81 years. Multivariable linear regression demonstrated that statin combined with ezetimibe therapy was significantly associated with decreased Δhs-CRP (%) (β = -0.253, 95% CI: [-0.501 to -0.005], p = 0.045). The increased ΔLDL-C (%) was an independent predictor of elevated levels of Δhs-CRP (%) (β = 0.487, 95% CI: [0.15-0.824], p = 0.005). Furthermore, structural equation model analysis proved that statin combined with ezetimibe therapy (β = -0.300, p < 0.001) and intensive statin therapy (β = -0.032, p = 0.043) had an indirect negative effect on Δhs-CRP via ΔLDL-C.
CONCLUSIONS
Compared with routine statin use, statin combined with ezetimibe therapy and intensive statin therapy could further reduce hs-CRP levels.
Topics: Humans; Male; Retrospective Studies; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; C-Reactive Protein; Coronary Artery Disease; Middle Aged; Biomarkers; Treatment Outcome; Percutaneous Coronary Intervention; Ezetimibe; Drug Therapy, Combination; Aged; Rosuvastatin Calcium; Atorvastatin; Cholesterol, LDL; Anticholesteremic Agents; Dyslipidemias
PubMed: 38895772
DOI: 10.1002/clc.24301 -
Frontiers in Medicine 2024[This corrects the article DOI: 10.3389/fmed.2024.1284199.].
[This corrects the article DOI: 10.3389/fmed.2024.1284199.].
PubMed: 38895189
DOI: 10.3389/fmed.2024.1416622 -
Journal of Chromatography. B,... Jun 2024Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in...
Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.
PubMed: 38878710
DOI: 10.1016/j.jchromb.2024.124196 -
Cureus May 2024Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon genetic disorder that affects small blood vessels in...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon genetic disorder that affects small blood vessels in the brain. It leads to neurological symptoms, disability-adjusted life years, and difficult emotional and physical situations for patients and their families. As unusual brain symptoms appear, it becomes important to understand the different clinical manifestations of CADASIL. Our case report and review examine several cases to demonstrate different presentations and management strategies of CADASIL. A 52-year-old male with a family history of strokes at a young age from his father and paternal grandfather presented to a neurology clinic for left facial droop and drooling. Brain magnetic resonance imaging showed extensive periventricular and subcortical white matter disease, including the external capsule and subcortical white matter of the temporal lobe. Findings were suggestive of small vessel vasculopathy. A cerebral angiogram showed that all large extra- and intracranial vessels were patent without evidence of aneurysm formation. There was no obvious evidence of beading of the distal intracranial vessels. Cerebrospinal fluid studies were normal. The NOTCH3 mutation was sent to test for CADASIL, which came back positive. The patient was started on aspirin (81 mg) and atorvastatin (20 mg) daily. The patient was counseled on the possibility of having an ischemic or hemorrhagic stroke. Aspirin and atorvastatin were continued, a neuropsychological evaluation was ordered, and CADASIL genetic counseling and testing were offered to him and his children. Over several years, patients developed several strokes and seizures due to infarcts. He also developed intraparenchymal hemorrhage complicated by dysphagia, requiring a feeding tube. Due to his severe physical debility, he was discharged to a nursing home for rehabilitation, where he did not improve with therapy and remained bedbound. He was discharged and sent home with his family. CADASIL can present as a diagnostic challenge due to its common presentation with migraines, transient ischemic attacks, and strokes, with or without risk factors. This unique presentation of CADASIL with facial palsy highlights the importance of emerging atypical presentations and the need for a detailed history of neuroimaging, family history, and personal history of neurovascular events. By accurately diagnosing the condition, patients and families can be counseled on the disease course and genetics. Management requires a multidisciplinary approach with neurology, genetic counseling, physical therapy, psychology, and psychiatry if depression or anxiety is present, with the aim of improving the patient's quality of life.
PubMed: 38868233
DOI: 10.7759/cureus.60165 -
European Heart Journal Supplements :... Apr 2024There is a clear demonstration of the inverse linear correlation between LDL cholesterol levels and clinical benefit. However, the timing of the action of lipid-lowering...
There is a clear demonstration of the inverse linear correlation between LDL cholesterol levels and clinical benefit. However, the timing of the action of lipid-lowering drugs is not clear. According to animal studies with recombinant lipoprotein A-1, the composition of atherosclerosis changes within 40 h (with variations in lipid and inflammatory contents). Progression-regression studies of atherosclerosis in humans confirm the data, highlighting a rapid change in the plaque over 5 weeks. The data are also in line with what emerges from the survival curves of the old study comparing atorvastatin 80 mg vs. placebo (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering). The spacing of the curves occurs after only 4 weeks, indicating the precociousness of the favourable effects of powerful statins. Finally, a recent Odyssey analysis compared the risk of cardiac death and coronary revascularization between a group in which alirocumab lowered LDL cholesterol to below 15 mg (Group 1 and in which the drug was therefore stopped) against the subjects in the placebo group (Group 2), applying a propensity score matching. The primary endpoint occurred in a lower percentage of patients in Group 1 (6.4 vs. 8.4%). Furthermore, patients in Group 1 had a significantly lower hazard ratio (HR) for major adverse cardiovascular events [0.72; 95% confidence interval (CI) 0.51-0.997; = 0.047] compared with the entire alirocumab group vs. placebo (HR 0.85; 95% CI 0.78-0.93; < 0.001). According to these preliminary observations, aggressive and early treatment of hypercholesterolaemia in subjects with acute coronary syndrome translates into improved clinical results compared with a strategy that provides for more gradual control. These data will need to be confirmed through further prospective clinical studies and ideally with early conducted atherosclerosis regression studies.
PubMed: 38867873
DOI: 10.1093/eurheartjsupp/suae010 -
Frontiers in Pharmacology 2024Neuroinflammation pathways have been associated with the development of major depressive disorders (MDD). The anti-inflammatory characteristics of statins have been...
Effect of a high dose atorvastatin as added-on therapy on symptoms and serum AMPK/NLRP3 inflammasome and IL-6/STAT3 axes in patients with major depressive disorder: randomized controlled clinical study.
BACKGROUND
Neuroinflammation pathways have been associated with the development of major depressive disorders (MDD). The anti-inflammatory characteristics of statins have been demonstrated to have significance in the pathophysiology of depression.
AIM
To investigate the mechanistic pathways of high dose atorvastatin in MDD.
PATIENTS AND METHODS
This trial included 60 patients with MDD who met the eligibility requirements. Two groups of patients (n = 30) were recruited by selecting patients from the Psychiatry Department. Group 1 received 20 mg of fluoxetine plus a placebo once daily. Group 2 received fluoxetine and atorvastatin (80 mg) once daily. All patients were assessed by a psychiatrist using the Hamilton Depression Rating Scale (HDRS). A HDRS score of ≤7 indicates remission or partial remission [HDRS<17 and>7]. Response was defined as ≥ 50% drop in the HDRS score. The serum concentrations of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP-3), interleukin-6 (IL-6), adenosine monophosphate activated protein kinase (AMPK), and signal transducer and activator of transcription factor-3 (STAT-3) were measured.
RESULTS
The atorvastatin group showed a significant reduction in the levels of all measured markers along with a statistical increase in the levels of AMPK when compared to the fluoxetine group. The atorvastatin group displayed a significant decrease in HDRS when compared to its baseline and the fluoxetine group. The response rate and partial remission were higher in the atorvastatin group than fluoxetine ( = 0.03, and = 0.005), respectively.
CONCLUSION
These results imply that atorvastatin at high doses may be a promising adjuvant therapy for MDD patients by altering the signaling pathways for AMPK/NLRP3 and IL-6/STAT-3.
CLINICAL TRIAL REGISTRATION
clinicaltrials.gov, identifier NCT05792540.
PubMed: 38855751
DOI: 10.3389/fphar.2024.1381523 -
Cureus May 2024Background and objectives Ginsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the...
Background and objectives Ginsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the mechanisms of Re in improving cardiac hypertrophy have not been fully elucidated. This study aimed to investigate the therapeutic effects and underlying mechanism of Re on isoproterenol (ISO)-induced cardiac hypertrophy and . Methods Rats were intraperitoneally injected with ISO 30 mg/kg thrice daily for 14 consecutive days to induce cardiac hypertrophy, and these rats were treated with atorvastatin (ATC, 20 mg/kg) or Re (20 mg/kg or 40 mg/kg) once daily for three days in advance until the end of the experiment. Heart weight index, hematoxylin and eosin staining, and hypertrophy-related fetal gene expression were measured to evaluate the effect of Re on cardiac hypertrophy . Meanwhile, the rat H9c2 cardiomyocyte hypertrophy model was induced by ISO 10 μM for 24 hours. Cell surface area and hypertrophy-related fetal gene expression were determined to assess the effect of Re on ISO-induced cardiomyocyte hypertrophy . The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in both serum and cardiomyocytes were detected by enzymatic colorimetric assays. Furthermore, we chose cholesteryl ester transfer protein (CETP) as a target to explore the influence of Re on CETP expression and through real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. Results Intraperitoneal administration of ISO into rats resulted in increases in cross-sectional cardiomyocyte area, the ratio of heart weight to body weight, the ratio of left ventricular weight to body weight, and the ratio of right ventricular weight to body weight, as well as reactivation of fetal genes; however, treatment with Re or ATC ameliorated most of these hypertrophic responses. Similarly, Re pronouncedly alleviated ISO-induced cardiomyocyte hypertrophy, as evidenced by a decreased cell surface area and downregulation of fetal genes. Moreover, our and data revealed that Re reduced TC, TG, and LDL-C levels, and enhanced HDL-C levels. Re improved cardiac hypertrophy mainly associated with the inhibition of mRNA level and protein expression of CETP, to an extent comparable to that of the classical CETP inhibitor, anacetrapib. Conclusions Our research found that CETP inhibition contributes to the protection of Re against ISO-induced cardiac hypertrophy, which provides evidence for the application of Re for cardiovascular disease treatments.
PubMed: 38854305
DOI: 10.7759/cureus.59942