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Diabetic retinopathy, a leading cause of vision impairment, is marked by microvascular complications in the retina, including pericyte loss, a key indicator of early-stage disease. This study explores the therapeutic potential of exosomes derived from immortalized adipose-mesenchymal stem cells differentiated into pericyte-like cells in restoring the function of mouse retinal microvascular endothelial cells damaged by high glucose conditions, thereby contributing to the understanding of early diabetic retinopathy intervention strategies. To induce immortalized adipose-mesenchymal stem cells differentiation into pericyte-like cells, the study employed pericyte growth supplement. And confirmed the success of cell differentiation through the detection of α-smooth muscle actin and neural/glial antigen 2 expression by western blot and immunofluorescence. Exosomes were isolated from the culture supernatant of immortalized adipose-mesenchymal stem cells using ultracentrifugation and characterized through Western blot for exosomal markers (CD9, CD81, and TSG101), transmission electron microscopy, and nanoparticle tracking analysis. Their influence on mouse retinal microvascular endothelial cells under high glucose stress was assessed through various functional assays. Findings revealed that exosomes, especially those from pericyte-like immortalized adipose-mesenchymal stem cells, were efficiently internalized by retinal microvascular endothelial cells and effectively counteracted high glucose-induced apoptosis. These exosomes also mitigated the rise in reactive oxygen species levels and suppressed the migratory and angiogenic properties of retinal microvascular endothelial cells, as demonstrated by Transwell and tube formation assays, respectively. Furthermore, they preserved endothelial barrier function, reducing hyperglycemia-induced permeability. At the molecular level, qRT-PCR analysis showed that exosome treatment modulated the expression of critical genes involved in angiogenesis (VEGF-A, ANG2, MMP9), inflammation (IL-1ß, TNF-α), gap junction communication (CX43), and cytoskeletal regulation (ROCK1), with the most prominent effects seen with exosomes from pericyte-like immortalized adipose-mesenchymal stem cells. High glucose increased the expression of pro-angiogenic and pro-inflammatory markers, which were effectively normalized post-exosome treatment. In conclusion, this research highlights the reparative capacity of exosomes secreted by pericyte-like differentiated immortalized adipose-mesenchymal stem cells in reversing the detrimental effects of high glucose on retinal microvascular endothelial cells. By reducing apoptosis, oxidative stress, inflammation, and abnormal angiogenic behavior, these exosomes present a promising avenue for therapeutic intervention in early diabetic retinopathy. Future studies can focus on elucidating the precise molecular mechanisms and exploring their translational potential in vivo.
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Toxoplasmosis is a significant global zoonosis with devastating impacts, and an effective vaccine against toxoplasmosis for humans has not yet been developed. In this study, we designed and formulated a novel DNA vaccine encoding the inhibitor of STAT1 transcriptional activity (IST) of T. gondii utilizing the eukaryotic expression vector pEGFP-N1 for the first time, with CL264 being a molecular adjuvant. Following intramuscular injection of the vaccine into mice, the levels of antibodies and cytokines were assessed to evaluate the immune response. Additionally, mice were challenged with highly virulent RH-strain tachyzoites of T. gondii, and their survival time was observed. The results show that the levels of IgG in serum, the ratio of IgG2a/IgG1 and the levels of IFN-γ in splenocytes of mice were significantly higher in the pEGFP-TgIST group and the pEGFP-TgIST + CL264 group than in the control group. In addition, the proportion of CD4+/CD8+ T cells was higher in mice immunized with either the pEGFP-TgIST group (p < 0.001) or the pEGFP-TgIST + CL264 group (p < 0.05) compared to the three control groups. Notably, TgIST-immunized mice exhibited prolonged survival times after T. gondii RH strain infection (p < 0.05). Our findings collectively demonstrate that the TgIST DNA vaccine elicits a significant humoral and cellular immune response and offers partial protection against acute T. gondii infection in the immunized mice, which suggests that TgIST holds potential as a candidate for further development as a DNA vaccine.
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BACKGROUND: The pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PURPOSE: This study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). METHODS: High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. RESULTS: A total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. CONCLUSION: XKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.
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ETHNOPHARMACOLOGICAL RELEVANCE: For numerous years, the Xiehuo Xiaoying decoction (XHXY), a traditional Chinese medicine formula, has demonstrated substantial promise in treating Graves' disease (GD) in clinical settings, showcasing significant potential. However, the therapeutic mechanism and efficacy material basis of XHXY remains obscure. AIM OF THE STUDY: This work aims to investigate the underlying mechanisms and to study the efficacy material basis of XHXY in anti-GD effect using a combination of TMT quantitative proteomics and molecular docking method. MATERIALS AND METHODS: GD model was initiated by administering Ad-TSH289. Subsequently, the mice underwent a four-week regimen that included oral gavage of XHXY at doses of 17 g/kg·d and 34 g/kg·d, along with intraperitoneal injections of Gentiopicroside (GPS). Utilizing the principles of pharmacological chemistry in traditional Chinese medicine, we employed high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-QTOF/MS) to discern prescribed prototype composition of XHXY in serum samples from mouse. TMT proteomics research provided evidence of XHXY's putative targets and important pathways in vivo. The binding activity of probable action targets and prototype composition was detected by molecular docking. Finally, Immunohistochemistry (IHC) and TUNEL staining were used to verify the mechanism of XHXY and GPS in anti-GD. RESULTS: XHXY and GPS alleviated GD by ameliorating the pathological changes and reducing thyroxine and TRAb levels. In mouse serum, a total of 31 prototypical XHXY ingredients were detected, and the majority of these components were from monarch and minister medicine. Proteomics study results indicated that the XHXY may mainly regulate targets including FAS-associated death domain protein (FADD), Apolipoprotein C-III, etc. and main pathways are Apoptosis, Cholesterol metabolism, TNF signalling pathway, etc. Strong binding activity of the prototypical active ingredient and GPS towards FADD, Caspase 8, and Caspase 3 was demonstrated by molecular docking. XHXY and its primary component, GPS, elevated the expression of FADD, Caspase 8, and Caspase 3, and enhance apoptosis in thyroid cells, as lastly validated by TUNEL and IHC staining. CONCLUSIONS: XHXY exhibits a favorable therapeutic effect in treating GD by promoting apoptosis in thyroid cells through the upregulation of FADD, Caspase 8, and Caspase 3 expression. And GPS is the main efficacy material basis for its therapeutic effect in anti-GD.
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Medicamentos Herbarios Chinos , Enfermedad de Graves , Animales , Ratones , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Simulación del Acoplamiento Molecular , Proteómica , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/metabolismo , Apoptosis , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Coke used as a filler to treat imidacloprid (IMI) wastewater by both adsorption biological coupling and microbial electrolysis cells (MEC)-adsorption biological coupling technologies, the removal efficiencies on pollutions in wastewater containing IMI were investigated, and the key functional genes related to IMI degradation pathways were also revealed. Results showed that the removal rates of COD, ammonia nitrogen, TP, and IMI under the adsorption biological coupling treatment and MEC-adsorption biological coupling treatment were 94.61-95.54%, 93.37-95.79%, 73.69-83.80%, and 100%, respectively. MEC increased the relative abundance of Proteobacteria by 9.01% and transformed the dominant bacteria from Lysobacter and Reyranella to Brevundimonas and Aquincola. Moreover, MEC up-regulated the abundance of the coding genes PK (9.30%), narG (2.26%), pstS (3.63%), and phnD (1.32%), and converted the IMI degradation products to smaller molecular weight C6H8N2 and C6H6ClNO. This study provided an important reference information for efficient treatment of IMI wastewater using the MEC-adsorption biological coupling technology.
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Eliminación de Residuos Líquidos , Aguas Residuales , Eliminación de Residuos Líquidos/métodos , Adsorción , ElectrólisisRESUMEN
Objective: It remains controversial whether to extend the course of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). We conducted a study to investigate the benefits and risks of applying DAPT for different durations after PCI in acute coronary syndromes (ACS) patients in China. What's more, we explored the efficacy of extended DAPT regimen based on ticagrelor. Methods: This single-center prospective cohort study used data obtained from the PHARM-ACS Patient Registration Database. We included all patients who were discharged between April and December 2018. All patients had at least 18 months of follow-up. Patients were divided into two groups according to the duration of DAPT: a 1-year group and a >1-year group. Potential bias between the two groups was adjusted for by propensity score matching using logistic regression. The primary outcomes were major adverse cardiovascular and cerebrovascular events (MACCE), defined as a composite of death, myocardial infarction, and stroke occurring from 12 months after discharge to follow-up visit. The safety endpoint was any significant bleeding event (BARC ≥ 2). Results: Of 3,205 patients enrolled, 2,201 (68.67%) had DAPT prolonged beyond one year. A total of 2,000 patients were successfully propensity score-matched; patients who received DAPT > 1-year (n = 1000), compared with DAPT = 1-year patients (n = 1000), had a similar risk of MACCE (adjusted HR 0.23, 95% CI 0.05-1.10) and significant bleeding events (adjusted HR 0.63, 95% CI 0.32-1.24). The DAPT > 1-year group had a higher risk of revascularization (adjusted HR 3.36, 95% CI 1.64-6.87). Conclusion: Prolonged DAPT may not be of sufficient benefit to ACS patients within 12-18 months after the index PCI to offset the increased risk of significant bleeding events.
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Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/cirugía , Intervención Coronaria Percutánea/efectos adversos , Estudios Prospectivos , Ticagrelor/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Resultado del TratamientoRESUMEN
ABSTRACT: Statins are considered the cornerstone of secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD). However, many patients fail to achieve the guide-recommended goal of low-density lipoprotein cholesterol (LDL-C) after statin monotherapy, leading to a high residual risk of cardiovascular events. Owing to individual differences in statin therapy, it is possible first to consider changing the type of statin before adding nonstatin medications in certain patients to improve LDL-C management. We developed and evaluated a statin recommendation system using real-world data. Ensemble learning was performed to develop the recommendation system that integrated the output results of support vector machines (SVM) and the similarity of patients. Model performance was assessed to investigate whether treatment according to the recommended model would increase the proportion of patients with the primary end point. Finally, a total of 3510 patients were enrolled in the development and validation of the recommender system. Of them, 1240 patients received atorvastatin (35.3%), 1714 patients received rosuvastatin (48.8%), and 556 patients received pitavastatin (15.8%). The statin recommendation system could significantly improve LDL-C target rate achievement in the recommended treatment group compared with the nonrecommended treatment group in the validation set (50.8% vs. 31.5%, P < 0.001). This study demonstrated that the statin recommendation system could significantly improve the achievement of LDL-C goals in ASCVD patients, providing a new approach to improve LDL-C management.
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Aterosclerosis , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , LDL-Colesterol , Prevención Secundaria , Rosuvastatina Cálcica/efectos adversos , Atorvastatina/efectos adversos , Aterosclerosis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
ABSTRACT: Platelet function test (PFT) is universally used to assess platelet reactivity to antiplatelet drugs in patients after percutaneous coronary intervention (PCI). However, it remains controversial whether individualized antiplatelet therapy guided by PFT can improve the prognosis in patients after PCI. This meta-analysis was conducted to explore the efficacy and safety of individualized antiplatelet therapy guided by PFT in patients after PCI. Studies that compared PFT-guided antiplatelet therapy with standard antiplatelet therapy were researched. The risks of major adverse cardiovascular and cerebrovascular events (MACCE) and major bleeding events were assessed. Pooled odds ratios (ORs) with 95% CIs were obtained. Finally, a total of 16,835 patients from 22 studies met the criteria and were included in the meta-analysis. Compared with standard antiplatelet therapy, individualized antiplatelet therapy guided by PFT significantly decreased the risk of MACCE (OR: 0.58, 95% CI: 0.43-0.77) in patients after PCI. There was no significant difference in major bleeding events (OR: 0.85, 95% CI: 0.70-1.05, P = 0.13). This study identified that PFT-guided individualized antiplatelet therapy could reduce the incidence of MACCE without increasing the risk of hemorrhage in patients after PCI.
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Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Resultado del Tratamiento , Pruebas de Función Plaquetaria , Hemorragia/tratamiento farmacológicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Xiehuo Xiaoying decoction (XHXY) has shown great potential in the treatment of GD, but its mechanism remains obscure. Increase of follicular helper T (Tfh) cells and reduction of follicular regulatory T (Tfr) cells contribute to a high thyrotropin receptor antibodies (TRAb) level and possible Graves' disease (GD). Oxidative stress (OS) disrupts T helper cell differentiation and aggravates autoimmunity. AIM OF THE STUDY: This study aimed to investigate whether XHXY decoction can ameliorate autoimmunity in GD via inhibiting OS and regulating Tfh and Tfr cells. MATERIALS AND METHODS: The main XHXY bioactive compounds were identified using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. GD was induced in the mice through three intramuscular injections of adenovirus expressing the TSH receptor. Then, the mice received oral gavage of XHXY (17 g/kg·d) and 34 g/kg·d) for 4 weeks. OS indicators were assessed. Flow cytometry was used to confirm the proportion of Tfh and Tfr cells in the lymph nodes and spleens of the mice. Cytokine expression levels were determined using enzyme-linked immunosorbent assay. Factors including interleukin-21, B-cell lymphoma-6, and forkhead box P3 (Foxp3) were detected using quantitative polymerase chain reaction. The mRNA and protein expression levels of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid-2-related factor 2 (Nrf2), and haem oxygenase 1 (HO-1) were detected using quantitative polymerase chain reaction and Western blotting, respectively. RESULTS: Twelve main ingredients of XHXY were identified. XHXY relieved GD by lowering thyroxine (p < 0.01) and TRAb levels (p < 0.01). XHXY ameliorated OS by decreasing the levels of NADPH oxidase 2 (p < 0.05), 4-hydroxynonenal (p < 0.01), and 8-oxo-2'-deoxyguanosine (p < 0.001). It inhibited Tfh cell expansion (p < 0.05), as well as the production of cytokine interleukin -21 (p < 0.01), interleukin -4 (p < 0.01) and transcription factor B-cell lymphoma 6 (p < 0.05). XHXY also induced Tfr cell amplification (p < 0.05), increased the production of interleukin -10 (p < 0.05) and transforming growth factor ß (p < 0.05) and the mRNA levels of Foxp3 (p < 0.05). Finally, the Tfh/Tfr ratio returned to normal. In addition, XHXY activated Nrf2 and HO-1 expression, but inhibited Keap1 activation. CONCLUSIONS: XHXY relieves autoimmunity in GD via inhibiting Tfh cell amplification and Tfr cell reduction, a mechanism which probably involves the Keap1/Nrf2 signaling pathway.
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Enfermedad de Graves , Linfoma de Células B , Animales , Ratones , Citocinas/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/metabolismo , Interleucinas/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Linfoma de Células B/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , ARN Mensajero/metabolismo , Células T Auxiliares Foliculares , Linfocitos T Colaboradores-Inductores , Linfocitos T Reguladores , Medicina Tradicional ChinaRESUMEN
BACKGROUND: The first 3 months after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) is a high-risk period for adverse events, including ischemic and bleeding events, which decrease greatly with time. It is worth investigating whether the use of potent P2Y12 inhibitors is necessary after the early stage. The purpose of this study was to investigate the differences in clinical outcomes between clopidogrel and ticagrelor in stable patients without ischemic or major bleeding events during the first 3 months after PCI. METHODS: Data for this study were obtained from the PHARM-ACS registry (NCT04184583). Patients who were free from ischemic and major bleeding events in the first 3 months after PCI were enrolled. Inverse probability of treatment weighting (IPTW) and Cox proportional hazards model were applied to compare the differences in clinical outcomes between the 2 groups. Major adverse cardiovascular and cerebrovascular events (MACCE) were considered the primary end point, and major bleeding was considered the secondary end point. RESULTS: A total of 6662 patients were included in this study. Of these, 3465 were treated with clopidogrel plus aspirin (clopidogrel group) and 3197 with ticagrelor plus aspirin (ticagrelor group). There were no significant differences in MACCE after IPTW adjustment for baseline variables (IPTW-adjusted HR, 1.06; 95% CI, 0.90-1.25) or major bleeding events (IPTW-adjusted HR, 0.97; 95% CI, 0.67-1.41) between the 2 groups. However, the incidence of minor bleeding in the clopidogrel group was significantly lower than that in the ticagrelor group (IPTW-adjusted HR, 0.65; 95% CI, 0.59-0.71). CONCLUSION: In patients with ACS who were free from ischemic or major bleeding events during the first 3 months after PCI, the subsequent clopidogrel treatment might reduce minor bleeding events without increasing the risk of MACCE compared with ticagrelor. However, the results still need to be confirmed by large randomized controlled studies in the future.
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Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Humanos , Clopidogrel/efectos adversos , Ticagrelor/efectos adversos , Síndrome Coronario Agudo/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Resultado del Tratamiento , Hemorragia/inducido químicamente , Aspirina/uso terapéutico , Isquemia/tratamiento farmacológico , Sistema de RegistrosRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Antiestrogen agents have been reported to enhance the anticoagulant activity of warfarin. The use of tamoxifen with warfarin has been contraindicated. However, warfarin in combination with toremifene has not been reported. We report a case in which warfarin was combined with toremifene and applied warfarin dose prediction models to predict the dose of warfarin. CASE SUMMARY: We report the case of a 50-year-old woman with a history of breast cancer, who underwent long-term toremifene therapy after mastectomy. The patient was treated with warfarin after prosthetic valve replacement and had a fluctuating international normalized ratio (INR) following the concomitant administration of toremifene. We applied the warfarin dose prediction model to adjust the warfarin dose during treatment. Finally, her INR stabilized with a lower dose of warfarin, and there was no serious bleeding during the 1-year follow-up. WHAT IS NEW AND CONCLUSION: Warfarin does not have a serious interaction with toremifene in this case, but it needed about 37.5% dose reduction which was comparable to the interaction of some common antibiotics with warfarin.
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Neoplasias de la Mama , Warfarina , Femenino , Humanos , Persona de Mediana Edad , Anticoagulantes , Toremifeno , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Mastectomía , Relación Normalizada InternacionalRESUMEN
Purpose: Previous trials have demonstrated that ticagrelor was superior to clopidogrel in acute coronary syndrome (ACS) patients. However, several recent studies showed that ticagrelor was associated with a significantly higher risk of bleeding compared with clopidogrel, especially in East Asian patients. Low-dose ticagrelor might improve the safety of ACS patients in the Chinese population. Therefore, this study mainly explored the low-dose ticagrelor in Chinese ACS patients. Methods: A total of 199 ACS patients were enrolled in this study. The maximum platelet aggregation rate induced by adenosine-5-diphosphate (ADP) was detected by light transmittance aggregometry (LTA). Platelet aggregation rate induced by ADP of more than or equal to 42.9% was defined as high on-treatment platelet reactivity (HPR) to P2Y12 inhibitors. All patients were followed up for at least 12 months. Clinical outcomes, changes of antiplatelet regimen, medication compliance and adverse reactions were collected. Results: Patients were divided into three groups according to the P2Y12 inhibitors, including 87 cases in clopidogrel (75 mg once a day) group, 41 cases in ticagrelor 60 mg (twice a day) group, and 71 cases in ticagrelor 90 mg (twice a day) group. ADP-induced platelet aggregation rates in ticagrelor 60 mg group and 90 mg group were 28.4 (19.6, 42.9) and 22.33 (15.1, 34.7) respectively, which were significantly lower than those in clopidogrel group 49.3 (36.5, 61.0) with adjusted P < 0.001. At the same time, there was no significant difference in ADP-induced platelet aggregation rate between ticagrelor 60 mg and 90 mg group (adjusted P = 0.105). Compared with clopidogrel, the proportion of normal on-treatment platelet reactivity (NPR) of ticagrelor 60 mg and ticagrelor 90 mg were significantly higher than that of clopidogrel, and the proportion of NPR of ticagrelor 90 mg group was significantly higher than that of ticagrelor 60 mg group. Conclusions: Patients of ticagrelor 60 mg and ticagrelor 90 mg had comparable platelet aggregation rates induced by ADP, and both of them had significantly more potent antiplatelet aggregation activity detected by LTA than clopidogrel.
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Background and Objectives: It is unclear whether more potent P2Y12 inhibitors are of benefit to older patients who are at high risk for both ischemia and bleeding. We conducted an observational study to compare the clinical outcomes of clopidogrel and ticagrelor uses in older patients with an acute coronary syndrome (ACS). Methods: Older patients (aged ≥65 years) with ACS who underwent percutaneous coronary intervention (PCI) were divided into clopidogrel-treated and ticagrelor-treated groups. The primary observational endpoint was the occurrence of net adverse clinical and cerebral events (NACCEs) during a 12-month period, which is defined as the composite endpoint of all-cause death, myocardial infarction (MI), stroke, stent thrombosis, urgent coronary revascularization, and clinically significant bleeding. The secondary endpoints were clinically significant bleeding and major adverse clinical and cerebral events (MACCEs). Results: This study included a total of 2,611 patients. Of them, 1,636 received clopidogrel and 975 received ticagrelor. Between patients receiving clopidogrel and those receiving ticagrelor, no significant differences were noted in NACCE (8.4 vs. 9.7%, respectively; adjusted hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.66-1.12) or MACCE (7.1 vs. 7.0%, respectively; adjusted HR, 1.13; 95% CI, 0.83-1.55) during the 12-month follow-up period. In contrast, the occurrence of clinically significant bleeding was significantly less in clopidogrel-treated patients compared with that in ticagrelor-treated patients (27, 1.7%, vs. 31, 3.2%, respectively; adjusted HR, 0.42; 95% CI, 0.25-0.69). Stratified analyses revealed no significant association between age (≥75 years vs. <75 years) and treatment condition in terms of primary or secondary endpoints. Conclusion: This study showed that clopidogrel and ticagrelor had comparable net clinical benefits in patients with ACS aged ≥65 years. Additionally, clopidogrel was associated with a significantly lower risk of major bleeding than ticagrelor without an increase in ischemic risk. These findings suggest that clopidogrel is an effective alternative to the more potent P2Y12 inhibitor ticagrelor in older patients.
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AIMS: The association between metformin use and neurodegenerative disease (ND) onset remains controversial. In this systematic review and meta-analysis, we aimed to determine the relationship between metformin use and ND risk based on data from population-based cohort studies. METHODS: Articles were systematically searched in PubMed, EMBASE and Cochrane Library databases. Pooled relative risks (RRs) with 95% CIs were obtained using a random-effects model. Subgroup analyses, sensitivity analyses and meta-regression were performed to identify the sources of heterogeneity and strengthen the results. RESULTS: Twelve population-based cohort studies involving 194,792 participants (94,462 metformin users and 100,330 metformin non-users) were eligible for inclusion in this meta-analysis. The pooled RR of NDs reached 0.77 (95% CI 0.67-0.88) when comparing metformin users with non-users. The effects were more prominent in long-term metformin users (≥4 years) (RR 0.29, 95% CI 0.13-0.44) and studies from Asian countries (RR 0.69, 95% CI 0.64-0.74). The effect estimates were stable when stratified by subtypes of NDs, study designs, and control definitions (p for interaction >0.05). Meta-regression did not identify the coefficients as the sources of heterogeneity (all p > 0.05). CONCLUSIONS: This systematic review and meta-analysis found that metformin use, especially long-term use, was associated with lower ND risk. However, because there was substantial heterogeneity among studies, high-quality randomized controlled trials are still needed to confirm this finding.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Metformina , Enfermedades Neurodegenerativas , Estudios de Cohortes , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Enfermedades Neurodegenerativas/epidemiologíaRESUMEN
OBJECTIVE: This article compares the clinical outcomes of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS) without cytochrome P450 (CYP)2C19 loss-of-function (LOF) alleles and investigates whether clopidogrel could be an alternative P2Y12 inhibitor without increasing the risk of ischemic events. METHODS: Patients were divided into the clopidogrel-treated group and the ticagrelor-treated group. Inverse probability of treatment weighting (IPTW) calculated by propensity scores was used to adjust confounding covariates. The primary outcome was major adverse cardiovascular or cerebrovascular events (MACCEs) within 12 months. The secondary outcomes were MACCEs plus unstable angina, and clinically significant bleeding events. RESULTS: Finally, 2,199 patients were included. Of them, 1,606 were treated with clopidogrel, and 593 were treated with ticagrelor. The mean age of the original cohort was 59.92 ± 9.81 years. During the 12-month follow-up period, MACCEs occurred in 89 patients (4.0%). No significant differences were observed in MACCEs (IPTW-adjusted hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.65-1.18), MACCEs plus unstable angina (IPTW-adjusted HR, 1.20; 95% CI, 0.91-1.59), or clinically significant bleeding events (IPTW-adjusted HR, 0.81; 95% CI, 0.53-1.23) between the clopidogrel- and ticagrelor-treated groups. CONCLUSION: In patients with ACS without CYP2C19 LOF alleles, clopidogrel was not associated with a higher risk of MACCEs when compared with ticagrelor. The main findings of this study support use of clopidogrel in CYP2C19 LOF noncarriers as an alternative P2Y12 inhibitor, which may reduce medical expenses and adverse reactions caused by more potent P2Y12 inhibitors in these patients.
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Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/genética , Anciano , Alelos , Angina Inestable/tratamiento farmacológico , Clopidogrel/efectos adversos , Citocromo P-450 CYP2C19/genética , Hemorragia/inducido químicamente , Humanos , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Ticagrelor/efectos adversos , Resultado del TratamientoRESUMEN
Background: The clinical benefits of cytochrome P450 (CYP) 2C19 genotype-guided antiplatelet therapy in Asians remain unclear. In this study, we aimed to investigate the clinical outcomes of pharmacogenomic antiplatelet therapy in Chinese patients. Methods: Patients with acute coronary syndrome planning to undergo percutaneous coronary intervention were eligible for this study and were randomly divided into a genotype-guided treatment (GT) group and routine treatment (RT) group, with a ratio of 2:1. Patients in the GT group underwent CYP2C19 genotyping (*2 and *3 alleles), and the results were considered in selecting P2Y12 receptor inhibitors. Patients in the RT group were treated with P2Y12 receptor inhibitors according to their clinical characteristics. The primary endpoint was a composite of major adverse cardiovascular or cerebrovascular events (MACCE). The secondary endpoint was significant bleeding events. Results: Finally, 301 patients were enrolled; 75.1% were men and the mean age was 59.7 ± 9.8 years. In total, 281 patients completed the follow-up procedure. The primary endpoint occurred in 16 patients, 6 patients in the GT group and 10 in the RT group. The GT group showed lower MACCE rates than the RT group (6/189 vs. 10/92, 3.2 vs. 10.9%, hazard ratio: 0.281, 95% confidence interval: 0.102-0.773, P = 0.009). There was no statistically difference in significant bleeding events between the GT and RT groups (4.2 vs. 3.3%, hazard ratio: 1.315, 95% confidence interval: 0.349-4.956, P = 0.685). Conclusion: Personalized antiplatelet therapy that is based on CYP2C19 genotypes could decrease MACCE within a 12-month period in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000034352.
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The distribution of active compounds of traditional Chinese medicine Salvia miltiorrhiza Bunge (Chinese name: Danshen) in vivo was determined by establishing a liquid extraction surface analysis coupled with the tandem mass spectrometry (LESA-MS/MS) method. Stability analysis and distribution analysis were designed in the present study using normal animals or a myocardial ischemia model. The model assessment was performed four weeks after surgery, and then three groups were created: a normal-dose group, a model-blank group, and a model-dose group. Meanwhile, Danshen decoction administration began in dose groups and lasted for four weeks. In stability analysis, four salvianolic acids-Danshensu (DSS), caffeic acid (CAA), rosmarinic acid (RA), and salvianolic acid A (SAA)-in kidney tissues from the normal-dose group were detected by LESA-MS/MS under four conditions, and then distribution analysis was conducted in different tissues using the same method. Ejection fraction (EF) and fractional shortening (FS) in animals from two model groups decreased significantly four weeks after surgery (P < 0.01) and were improved after four weeks of Danshen decoction administration (P < 0.01). Results of stability analysis demonstrated that this method was basically stable since there were no significant differences in signal intensities of DSS, CAA, and SAA under four conditions (P > 0.05). Distribution analysis showed the signal intensities of DSS in the liver and kidney and SAA in the heart were higher in the model-dose group than in the normal-dose group (P < 0.05 or P < 0.01). Signal intensities of RA in the liver and kidney, and SAA in the liver were lower in the model-dose group compared with the normal-dose group (P < 0.05 or P < 0.01). In conclusion, Danshen decoction has the effect of improving the ischemic condition in a chronic myocardial ischemia model, and the content of two active compounds increased in the targets. These findings contribute to an understanding of the therapeutic role of Danshen in cardiovascular disease.
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AIMS: We performed an updated meta-analysis to verify correlations between gene polymorphisms and adverse events in methotrexate (MTX)-treated rheumatoid arthritis (RA) patients. Then, we conducted a retrospective cohort study of Han Chinese in China. METHODS: Relevant studies were collected from the PubMed database and the EMBASE database until December 2017. Pre-allele, dominant, recessive, codominant, and homozygotic models were applied. In addition, a retrospective cohort study enrolling 162 RA patients treated with MTX was conducted. Single nucleotide polymorphism (SNP) genotyping was analyzed by PCR and product sequencing. RESULTS: A total of 39 studies were included in 20 meta-analyses; meta-analysis showed a significant association between MTX-related toxicity and 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T(rs1801133) polymorphism in East Asian RA patients, and significant associations were observed between MTX-related toxicity and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) 347C>G (rs2372536), reduced folate carrier 1 (RFC-1) 80G>A (rs1051266), and adenosine triphosphate-binding cassette B1 (ABCB1) 3435C>T(rs1045642) polymorphisms in European RA patients but not in East Asian RA patients. Moreover, in our retrospective cohort study, ATIC 347C>G(rs2372536) and ABCB1 3435C>T(rs1045642) polymorphisms were not associated with MTX-related toxicity. However, a significant association was observed between MTX-related toxicity and RFC-1 80G>A (rs1051266) polymorphism in Chinese Han RA patients. CONCLUSION: Evidence-based results suggest that the MTHFR 677C>T(rs1801133), ATIC 347C>G(rs2372536), RFC-1 80G>A (rs1051266), ABCB1 3435C>T(rs1045642) polymorphisms are associated with MTX-related toxicity. Larger and more stringent study designs may provide more accurate findings for the effects of these SNPs on MTX-related toxicity, and larger sample-size studies of the Chinese Han population should be conducted for further validation.
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Background: CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice. Methods: This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ≥2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors. Results: Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; p = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank p = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300-3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank p = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864-2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank p = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582-2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups. Conclusion: This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.