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1.
Acta Pharmacol Sin ; 43(3): 613-623, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34035486

RESUMO

Heart aging is characterized by structural and diastolic dysfunction of the heart. However, there is still no effective drug to prevent and treat the abnormal changes in cardiac function caused by aging. Here, we present the preventive effects of emodin and its derivative Kanglexin (KLX) against heart aging. We found that the diastolic dysfunction and cardiac remodeling in mice with D-galactose (D-gal)-induced aging were markedly mitigated by KLX and emodin. In addition, the senescence of neonatal mouse cardiomyocytes induced by D-gal was also reversed by KLX and emodin treatment. However, KLX exhibited better anti-heart aging effects than emodin at the same dose. Dysregulated mitophagy was observed in aging hearts and in senescent neonatal mouse cardiomyocytes, and KLX produced a greater increase in mitophagy than emodin. The mitophagy-promoting effects of KLX and emodin were ascribed to their abilities to enhance the protein stability of Parkin, a key modulator in mitophagy, with different potencies. Molecular docking and SPR analysis demonstrated that KLX has a higher affinity for the ubiquitin-like (UBL) domain of Parkin than emodin. The UBL domain might contribute to the stabilizing effects of KLX on Parkin. In conclusion, this study identifies KLX and emodin as effective anti-heart aging drugs that activate Parkin-mediated mitophagy and outlines their putative therapeutic importance.


Assuntos
Envelhecimento/efeitos dos fármacos , Antraquinonas/farmacologia , Emodina/farmacologia , Cardiopatias/patologia , Mitofagia/efeitos dos fármacos , Animais , Benzofuranos , Modelos Animais de Doenças , Feminino , Galactose/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/efeitos dos fármacos , Quinolinas , Distribuição Aleatória , Ubiquitina-Proteína Ligases/efeitos dos fármacos
2.
Med Chem ; 18(4): 509-520, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34182915

RESUMO

BACKGROUND: TGF-ß signaling pathway inhibition is considered an effective way to prevent the development of several diseases. In the design and synthesis of TGF-ß inhibitors, a rhodanine compound containing a quinoxalinyl imidazole moiety was found to have strong antimicrobial activity. OBJECTIVE: The purpose of this work was to investigate the antimicrobial activity of other chiral rhodanine TGF-ß inhibitors synthesized. METHODS: Two series of 3-substituted-5-(5-(6-methylpyridin-2-yl)-4-(quinoxalinyl-6-yl)- 1Himidazol- 2-yl)methylene)-2-thioxothiazolin-4-ones (12a-h and 13a-e) were synthesized and evaluated for their ALK5 inhibitory and antimicrobial activity. The structures were confirmed by their 1H NMR, 13C NMR and HRMS spectra. All the synthesized compounds were screened against Grampositive strains, Gram-negative strains, and fungi. RESULTS: Among the synthesized compounds, compound 12h showed the highest activity (IC50 = 0.416 µM) against ALK5 kinase. Compound 12h exhibited a good selectivity index of >24 against p38α MAP kinase and was 6.0-fold more selective than the clinical candidate, compound 2 (LY- 2157299). Nearly all the compounds displayed high selectivity toward both Gram-positive and Gram-negative bacteria. They also showed similar or 2.0-fold greater antifungal activity (minimum inhibitory concentration [MIC] = 0.5 µg/mL) compared with the positive control compounds Gatifloxacin (MIC = 0.5 µg/mL) and fluconazole (MIC = 1 µg/mL). CONCLUSION: The findings suggest that the synthesized rhodanine compounds have good ALK5 inhibitory activity, and merit further research and development as potential antifungal drugs.


Assuntos
Rodanina , Antibacterianos , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Imidazóis/farmacologia , Testes de Sensibilidade Microbiana , Rodanina/farmacologia , Relação Estrutura-Atividade
3.
Small ; 18(9): e2105021, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35088527

RESUMO

Atherosclerosis (AS) is associated with high morbidity and mortality, thus imposing a growing burden on modern society. Herb-derived bicyclol (BIC) is a versatile bioactive compound that can be used to treat AS. However, its efficacy in AS is not yet described. Here, it is shown that BIC normalizes gut microflora dysbiosis induced by a high fat diet in Apoe(-/-) mice. Metagenome-wide association study analysis verifies that the modulation on carbohydrate-active enzymes and short-chain fatty acid generating genes in gut flora is among the mechanisms. The gut healthiness, especially the gut immunity and integrity, is restored by BIC intervention, leading to improved systemic immune cell dynamic and liver functions. Accordingly, the endothelial activation, macrophage infiltration, and cholesterol ester accumulation in the aortic arch are alleviated by BIC to lessen the plaque onset. Moreover, it is proved that the therapeutic effect of BIC on AS is transmissible by fecal microbiota transplantation. The current study, for the first time, demonstrates the antiatherosclerotic effects of BIC and shows that its therapeutic value can at least partially be attributed to its manipulation of gut microbiota.


Assuntos
Aterosclerose , Microbioma Gastrointestinal , Animais , Aterosclerose/tratamento farmacológico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Disbiose , Camundongos , Camundongos Endogâmicos C57BL
4.
Signal Transduct Target Ther ; 6(1): 414, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873151

RESUMO

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.


Assuntos
Antivirais/administração & dosagem , Azidas/administração & dosagem , COVID-19/tratamento farmacológico , Desoxicitidina/análogos & derivados , SARS-CoV-2/metabolismo , Timo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Coronavirus Humano OC43/metabolismo , Desoxicitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Timo/metabolismo , Timo/virologia
5.
Front Endocrinol (Lausanne) ; 12: 743807, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925229

RESUMO

Recently, Lin and colleagues assessed the safety of sodium-glucose cotransporter 2 inhibitors (SGLT2is) by a meta-analysis [1], in which the authors assessed 16 kinds of adverse events (AE) reported in the published articles based on 10 randomized controlled trials. We conducted a further meta-analysis and targeted the association between use of SGLT2is and occurrences of various kinds of serious AE published in the Clinical Trials website (clinicaltrials.gov). Our meta-analysis revealed that use of SGLT2is was not significantly associated with occurrences of 980 kinds of serious AE but was significantly associated with lower risks of 29 kinds of serious AE, especially including several important respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease, sleep apnoea syndrome, and pneumonia). These findings may cause more studies to evaluate the possibilities of gliflozins being used for prevention of these specific diseases.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Humanos , Hipoglicemiantes/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
6.
Medicine (Baltimore) ; 100(47): e27802, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34964748

RESUMO

BACKGROUND: It is unclear whether demographic characteristics and baseline use of hypoglycemic and cardiovascular drugs significantly affect the efficacy of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS: Randomized trials assessing the efficacy of SGLT2 inhibitors on cardiorenal outcomes in adult patients with T2DM were included in analysis. Three endpoints of interest were major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular death (HHF or CV death), and kidney composite outcome (KCO). We performed random-effects meta-analysis using the aggregate data of hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses were done according to 17 factors of interest, including 7 factors related to demographic characteristics and 10 related to baseline use of antihyperglycemic and cardiovascular drugs such as renin-angiotensin system (RAS) inhibitor. We conducted meta-regression analyses to calculate P values for subgroup differences. RESULTS: Seven trials were included in this meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of MACE (HR 0.90, 95% CI 0.84-0.97) regardless of demographic characteristics and baseline use of insulin, statin or ezetimibe, RAS inhibitor, beta-blocker, and diuretic (Psubgroup from 0.088-0.981); that of HHF or CV death (HR 0.78, 95% CI 0.71-0.85) regardless of demographic characteristics and baseline use of 10 antihyperglycemic and cardiovascular drugs (Psubgroup from 0.147-0.999); and that of KCO (HR 0.63, 95% CI 0.57-0.69) regardless of demographic characteristics and baseline use of statin or ezetimibe, RAS inhibitor, and diuretic (Psubgroup from 0.073-0.918). CONCLUSIONS: The cardiorenal benefits of SGLT2 inhibitors were consistent in a broad population of T2DM patients. The findings of this meta-analysis suggest that SGLT2 inhibitors should be recommended in T2DM patients for the prevention of cardiorenal events, regardless of various demographic characteristics and baseline use of various hypoglycemic and cardiovascular drugs.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diuréticos/uso terapêutico , Ezetimiba , Insuficiência Cardíaca , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Metanálise como Assunto , Fatores Socioeconômicos , Revisões Sistemáticas como Assunto
11.
Medicine (Baltimore) ; 100(39): e27362, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596148

RESUMO

BACKGROUND: Individual randomized trials are not powered to assess the relationship between use of sodium-glucose transporter 2 inhibitors and risk of stroke. We sought to explore this issue by a meta-analysis incorporating relevant trials including several latest trials. METHODS: Cardiovascular outcome trials of gliflozins were included. Primary outcome was stroke, while secondary outcome was major adverse cardiovascular events (MACE), which was a composite of stroke, myocardial infarction, or cardiovascular death. Meta-analysis was conducted stratified by with/without chronic kidney disease (CKD), with/without heart failure (HF), and with/without atherosclerotic cardiovascular disease (ASCVD), and stratified by different gliflozins. RESULTS: We included 9 trials in this meta-analysis. Compared with placebo, gliflozins significantly lowered stroke (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.55-0.84) and MACE (HR 0.77, 95% CI 0.69-0.86) in type 2 diabetes (T2D) patients with CKD, but did not significantly affect stroke (HR 1.00, 95% CI 0.86-1.16) and MACE (HR 0.94, 95% CI 0.86-1.02) in T2D patients without CKD. Gliflozins had no significant effects on the stroke risk (HR 0.94, 95% CI 0.82-1.07) in T2D patients regardless of HF status (Psubgroup = .684) and ASCVD status (Psubgroup = .915), but significantly lowered MACE (HR 0.89, 95% CI 0.83-0.96) in T2D patients regardless of HF status (Psubgroup = .428) and ASCVD status (Psubgroup = .423). Canagliflozin (HR 0.84, 95% CI 0.69-1.01) showed the trend of a reduction in the stroke risk versus placebo, and sotagliflozin (HR 0.73, 95% CI 0.54-0.98) significantly lowered the stroke risk; whereas the other 3 gliflozins did not significantly affect that risk. Ertugliflozin (HR 0.97, 95% CI 0.85-1.11) had no significant effects on the MACE risk, whereas the other 4 gliflozins significantly lowered that risk. CONCLUSIONS: Gliflozins, especially canagliflozin and sotagliflozin, should be recommended in T2D patients with CKD to prevent stroke. Most gliflozins lower the risk of MACE in T2D patients regardless of HF status and ASCVD status, whereas ertugliflozin is not observed to lower that risk.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/complicações , Humanos , Metanálise como Assunto , Insuficiência Renal Crônica/complicações
12.
Photodiagnosis Photodyn Ther ; 36: 102547, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34562647

RESUMO

BACKGROUND: Nucleic acids used as drug delivery systems (DDS) have gained attention because of their biosafety and effortless synthesis. G-quadruplex (G4) structured aptamer such as AS1411 was frequently employed to deliver photosensitizers or chemotherapeutic agents while other aptamers were seldomly reported in this field. METHODS: Herein, a chemical anticancer drug daunomycin (DNM), and a photosensitizer 5, 10, 15, 20-tetra (phenyl-4-N-methyl-4-pyridyl) porphyrin (TMPyP) were physically assembled with a novel DNA structure composed of an aptamer of vascular endothelial growth factor (VEGF) and a cytosine (C)-rich DNA fragment (gc-34). Spectral and molecular mimicking methods were employed to research the drug loading/releasing process. The in vitro cytotoxicity was studied by MTT, ROS, cell cycle, and cell apoptotic assays and the in vivo anticancer efficiency was evaluated by the inhibitive effect on the cancerous growth of MCF-7 tumor-bearing nude mice. RESULTS: The G4-structured VEGF aptamer delivered TMPyP successfully for the first time. The designed DDS displayed sensitive VEGF/pH controlled drug release. The co-delivery of DNM and TMPyP exhibited high ROS production, significant cell cycle arresting and evident cell apoptosis, and displayed superior cytotoxicity against tumor cells compared with individual agents in vitro. In vivo studies showed that the dual-drug loaded system can greatly inhibit tumor growth with chemotherapeutic/photodynamic synergistic effects. CONCLUSION: The co-delivery of DNM and TMPyP with aptamer/C-rich DNA successfully integrates the functions of VEGF/pH stimuli-responsive drug release and chemotherapeutic/phototherapeutic modalities into one single system, and may have great potential in cancer treatment.


Assuntos
Nanopartículas , Preparações Farmacêuticas , Fotoquimioterapia , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Camundongos , Camundongos Nus , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fator A de Crescimento do Endotélio Vascular
13.
Ther Adv Endocrinol Metab ; 12: 20420188211044945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589202

RESUMO

BACKGROUND: The effects of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiovascular death (CV death) and all-cause death (AC death) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) are currently under intensive investigation. We intended to conduct an updated meta-analysis including the SCORED trial to evaluate the effects of SGLT2 inhibitors on death and cardiorenal events in this vulnerable population. METHODS: Cardiorenal outcome trials of SGLT2 inhibitors were included. Primary outcomes were CV death and AC death, while secondary outcomes were hospitalization for heart failure (HHF), myocardial infarction (MI), CKD progression, cardiovascular death or hospitalization for heart failure (CV death or HHF), major adverse cardiovascular events (MACE), and stroke. Meta-analysis was conducted for each outcome. RESULTS: Eight trials were included for meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of CV death (HR = 0.86, 95% CI = 0.75-0.98), AC death (HR = 0.87, 95% CI = 0.79-0.96), HHF (HR = 0.64, 95% CI = 0.56-0.74), MI (HR = 0.76, 95% CI = 0.65-0.89), CKD progression (HR = 0.62, 95% CI = 0.54-0.72), and CV death or HHF (HR = 0.73, 95% CI = 0.67-0.80). No heterogeneity existed in the above meta-analyses (all I2 values = 0%), whereas moderate heterogeneity existed in the meta-analyses for MACE and stroke (I2 = 31.6% and 44.5%, respectively). CONCLUSIONS: Our findings suggest that SGLT2 inhibitors versus placebo significantly lower death, heart failure, renal failure, and MI events in patients with T2D and CKD. Head-to-head trials are needed to examine the possible differences in the effects of various gliflozins on MACE and stroke.

14.
Front Med (Lausanne) ; 8: 679755, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381797

RESUMO

Non-tuberculou Mycobacteria (NTM) is ubiquitous in the environment and is conditional pathogen. Due to NTM and Mycobacterium tuberculosis belong to the genus Mycobacterium, their pathogenic mechanisms and clinical manifestations are similar. Therefore, NTM can cause tuberculosis-like lesions and lead to misdiagnosis. Early diagnosis and treatment greatly improve prognosis. However, traditional pathogenic microorganism detection has limitations, and it is difficult to accurately identify strains in clinical practice. Here, we report a 65-year-old man with NTM who presented with recurrent fever and cough. Computed tomography of the chest revealed a lung infection. The previous improper diagnosis and treatment did not improve his condition. With the aid of metagenomic next-generation sequencing, the pathogen was identified as Mycobacterium avium complex. Subsequently, he received accurate treatment and made significant improvements in clinical and radiology.

15.
Sci Rep ; 11(1): 17111, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429489

RESUMO

Interferon-gamma (IFN-γ) is a cytokine involved in the pathogenesis of Takayasu's arteritis (TAK). However, the source of IFN-γ in TAK patients is not fully clear. We aimed to investigate the source of IFN-γ in TAK. 60 TAK patients and 35 health controls were enrolled. The lymphocyte subsets of peripheral blood were detected by flow cytometry, cytokines were detected by Bio-plex. The correlation among lymphocyte subsets, cytokines and disease activity indexes was analyzed by person correlation. The level of serum IFN-γ in TAK patients was significantly increased (P < 0.05). The percentage of CD3+IFN-γ+ cells in peripheral blood CD3+ cells was significantly higher in TAK patients than that of healthy control group (P = 0.002). A higher proportion of CD3+CD8+IFN-γ+ cells/CD3+IFN-γ+ cells (40.23 ± 11.98% vs 35.12 ± 11.51%, P = 0.049), and a significantly lower CD3+CD4+IFN-γ+/ CD3+CD8+IFN-γ+ ratio (1.34 ± 0.62% vs 1.80 ± 1.33%, P = 0.027) were showed in the TAK group than that of control group. The CD3+CD8+IFN-γ+/CD3+IFN-γ+ ratio was positively correlated with CD3+IFN-γ+cells/ CD3+cells ratio (r = 0.430, P = 0.001), serum IFN-γ level (r = 0.318, P = 0.040) and IL-17 level (r = 0.326, P = 0.031). It was negatively correlated with CD3+CD4+IFN-γ+/CD3+IFN-γ+ ratio (r = - 0.845, P < 0.001). IFN-γ secreted by CD3+CD8 + T cells is an important source of serum IFN-γ in TAK patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Interferon gama/metabolismo , Arterite de Takayasu/imunologia , Adulto , Células Cultivadas , Feminino , Humanos , Interferon gama/genética , Masculino , Pessoa de Meia-Idade , Arterite de Takayasu/sangue
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