RESUMO
Tectorigenin (TEC) as a plant extract has the advantage of low side effects on metabolic dysfunction-associated steatohepatitis (MASH) treatment. Our previous study have shown that tRNA-derived RNA fragments (tRFs) associated with autophagy and pyroptosis in MASH, but whether TEC can mitigate MASH through tRFs-mediated mitophagy is not fully understood. This study aims to investigate whether TEC relies on tRFs to adjust the crosstalk of hepatocyte mitophagy with pyroptosis in MASH. Immunofluorescence results of PINK1 and PRKN with MitoTracker Green-labeled mitochondria verified that TEC enhanced mitophagy. Additionally, TEC inhibited pyroptosis, as reflected by the level of GSDME, NLRP3, IL-1ß, and IL-18 decreased after TEC treatment, while the effect of pyroptosis inhibition by TEC was abrogated by Pink1 silencing. We found that the upregulation expression of tRF-3040b caused by MASH was suppressed by TEC. The promotion of mitophagy and the suppression of pyroptosis induced by TEC were abrogated by tRF-3040b mimics. TEC reduced lipid deposition, inflammation, and pyroptosis, and promoted mitophagy in mice, but tRF-3040b agomir inhibited these effects. In summary, our findings provided that TEC significantly reduced the expression of tRF-3040b to enhance mitophagy, thereby inhibiting pyroptosis in MASH. We elucidated a powerful theoretical basis and provided safe and effective potential drugs for MASH with the prevention and treatment.
Assuntos
Regulação para Baixo , Isoflavonas , Camundongos Endogâmicos C57BL , Mitofagia , Piroptose , Piroptose/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Animais , Camundongos , Masculino , Isoflavonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , HumanosRESUMO
AIMS: Programmed death-ligand 1 (PD-L1) is known to be highly expressed in various malignancies, including head and neck squamous cell carcinoma (HNSCC). We aimed to determine the prevalence of PD-L1 expression in recurrent or metastatic HNSCC (R/M HNSCC) among Chinese patients. METHODS: This multicentre, retrospective analysis of data from six centres in China included patients with R/M HNSCC treated from 9 August 2021 to 28 February 2022. PD-L1 expression in tumour tissue was assessed and represented using a combined positive score (CPS). The χ2 and Cochran-Mantel-Haenszel χ2 tests were used to compare the prevalence of different PD-L1 expression statuses according to related co-variables. RESULTS: For all 402 examined patients with R/M HNSCC, 168 cases (41.8%) had PD-L1 expression with a CPS ≥20, and 337 cases (83.8%) had PD-L1 expression with a CPS ≥1. Between the PD-L1 CPS ≥20 group and PD-L1 CPS <20 group, statistically significant differences were observed for variables of sex (p<0.001), smoking habit (p=0.0138 for non-smokers vs current smokers) and primary tumour site (p<0.001 for hypopharynx vs oral cavity and p=0.0304 for larynx vs oral cavity, respectively). CONCLUSION: PD-L1 with CPS ≥20 was expressed in about 41.8% of cases with R/M HNSCC among Chinese patients, and PD-L1 expression was significantly associated with sex, smoking history and primary tumour site. Our findings regarding the variables related to PD-L1 expression level provide insight for clinical practice and a solid basis for future research on immunotherapy in HNSCC. TRIAL REGISTRATION NUMBER: ISRCTN10570964.
RESUMO
Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The inâ vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10â mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.
Assuntos
Antineoplásicos , Bufanolídeos , Animais , Camundongos , Humanos , Linhagem Celular Tumoral , Cardiotoxicidade/tratamento farmacológico , Camundongos Nus , Antineoplásicos/farmacologia , Bufanolídeos/química , Apoptose , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de CélulasRESUMO
Purpose: Curcumin and icariin have multiple pharmacological effects and are widely used in various fields, but their short half-life, poor bioavailability and low water solubility greatly limit their application in clinical medicine. Poly(lactide-co-glycolide) (PLGA) loaded microspheres not only solve these problems, but also have no toxicity in degradation. Methods: To verify whether PLGA drugloaded microspheres have good biocompatibility, the present experiments used the emulsification-solvent evaporation method to prepare PLGA drug-loaded microspheres and successfully performed the loading of curcumin and icariin. Results: The scanning electron microscopy showed that the particle sizes of the PLGA microspheres were 2-15 µm, icariin/PLGA microspheres were 3-22 µm and curcumin/PLGA microspheres were 5-30 µm. Moreover, the surface of the microspheres was smooth and spherical. Furthermore, the drug loading and encapsulation rate were good. In vitro experiments revealed that the prepared PLGA microspheres were safe and nontoxic, and that they could release drugs stably and slowly. Moreover, their proliferation ability was unaffected after inoculation into bone marrow mesenchymal stem cells (BMSCs), and Alcian blue Staining was performed at last, demonstrating their biocompatibility and important applications in tissue engineering.
Assuntos
Materiais Biocompatíveis , Células-Tronco Mesenquimais , Microesferas , Materiais Biocompatíveis/farmacologia , Animais , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Teste de Materiais , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Curcumina/química , Curcumina/farmacocinética , Tamanho da Partícula , Poliglactina 910/químicaRESUMO
The ecto-5'-nucleotidase (CD73) is an important enzyme in the adenosine pathway and catalyzes the extracellular hydrolysis of adenosine monophosphate (AMP) yielding adenosine which is involved in the inflammation and immunosuppression. Inhibitors of CD73 have potential as novel immunotherapy agents for the treatment of cancer and infection. In this study, we discovered a series of fluorinated betulinic acid derivatives as potent CD73 inhibitors by a fluorine scanning strategy. Among these, three compounds ZM522, ZM553 and ZM557 exhibited inhibitory activity with IC50 values of 0.56 uM, 0.74 uM and 0.47 uM, respectively. In addition, these compounds showed a 7-fold, 5-fold and 8-fold increase in activity compared to the positive control drug α, ß-methylene adenosine diphosphate (APCP) against the human CD73 enzyme. Two of these (ZM522 and ZM553) also exhibited effective interferon gamma (INF-γ) elevation and indicated the regulation of rescued T cell activation. Therefore, our study provides both a lead optimization strategy and potential compounds for further development of small molecule CD73 inhibitors.
Assuntos
5'-Nucleotidase , Flúor , Humanos , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Adenosina , Triterpenos Pentacíclicos/química , Ácido BetulínicoRESUMO
BACKGROUND: Dyslipidemia International Study II (DYSIS II)-China was conducted to determine the low-density lipoprotein cholesterol (LDL-C) goal (<1.8 mmol/L) attainment rate in patients with post-acute coronary syndrome (ACS). HYPOTHESIS: Compliance with treatment guideline recommendations improves the LDL-C goal attainment rate in post-ACS patients. METHODS: This multicenter prospective observational study conducted at 28 tertiary hospitals determined the LDL-C goal attainment rates at admission and 6-month follow-up in patients on lipid-lowering treatment (LLT) for ≥3 months and those not on LLT (LLT-naive or off LLT for ≥3 months) at admission. Predictors of goal attainment at 6 months were identified using multivariate logistic regression. RESULTS: The LDL-C goal attainment rate at admission in 1102/1103 enrolled patients was 17.1%; it was 41.2% among 752 patients with available lipid results at 6 months. The distance to goal was 0.7 mmol/L at 6 months. Statin monotherapy was the most prescribed LLT. Only 7.7% of patients were receiving statin + ezetimibe and 8.4% of patients were receiving an atorvastatin-equivalent dose of ≥40 mg/day at 6 months. Being male (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.1-2.6) and undergoing percutaneous coronary intervention during index hospitalization (OR 1.5, 95% CI 1.1 to 2.1) were the independent predictors for LDL-C goal attainment. CONCLUSIONS: This real-world DYSIS II study in China reports a low LDL-C goal attainment rate in post-ACS patients even after 6 months of LLT. Lack of intensification of statin therapy and underutilization of combinations suggest gaps between real-world treatment practices and guideline recommendations.
Assuntos
Síndrome Coronariana Aguda , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/tratamento farmacológico , China/epidemiologia , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Objetivos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos , Masculino , Resultado do TratamentoRESUMO
Objective: This study aimed to investigate the prevalence of tumor programmed death-ligand 1 (PD-L1) expression in Chinese patients with advanced Non-Small Cell Lung Cancer (NSCLC). Methods: Tumor tissues with histologically confirmed stage IIIB/IV NSCLC were retrospectively obtained from 10 centers in China. PD-L1 expression was determined using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA) and the samples were repetitively assayed with the PD-L1 IHC 22C3 Ab concentrate (Agilent, Santa Clara, CA, USA). Results: Out of 901 patients who met the inclusion criteria, 879 (97.6%) had evaluable PD-L1 data. The number of patients with a PD-L1 tumor proportion score (TPS) < 1%, 1-49%, and ≥ 50% (corresponding to PD-L1 non-expression, low expression, and high expression) was 424 (48.2%), 266 (30.3%), and 189 (21.5%), respectively. PD-L1 expression was more likely to be found in patients younger than 75 years, men, current or former smokers, those with good performance status (PS) scores, and those with a wild-type epidermal growth factor receptor (EGFR). PD-L1 TPS ≥ 50% and ≥ 1% were respectively 28.0% and 50.2% among patients negative for both EGFR mutation and anaplastic lymphoma kinase (ALK) rearrangement. PD-L1 expression determined using the 22C3 antibody concentrate and pharmDx kit had comparable results. Conclusions: The prevalence of PDL1 expression in advanced NSCLC was consistent with that reported in the global EXPRESS study. Age, gender, smoking history, PS scores, and EGFR/ALK mutation status affected PD-L1 expression. The 22C3 antibody concentrate appears to be an alternative reagent for the PD-L1 assay.
RESUMO
Few studies in China focused on serotypes of Streptococcus pneumoniae in patients with invasive pneumococcal disease (IPD). We aimed at investigating the serotype distribution for IPD-causing S. pneumoniae and vaccine coverage among Chinese children and adults. This was a multicenter, observational study to collect S. pneumoniae isolates from normal sterile sites and IPD-related clinical information among children and adults. Serotyping was performed by a Capsule-Quellung reaction test using type-specific antisera. The study collected a total of 300 eligible isolates (pediatric = 148, adult = 152) were serotyped in a central laboratory. The most prevalent serotypes were 19A (20.9%) and 23 F (20.3%) in the pediatric group; 3 (21.7%) and 19 F (11.8%) in the adult group. PCV10 had low-to-moderate serotype coverage rates for children (60.8%) and adults (34.2%). PCV13 and PPV23 had high coverage rates for children (89.9%, 93.2%) and adults (70.4%, 82.9%), respectively, Investigational PCVs including PCV15 and PCV20 had high estimated coverage rates in children (89.9%, 93.9%). The study identified 269 subjects with IPD reported as the primary diagnosis in the medical records. Sepsis (48/136, 35.3%) and pneumonia (48/133, 36.1%) had the highest occurrence in the pediatric and adult groups, respectively. Study findings showed that non-PCV7 S. pneumoniae 19A and 3 were the most prevalent serotypes in Chinese children and adults, respectively. High-valent vaccines had similar coverage rates and may have a greater potential in preventing IPD.
Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Adulto , Criança , China/epidemiologia , Humanos , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Sorogrupo , Sorotipagem , Vacinas ConjugadasRESUMO
Biallelic pathogenic mutations of the LAMA2 gene result in congenital muscular dystrophy type 1A (CMD1A). The patient in this study was a boy aged 19 months, with the clinical manifestations of motor development delay and increases in the serum levels of creatine kinase, aminotransferases, and lactate dehydrogenase. Genetic analysis showed that the patient had compound heterozygous mutations in the LAMA2 gene, among which c.7147C>T (p.Ala2383Ter) from his mother was a known nonsense mutation, and c.8551_8552insAA (p.Ile2852ArgfsTer2) from his father was a frameshift mutation which had never been reported before and was identified as a pathogenic mutation based on the ACMG guideline. The boy was confirmed with CMD1A. A literature review of related articles in China and overseas revealed that most children with CMD1A have disease onset within 6 months after birth, with the features of motor developmental delay, elevated serum creatine kinase, and white matter impairment on imaging examination. The mutations of the LAMA2 gene have remarkable heterogeneity, the majority of which are null mutations. There are no specific treatment methods for CMD1A currently, and children with CMD1A usually have a poor long-term prognosis.