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1.
Cell Death Dis ; 12(4): 387, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846304

RESUMO

Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma and is required to establish and support pregnancy. Dysregulated decidualization has been reported to be a critical cause of recurrent implantation failure (RIF). In this study, we found that Activating transcription factor 3 (ATF3) expression was significantly downregulated in the endometrium of RIF patients. Knockdown of ATF3 in human endometrium stromal cells (hESCs) hampers decidualization, while overexpression could trigger the expression of decidual marker genes, and ameliorate the decidualization of hESCs from RIF patients. Mechanistically, ATF3 promotes decidualization by upregulating FOXO1 via suppressing miR-135b expression. In addition, the endometrium of RIF patients was hyperproliferative, while overexpression of ATF3 inhibited the proliferation of hESCs through CDKN1A. These data demonstrate the critical roles of endometrial ATF3 in regulating decidualization and proliferation, and dysregulation of ATF3 in the endometrium may be a novel cause of RIF and therefore represent a potential therapeutic target for RIF.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33846912

RESUMO

Underground mining activity has existed for more than 100 years in Nansi lake. Coal mining not only plays a supporting role in local social and economic development but also has a significant impact on the ecological environment in the region. Landsat series remote sensing data (1988~2019) are used to research the impact of coal mining on the ecological environment in Nansi lake. Then support vector machine (SVM) classifier is applied to extract the water area of the upstream lake from 1988 to 2019, and ecological environment and spatiotemporal variation characteristics are analyzed by Remote Sensing Ecology Index (RSEI). The results illustrate that the water area change is associated with annual precipitation. In terms of ecological quality, the area of poor ecological quality areas increased by 101.782 km2, while the area of good and excellent quality areas decreased by 218.988 km2 from 2009 to 2019. So compared with 2009, the ecological quality of the lake is worse in 2019, and then the reason for this change is due to large-scale underground mining. Therefore, the coal mines from the natural reserve may be closed or limited to the mining boundary for protecting the lake's ecological environment.

3.
Mol Cancer ; 20(1): 67, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849552

RESUMO

N6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments.

4.
Phytochemistry ; 186: 112729, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33721798

RESUMO

Five pairs of undescribed naphthalenone derivative enantiomers, xylarinaps A-E, including one pair of indole naphthalenones and four pairs of naphthalene-naphthalenone dimers, were isolated from the ethyl acetate extracts of the solid fermentation of Xylaria nigripes, which has been used as a traditional Chinese medicinal fungus for the treatment of insomnia, trauma, and depression. The structures of these enantiomers were elucidated based on comprehensive spectroscopic analysis, including NMR and HRESIMS. Their absolute configurations were assigned by the experimental and calculated ECD data. The neuroprotective effects of all the compounds against damage to PC12 cells by oxygen and glucose deprivation (OGD) were evaluated by an in vitro bioassay. The results revealed that xylarinaps A, B, D, and E significantly enhanced cell viability, decreased the levels of malondialdehyde (MDA), increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as further markedly inhibiting apoptosis, which indicated that these results could be the mode of action of their neuroprotective effect.

5.
Med Sci Monit ; 27: e928933, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33735157

RESUMO

BACKGROUND Skin fibroblasts are primary mediators underlying wound healing and therapeutic targets in scar prevention and treatment. CD26 is a molecular marker to distinguish fibroblast subpopulations and plays an important role in modulating the biological behaviors of dermal fibroblasts and influencing skin wound repair. Therapeutic targeting of specific fibroblast subsets is expected to reduce skin scar formation more efficiently. MATERIAL AND METHODS Skin burn and excisional wound healing models were surgically established in mice. The expression patterns of CD26 during wound healing were determined by immunohistochemical staining, real-time RT-PCR, and western blot assays. Normal fibroblasts from intact skin (NFs) and fibroblasts in wounds (WFs) were isolated and sorted by fluorescence-activated cell sorting (FACS) into 4 subgroups - CD26⁺ NFs, CD26⁻ NFs, CD26⁺ WFs, and CD26⁻ WFs - for comparisons of their capacities of proliferation, migration, and collagen synthesis. Pharmacological inhibition of CD26 by sitagliptin in skin fibroblasts and during wound healing were further assessed both in vitro and in vivo. RESULTS Increased CD26 expression was observed during skin wound healing in both models. The CD26⁺ fibroblasts isolated from wounds had significantly stronger abilities to proliferate, migrate, and synthesize collagen than other fibroblast subsets. Sitagliptin treatment potently diminished CD26 expression, impaired the proliferation, migration, and collagen synthesis of fibroblasts in vitro, and diminished scar formation in vivo. CONCLUSIONS Our data reveal that CD26 is functionally involved in skin wound healing by regulating cell proliferation, migration, and collagen synthesis in fibroblasts. Pharmacological inhibition of CD26 by sitagliptin might be a viable strategy to reduce skin scar formation.

6.
J Clin Gastroenterol ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33780222

RESUMO

GOAL: The goal of this study was to determine if bariatric surgeries are associated with de novo alcohol-related complications. BACKGROUND: Bariatric surgery is associated with an increased risk of alcohol use disorders. The effect of bariatric surgeries on other alcohol-related outcomes, including liver disease, is understudied. MATERIALS AND METHODS: Using the IMS PharMetrics database, we performed a cohort study of adults undergoing bariatric surgery or cholecystectomy, excluding patients with an alcohol-related diagnosis within 1 year before surgery. The primary outcome was any alcohol-related diagnosis after surgery. We fit a multivariable Cox proportional hazards model to determine independent associations between bariatric surgeries [Roux-en-Y gastric bypass (RYGB); adjustable gastric band; sleeve gastrectomy] versus cholecystectomy and the development of de novo alcohol-related outcomes. We further fit complication-specific models for each alcohol-related diagnosis. RESULTS: RYGB was significantly associated with an increased hazard of any de novo alcohol-related diagnosis [adjusted hazard ratio (AHR)=1.51, 95% confidence interval (CI): 1.40-1.62], while adjustable gastric band (AHR=0.55, 95% CI: 0.48-0.63) and sleeve gastrectomy (AHR=0.77, 95% CI: 0.64-0.91) had decreased hazards. RYGB was associated with a 2- to 3-fold higher hazard for alcoholic hepatitis (AHR=1.98, 95% CI: 1.17-3.33), abuse (AHR=2.05, 95% CI: 1.88-2.24), and poisoning (3.14, 95% CI: 1.80-5.49). CONCLUSIONS: RYGB was associated with higher hazards of developing de novo alcohol-related hepatitis, abuse, and poisoning compared with a control group. Patients without a history of alcohol use disorder should still be counseled on the increased risk of alcohol use and alcohol-related complications, including alcohol-related liver disease, following RYGB, and should be monitored long term for the development of alcohol-related complications.

7.
Sci Total Environ ; 779: 146430, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33752002

RESUMO

Elevated CO2 (eCO2) and nanoparticles release are considered among the most noteworthy global concerns as they may impose negative effects on human health and ecosystem functioning. A mechanistic understanding of their combined impacts on soil microbiota is essential due to the profound eCO2 effect on soil biogeochemical processes. In this study, the impacts of Cr2O3 nanoparticles (nano-Cr2O3) on the activity, structure and co-occurrence networks of bacterial communities under ambient and eCO2 were compared between a clay loam and a sandy loam soil. We showed that eCO2 substantially mitigated nano-Cr2O3 toxicity, with microbial biomass, enzyme activity and bacterial alpha-diversity in clay loam soil were much higher than those in sandy loam soil. Nano-Cr2O3 addition caused an increase in alpha-diversity except for clay loam soil samples under eCO2. 16S rRNA gene profiling data found eCO2 remarkably reduced community divergences induced by nano-Cr2O3 more efficiently in clay loam soil (P < 0.05). Network analyses revealed more complex co-occurrence network architectures in clay loam soil than in sandy loam soil, however, nano-Cr2O3 decreased but eCO2 increased modularity and network complexity. Rising CO2 favoured the growth of oligotrophic (Acidobacteriaceae, Bryobacteraceae) rather than the copiotrophic bacteria (Sphingomonadaceae, Caulobacteraceae, Bacteroidaceae), which may contribute to community recovery and increase available carbon utilization efficiency. Our results suggested that the degree to which eCO2 mitigates nano-Cr2O3 toxicity is soil dependent, which could be related to the variation in clay and organic matter content, resilience of the resistant bacterial taxa, and microbial network complexity in distinct soils.

8.
Nano Lett ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33728921

RESUMO

Graphene nanoribbons are predicted to support low-loss and tunable plasmonic waveguide modes with an ultrasmall mode area. Experimental observation of the plasmonic waveguide modes in graphene nanoribbons, however, is challenging because conventional wet lithography has difficulty creating a clean graphene nanoribbon with a low edge roughness. Here, we use a dry lithography method to fabricate ultraclean and low-roughness graphene nanoribbons, which are then encapsulated in hexagonal boron nitride (hBN). We demonstrate low-loss plasmon propagation with a quality factor up to 35 in the ultraclean nanoribbon waveguide using cryogenic infrared nanoscopy. In addition, we observe both the fundamental and the higher-order plasmonic waveguide modes for the first time. All the plasmon waveguide modes can be tuned through electrostatic gating. The observed tunable plasmon waveguide modes in ultraclean graphene nanoribbons agree well with the finite-difference time-domain (FDTD) simulation results. They are promising for reconfigurable photonic circuits and devices at a subwavelength scale.

9.
Medicine (Baltimore) ; 100(5): e24127, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592863

RESUMO

BACKGROUND: It is well known that morning blood pressure surge increases the risk of myocardial events in the first several hours post-awakening. This meta-analysis was performed to compare the antihypertensive efficacy of morning and bedtime dosing on decreasing morning blood pressure surge. METHODS: Articles in 4 databases about clinical trials of ingestion time of antihypertensive drugs were searched and performed a meta-analysis to evaluate the different effects on morning blood pressure and absolute blood pressure (BP) reduction from baseline of between bedtime administration (experimental group) and morning awaking administration (control group). RESULTS: The aim of this study is to compare the antihypertensive efficacy of morning and bedtime dosing on decreasing morning blood pressure surge. CONCLUSIONS: The bedtime will provide evidence support for clinicians and patients for reducing morning blood pressure surge. ETHICS AND DISSEMINATION: This study does not require ethical approval.


Assuntos
Anti-Hipertensivos , Cronoterapia Farmacológica , Hipertensão , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial/métodos , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Metanálise como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do Tratamento
10.
BMC Infect Dis ; 21(1): 226, 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33639863

RESUMO

BACKGROUND: The lab-confirmed interval is the date from lab confirmation in a core case (infector) to lab confirmation in a second case (infectee); however, its distribution and application are seldom reported. This study aimed to investigate the lab-confirmed interval and its application in the preliminary evaluation of the strength of disease prevention and control measures. METHODS: Taking European countries and Chinese provinces outside Hubei as examples, we identified 63 infector-infectee pairs from European countries from Wikipedia, and 103 infector-infectee pairs from official public sources in Chinese provinces outside Hubei. The lab-confirmed intervals were obtained through analysis of the collected data and adopting the bootstrap method. RESULTS: The mean lab-confirmed interval was 2.6 (95% CI: 2.1-3.1) days for Europe and 2.6 (95% CI: 1.9-3.3) days for China outside Hubei, which were shorter than the reported serial intervals. For index patients aged ≥60 years old, the lab-confirmed interval in Europe was slightly longer (mean: 2.9; 95% CI: 2.0-3.6) and obviously longer in China outside Hubei (mean: 3.8; 95% CI: 1.9-5.5) than that for patients aged < 60 years. CONCLUSION: Investigation of the lab-confirmed interval can provide additional information on the characteristics of emergent outbreaks and can be a feasible indication to evaluate the strength of prevention and control measures. When the lab-confirmed interval was shorter than the serial interval, it could objectively reflect improvements in laboratory capacity and the surveillance of close contacts.


Assuntos
/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Laboratórios , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Cell Death Dis ; 12(1): 101, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473116

RESUMO

Leukemia arises from blockage of the differentiation/maturation of hematopoietic progenitor cells at different stages with uncontrolled proliferation of leukemic cells. However, the signal pathways that block cell differentiation remain unclear. Herein we found that SUMOylation of the M2 isoform of pyruvate kinase (PKM2), a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, is prevalent in a variety of leukemic cell lines as well as primary samples from patients with leukemia through multiple-reaction monitoring based targeted mass spectrometry analysis. SUMOylation of PKM2 lysine 270 (K270) triggered conformation change from tetrameric to dimeric of PKM2, reduced PK activity, and led to nuclear translocation of PKM2. SUMO1 modification of PKM2 recruits and promotes degradation of RUNX1 via a SUMO-interacting motif, resulting in blockage of myeloid differentiation of NB4 and U937 leukemia cells. Replacement of wild type PKM2 with a SUMOylation-deficient mutant (K270R) abrogated the interaction with RUNX1, and the blockage of myeloid differentiation in vitro and in xenograft model. Our results establish PKM2 as an essential modulator of leukemia cell differentiation and a potential therapeutic target, which may offer synergistic effect with differentiation therapy in the treatment of leukemia.

12.
Oral Dis ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33503275

RESUMO

BACKGROUND: Cyclin-dependent kinase 7 (CDK7) has been critically linked to human cancer. However, the roles of CDK7 in head and neck squamous cell carcinoma (HNSCC) remain incompletely known. Here, we sought to dissect the functions of CDK7 underlying HNSCC tumorigenesis and explore whether pharmacological inhibition of CDK7 could induce anti-cancer effects. METHODS: CDK7 expression was measured in a panel of HNSCC cell lines with p53 mutation and 20 pairs of HNSCC samples and adjacent non-tumor tissues. Genetic targeting and pharmacological inhibition of CDK7 were conducted to dissect the biological roles of CDK7 in p53-mutated HNSCC cells. An HNSCC xenograft model was developed to determine the therapeutic effects of THZ1 in vivo. Potential genes and pathways responsible for therapeutic effects of THZ1 were identified by genome-wide RNA-sequencing and bioinformatics interrogations. RESULTS: CDK7 expression was significantly elevated in cancerous cells and samples as compared with their adjacent non-tumor counterparts. Impaired cell proliferation, migration, and invasion as well increased apoptosis were observed in cells upon CDK7 knockdown or THZ1 exposure. THZ1 administration potently inhibited tumor overgrowth in vivo. Mechanistically, hundreds of genes enriched in cell proliferation, apoptosis, and cancer-related categories were identified to be potentially mediated the therapeutic effects of THZ1 in HNSCC. CONCLUSION: Our findings reveal that CDK7 might serve as a novel putative pro-oncogenic gene underlying HNSCC tumorigenesis and therapeutic targeting of CDK7 might be a promising strategy for p53-mutated HNSCC.

13.
Chemosphere ; 262: 127791, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32799141

RESUMO

Mercury (Hg) that leaches from municipal sewage sludge (MSS) landfill under natural rain is of increasing concern. The column leaching experiments were conducted to investigate the leaching characteristics of total mercury (THg) and methylmercury (MeHg) as well as pH, total organic carbon (TOC), and total suspended solids (TSS) in the raw sludge (RS) and lime-conditioned sludge (LCS) under simulated rain with different acidities (pH 6.5 and 2.9). Results showed the release of MeHg in the leachates presented different patterns from THg. And the final amounts of MeHg in the MSS columns were 1.49 (RS at pH = 6.5), 1.88 (RS at 2.9), 1.97 (LCS at pH = 6.5), and 2.06 times (LCS at pH = 2.9) higher than the initial amounts, suggesting methylation of inorganic Hg (IHg) occurred in the leaching process. The leaching efficiencies of THg and MeHg in RS was lower than that in LCS, indicating lime was more favorable for the release of THg and MeHg. And lower values of pH of the simulated rain promoted the release of THg and MeHg from RS while the opposite was true for LCS. This study provides a better understanding of the release and biogeochemical transformations of Hg in MSS.


Assuntos
Monitoramento Ambiental/métodos , Mercúrio/análise , Compostos de Metilmercúrio/análise , Chuva/química , Esgotos/química , Poluentes Químicos da Água/análise , Compostos de Cálcio/química , China , Modelos Teóricos , Óxidos/química
14.
J Cell Physiol ; 236(2): 889-899, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33020901

RESUMO

Long intergenic noncoding RNAs (lincRNAs) play a vital role in the occurrence and progression of cancer. The mechanism of lincRNAs in colorectal cancer (CRC) has not been fully elucidated. In this context, an integrated comparative long noncoding RNA (lncRNA) microarray technology was used to determine the expression profile of lncRNAs in CRC. The roles of LINC00908 are unclear. We found that LINC00908 was significantly upregulated in CRC. Inhibition of LINC00908 resulted in reduced cell proliferation and G1 cell cycle arrest, which was mediated by cyclin D1, cyclin-dependent kinase 4, and phosphorylated retinoblastoma. Moreover, inhibition of LINC00908-induced apoptosis through the intrinsic apoptosis signaling pathway, as shown by the activation of caspase-9 and caspase-3. Mechanistically, miR-143-3p directly bound to LINC00908. miR-143-3p expression was negatively correlated with LINC00908 expression in CRC tissue. Functional experiments revealed opposing roles for miR-143-3p and LINC00908, suggesting that LINC00908 negatively regulates miR-143-3p. Mechanistically, miR-143-3p directly targets LINC00908. The KLF5 inhibitor ML264 affected proliferation and apoptosis, indicating that LINC00908 may act as a competing endogenous RNA to facilitate the expression of the miR-143-3p target gene KLF5. Thus, LINC00908 has an important proliferative and antiapoptotic role in CRC by regulating the cell cycle and intrinsic apoptosis. LINC00908 could be a potential biomarker and a new therapeutic target for CRC.

15.
J Colloid Interface Sci ; 587: 358-366, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33360905

RESUMO

Chemodynamic therapy (CDT) utilizes Fenton catalysts to convert intracellular hydrogen peroxide (H2O2) into cytotoxic hydroxyl radical (OH∙) for tumor therapy, but endogenous H2O2 is usually insufficient to achieve satisfactory tumor therapy effect. Engineering an efficient CDT nanoplatform for satisfactory cancer therapy remains a challenge. Herein, we rationally designed a Cu-based metal-organic framework-199 (MOF-199) nanoplatform integrating vitamin k3 (Vk3) for amplified CDT-mediated cancer therapy, which could accumulate efficiently in tumor tissues through enhanced permeability and retention (EPR) effect. The MOF-199 nanoparticles (MOF-199 NPs) were dissociated by glutathione (GSH) into MOF-199 fragments, which triggered Fenton-like reaction for CDT. On the one hand, Vk3 was catalyzed by NAD(P)H quinone oxidoreductase-1 (NQO1) to produce sufficient H2O2 to activate Fenton-like reaction. On the other hand, GSH was largely consumed in the tumor microenvironment. Thus, this nanoplatform enabled sufficient cytotoxic reactive oxygen species (ROS) for amplified CDT effect, demonstrating effective tumor growth inhibition with minimal side-effect in vivo. Our work provides an innovative strategy to modulate GSH and H2O2 levels for amplified CDT.

16.
J Ethnopharmacol ; 269: 113768, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33383113

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Astragalus membranaceus and Salvia miltiorrhiza (AS) is an effective prescription that is widely used to treat chronic kidney disease (CKD) clinically in traditional Chinese medicine. Our previous studies have shown that AS can alleviate early CKD through the "gut-kidney axis", but the regulatory role of AS in the "gut-kidney axis" in the middle and late stages of CKD caused by cyclosporin A-induced chronic nephrotoxicity (CICN) has remained unclear. AIM OF THE STUDY: To explore the protective effect of AS by regulating the intestinal flora to further control the miRNA-mRNA interaction profiles in CICN. MATERIALS AND METHODS: Thirty-two mice were divided into four groups: Normal (N) (olive oil), Model (M) (CsA, 30 mg kg-1 d-1), AS (CsA + AS, 30 + 8.4 g kg-1 d-1) and FMT-AS (CsA + Faeces of AS group, 30 mg + 10 mL kg-1 d-1). The mice were treated for 6 weeks. Changes in renal function related metabolites were detected, pathological changes in the colon and kidney were observed, and 16S rDNA sequencing was performed on mouse faeces. In addition, miRNA and mRNA sequencing were performed on the kidney to construct differential expression (DE) profiles of the other 3 groups compared with group M. The target mRNAs among the DE miRNAs were then predicted, and an integrated analysis was performed with the DE mRNAs to annotate gene function by KEGG. DE miRNAs and DE mRNAs related to CICN in the overlapping top 20 KEGG pathways were screened and verified. RESULTS: Eight metabolites that could worsen renal function were increased in group M, accompanied by thickening of the glomerular basement membrane, vacuolar degeneration of renal tubules, and proliferation of collagen fibres, while AS and FMT-AS intervention amended these changes to varying degrees. Simultaneously, intestinal permeability increased, the abundance and diversity of the flora decreased, and the ratio of Firmicum to Bacteroides (F/B) increased in group M. The AS and FMT-AS treatments reversed the flora disorder and increased probiotics producing butyric acid and lactic acid, especially Akkermansia and Lactobacillus, which might regulate the 12 overlapping top 20 KEGG pathways, such as Butanoate metabolism, Tryptophan metabolism and several RF-related pathways, leading to the remission of renal metabolism. Finally, 15 DE miRNAs and 45 DE mRNAs were screened as the therapeutic targets, and the results coincided with the sequencing results. CONCLUSION: AS could alleviate renal fibrosis and metabolism caused by CICN through the "gut-kidney axis". Probiotics such as Akkermansia and Lactobacillus were the primary driving factors, and the miRNA-mRNA interaction profiles, especially Butanoate metabolism and Tryptophan metabolism, may be an important subsequent response and regulatory mechanism.

17.
J Ethnopharmacol ; 266: 113453, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33039628

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Baizhu Tianma decoction (BBTD) is a classical representative prescription for expelling phlegm, extinguishing wind, strengthening the spleen and dissipating excessive fluid in traditional Chinese medicine (TCM). According to both TCM theory and about 300 years of clinical practice, BBTD is especially suitable for hypertensive patients of abdominal obesity and lacking physical activity. AIM OF THE STUDY: The present study tried to interpret the pharmacology of the ancient formula of BBTD. Herein, we focused on the plasma metabonomics of BBTD and evaluated the effect and targets of BBTD on endothelial protective effect. METHODS: Obesity-related hypertensive mice were induced by high-fat diet for 20 weeks. BBTD (17.8 g/kg) was administered intragastrically for 8 weeks, and telmisartan group (12.5 mg/kg) was used as positive drug. Body weight, blood pressure, triglyceride and cholesterol were recorded to evaluate the efficacy of BBTD in vivo. Lipid deposition in aortic roots was assessed by oil red O staining, while morphology of aortas was observed by HE staining. Ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed to study the plasma non-targeted metabonomics. According to the data of metabonomics, human aortic endothelial cells (HAECs) were treated by oxidized low-density lipoprotein (ox-LDL, 50 µg/mL) with/without BBTD (2, 1 or 0.5 mg/mL). Apoptosis rate (Annexin V-FITC/PI), migration (Transwell), cytoskeleton (Phalloidin) and density of VE-cadherin (Immunofluorescence staining) were used to investigate the effect of BBTD in vitro. Transcriptome sequencing was performed (2 mg/mL BBTD vs ox-LDL) to screen the possible targets of BBTD in endothelial protection against ox-LDL. RESULTS: BBTD effectively reduced the body weight and total cholesterol, and decreased 12.1 mmHg in SBP and 10.5 mmHg in DBP of obesity-related hypertensive mice (P < 0.05). BBTD attenuated lipid deposition in arterial roots and improved the morphology of aortas in vivo. Plasma metabolite profiles identified 94 differential metabolites and suggested BBTD mainly affected glycerophospholipids and fatty acyls. Bioinformatics analysis indicated sphingolipid metabolism and fluid shear stress and atherosclerosis were main pathways. Therefore, we focused on endothelial protective effect of BBTD against ox-LDL. In vitro, BBTD demonstrated endothelial protective effects, decreasing apoptosis rate, improving cell migration in dose-dependent manner and maintaining cell morphology. Transcriptome sequencing identified 251 downregulated and 603 upregulated mRNAs after 24h-BBTD treatment, which reversed 51.8% change in mRNAs (393 DE mRNAs) induced by ox-LDL. Bioinformatics analysis supported the potential of BBTD in hypertension and suggested that BBTD improved endothelial cells by targeting mainly on p53 and PPAR signaling pathways. CONCLUSIONS: BBTD attenuates obesity-related hypertension by regulating metabolism of glycerophospholipids and endothelial protection.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hipertensão/tratamento farmacológico , Metabolômica , Obesidade/prevenção & controle , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Lipoproteínas LDL/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo
18.
Nanoscale Horiz ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206735

RESUMO

Photosensitizer-based photodynamic therapy (PDT) can not only kill tumor cells by the generated cytotoxic reactive oxygen species (ROS), but also trigger immunogenic cell death (ICD) and activate an immune response for immunotherapy. However, such photodynamic immunotherapy suffers from major obstacles in the tumor microenvironment. The hypoxic microenvironment greatly weakens PDT, while the immunosuppressive tumor microenvironment caused by aberrant tumor blood vessels and indoleamine 2,3-dioxygenase (IDO) leads to a significant reduction in immunotherapy. To overcome these obstacles, herein, an engineered photosensitizer nanoplatform is designed for amplified photodynamic immunotherapy by integrating chlorin e6 (Ce6, a photosensitizer), axitinib (AXT, a tyrosine kinase inhibitor) and dextro-1-methyl tryptophan (1MT, an IDO inhibitor). In our nanoplatform, AXT improves the tumor microenvironment by normalizing tumor blood vessels, which not only promotes PDT by reducing the level of hypoxia of the tumor microenvironment, but also promotes immunotherapy through facilitating infiltration of immune effector cells into the tumor and reversing the immunosuppressive effect of vascular endothelial growth factor (VEGF). Moreover, 1MT effectively inhibits the activity of IDO, further reducing the immunosuppressive nature of the tumor microenvironment. Therefore, this nanoplatform demonstrates an amplified photodynamic immunotherapy via tumor microenvironment modulation, exhibiting outstanding therapeutic efficacy against tumor growth and metastasis with negligible side toxicity. The current concept of engineering photosensitizer nanoplatforms for overcoming photodynamic immunotherapy obstacles provides a promising strategy against tumors.

19.
Biomed Res Int ; 2020: 4261485, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204695

RESUMO

The combination of Eucommia ulmoides and Tribulus terrestris (ET) has been widely utilized in clinical practice for thousands of years, but the mechanism underlying its efficacy has not been elucidated to date. This study attempted to investigate the role played by the intestinal microbiota and fecal metabolism in the response of elderly spontaneous hypertensive rats (SHRs) to ET administration as a treatment for hypertension. Fourteen male spontaneously hypertensive rats (SHRs, 18 months old) were randomly divided into an ET group and an SHR group, and 7 Wistar-Kyoto (WKY) rats of the same age were employed as the control group. The ET group was intragastrically administered 1.0 g/kg/d ET for 42 days, and SHRs and WKY rats were administered an equal amount of normal saline intragastrically. The intestinal microbiota and fecal metabolism were analyzed by 16S rRNA sequencing and the GC-MS (gas chromatography-mass spectrometry)/MS assay. ET treatment decreased blood pressure steadily, improved the colonic tissue morphology, and changed the structure and composition of the imbalanced microbiota in SHRs. Specifically, ET treatment increased the abundance of Eubacterium, which might be one of the target microbes for ET, and had a negative correlation with the levels of α-tocopherol, chenodeoxycholic acid, and deoxycholic acid according to the Spearman correlation analysis. The change in the intestinal microbiota affected the fecal metabolic pattern of SHRs. Eight potential biomarkers were determined to be primarily enriched in ABC transporters, phenylalanine metabolism, central carbon metabolism in cancer, purine metabolism, and protein digestion and absorption. The correlation analysis demonstrated that the abundance of Eubacterium and the decreased levels of α-tocopherol, chenodeoxycholic acid, and deoxycholic acid in the ET group were highly correlated. Our results suggest that ET has a good antihypertensive effect, which may be driven by the intestinal microbiota and their beneficial metabolites. The results of this study may help to elucidate the antihypertensive mechanism of ET.

20.
Lancet Oncol ; 21(10): 1378-1386, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002439

RESUMO

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.


Assuntos
Predisposição Genética para Doença/genética , Estilo de Vida Saudável , Neoplasias Gástricas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/psicologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/psicologia
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