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2.
Front Endocrinol (Lausanne) ; 12: 740902, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621244

RESUMO

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P>0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only.

3.
J Ethnopharmacol ; : 114735, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34637969

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Qing' E Formula (QEF) is a compound preparation that was originally recorded in the 'Prescriptions of the Bureau of Taiping People's Welfare Pharmacy' during the Song Dynasty (10th century CE). It consists of four Chinese medicinal herbs, Eucommiae Cortex (Eucommia ulmoides), Psoraleae Fructus (Psoralea corylifolium), Juglandis Semen (Juglans regia), and Garlic Rhizoma. According to traditional Chinese medicine (TCM), QEF has the ability to tonify the kidney and strengthen muscle and bone. According to the 'kidney governing bone' theory in TCM, QEF is also used to treat the symptoms of climacteric syndrome, especially osteoporosis caused by reduced production of estrogen during the perimenopausal period; however, the therapeutic roles of the individual components of the QEF and their compatibility within the formula has not been investigated. AIM OF THE STUDY: In this study, the compatibility mechanism and estrogen-like action properties of the four herbal components in the QEF was elucidated according to the organizing principle of Chinese medicine formulas using both in vitro and in vivo models. MATERIALS AND METHODS: The estrogen-like effects of QEF and its herbal components were investigated in MCF7 and HEK293 cells as well as ovariectomized (OVX) rats. The estrogen-like effects of the QEF and its components were analyzed in vitro using Cell Counting Kit-8 and Luciferase reporter gene assays. In the in vivo studies, the blood plasma levels of hormones, lipids, neurotransmitters, aromatase, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured through enzyme-linked immunosorbent assays (ELISAs). The histological morphologies of the target organs after exposure to QEF were investigated by HE staining and immunohistochemical methods. The expression levels of estrogen pathway-related proteins and genes in the OVX rats were measured by Western blotting and real time quantitative PCR (RT-qPCR), respectively. RESULTS: The in vitro results showed that the QEF, Eucommia (EC) and Psoralea (PF) promoted the proliferation of MCF-7 cells and upregulated the expression of ERα, ERß and pS2 genes in the MCF-7 cells. Notably, the QEF demonstrated the most active estrogen-like effects compared to the individual ingredients. The in vivo results showed that the QEF, EC, and PF increased the uterine coefficient, the upregulated the expression of both ERs (ERα and ERß) in the uterus, and increased blood serum hormone levels. QEF and its individual components ameliorated menopausal-derived lipid metabolism dysfunction, increased neurotransmitter production by stimulating the adrenal glands, enhanced the antioxidant activity in the serum by increasing the concentration of SOD, reversed ovariectomy-derived atrophy in the uterus, and reduced the weight gain associated with estrogen reduction in the OVX rats. The QEF also antagonize the loss of appetite of OVX animals caused by feeding Psoralea alone, which could explain the compatibility mechanism of Qing' E Formula with reducing toxicity and increasing efficiency. CONCLUSIONS: The estrogen-like effects of Eucommia and Psoralea were mainly mediated through activation of ERα and ERß. The phytoestrogen components regulated hormone production and the expression of related proteins and genes, which indicated that these components exhibited estrogen-like therapeutic effects. However, the QEF showed the greatest estrogen-like effects compared to the individual components. Overall, this corroborated the therapeutic prowess of the QEF and clarified the pharmacodynamic interactions between the different extracts in the QEF.

4.
J Med Chem ; 64(18): 13410-13428, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34499493

RESUMO

Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.

5.
Inflamm Bowel Dis ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34473281

RESUMO

BACKGROUND: Stimulator of interferon genes (STING) has essential functions in the immune responses and can induce cancer cell apoptosis. However, it is not completely clear how STING plays a role in colitis-associated colorectal cancer (CAC) and whether it can trigger pyroptosis during the tumorigenesis of CAC. METHODS: To investigate the role of STING-modulated pyroptosis in the development of CAC, STING knockout and Wild type mice were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to establish a murine CAC model. STING pharmacological agonist was used to further study the functions of STING signaling in the tumorigenesis. Moreover, STING endogenous ligand was employed to verify the effects of STING in human colon cancer cells. RESULTS: STING deficiency mice were more susceptible to CAC by reducing pyroptosis of tumor cells, whereas overactivation of STING with the agonist suppressed tumorigenesis of CAC. STING also managed CAC development by modulating tumor cells proliferation, adhesion, and invasion, as well as inflammatory response. The ex vivo studies indicated that STING could induce pyroptosis via spleen tyrosine kinase (Syk), and Syk knockdown weakened such pyroptotic tumor cells death. In addition, the visible physical interaction between STING and Syk was observed in colorectal tumor samples of CAC patients. CONCLUSIONS: STING-mediated Syk signaling may regulate the tumorigenesis of CAC by modulating pyroptosis of tumor cells, and modulation of STING/Syk serves as a novel therapeutic strategy for CAC therapy.

6.
Sci Rep ; 11(1): 18448, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531460

RESUMO

The identification and characterization of new ß-galactosidases will provide diverse candidate enzymes for use in food processing industry. In this study, two ß-galactosidases, Nf-LacZ and WspA1, from the terrestrial cyanobacterium Nostoc flagelliforme were heterologously expressed in Escherichia coli, followed by purification and biochemical characterization. Nf-LacZ was characterized to have an optimum activity at 40 °C and pH 6.5, different from that (45 °C and pH 8.0) of WspA1. Two enzymes had a similar Michaelis constant (Km = 0.5 mmol/liter) against the substrate o-nitrophenyl-ß-D-galactopyranoside. Their activities could be inhibited by galactostatin bisulfite, with IC50 values of 0.59 µM for Nf-LacZ and 1.18 µM for WspA1, respectively. Gel filtration analysis suggested that the active form of WspA1 was a dimer, while Nf-LacZ was functional as a larger multimer. WspA1 was further characterized by the truncation test, and its minimum central region was found to be from residues 188 to 301, having both the glycosyl hydrolytic and transgalactosylation activities. Finally, transgenic analysis with the GFP reporter protein found that the N-terminus of WspA1 (35 aa) might play a special role in the export of WspA1 from cells. In summary, this study characterized two cyanobacterial ß-galactosidases for potential applications in food industry.

7.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3853-3858, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472259

RESUMO

Fifteen bibenzyls were isolated and purified from the ethyl acetate extract of the stems of Dendrobium officinale by macroporous resin, MCI, silica gel, Sephadex LH-20, and ODS column chromatographies, as well as preparative thin-layer chromatography and preparative HPLC. The structures of compounds were identified according to the spectra data of ~1H-NMR, ~(13)C-NMR, and MS, and the physical and physiochemical properties: dendrocandin X(1), 3,4'-dihydroxy-4,5-dimethoxybibenzyl(2), 6″-de-O-methyldendrofindlaphenol A(3), 3,4-dihydroxy-4',5-dimethoxybibenzyl(4), dendrosinen B(5), 3,4,4'-trihydroxy-5-methoxybibenzyl(6), 3,3'-dihydroxy-4,5-dimethoxybibenzyl(7), 3,4'-dihydroxy-5-methoxybibenzyl(8), moscatilin(9), gigantol(10), 4,4'-dihydroxy-3,5-dimethoxybibenzyl(11), 3,4',5-trihydroxy-3'-methoxybibenzyl(12), 3-O-methylgigantol(13), dendrocandin U(14), and dendrocandin N(15). Compound 1 was a novel compound. Compound 2 was isolated from Dendrobium species for the first time. Compounds 3-7 were isolated from D. officinale for the first time.


Assuntos
Bibenzilas , Dendrobium , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética
8.
Oxid Med Cell Longev ; 2021: 6614574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457117

RESUMO

Inflammatory reactions mediated by the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome contributes to non-small-cell lung cancer (NSCLC) progression, particularly in patients with bacterial infections. Salidroside (SAL) has recently been shown to suppress lipopolysaccharide- (LPS-) induced NSCLC proliferation and migration, but its mechanism of action remains unclear. It has been shown that SAL improves metabolic inflammation in diabetic rodents through AMP-activated protein kinase- (AMPK-) dependent inhibition of the NLRP3 inflammasome. However, whether the NLRP3 inflammasome is regulated by SAL in NSCLC cells and how its underlying mechanism(s) can be determined require clarification. In this study, human lung alveolar basal carcinoma epithelial (A549) cells were treated with LPS, and the effects of SAL on cell proliferation, migration, AMPK activity, reactive oxygen species (ROS) production, and NLRP3 inflammasome activation were investigated. We found that LPS induction increases the proliferation and migration of A549 cells which was suppressed by SAL. Moreover, SAL protected A549 cells against LPS-induced AMPK inhibition, ROS production, and NLRP3 inflammasome activation. Blocking AMPK using Compound C almost completely suppressed the beneficial effects of SAL. In summary, these results indicate that SAL suppresses the proliferation and migration of human lung cancer cells through AMPK-dependent NLRP3 inflammasome regulation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glucosídeos/farmacologia , Inflamassomos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Humanos , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais , Células Tumorais Cultivadas
9.
Nat Commun ; 12(1): 5089, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429424

RESUMO

The current nucleic acid signal amplification methods for SARS-CoV-2 RNA detection heavily rely on the functions of biological enzymes which imposes stringent transportation and storage conditions, high cost and global supply shortages. Here, a non-enzymatic whole genome detection method based on a simple isothermal signal amplification approach is developed for rapid detection of SARS-CoV-2 RNA and potentially any types of nucleic acids regardless of their size. The assay, termed non-enzymatic isothermal strand displacement and amplification (NISDA), is able to quantify 10 RNA copies.µL-1. In 164 clinical oropharyngeal RNA samples, NISDA assay is 100 % specific, and it is 96.77% and 100% sensitive when setting up in the laboratory and hospital, respectively. The NISDA assay does not require RNA reverse-transcription step and is fast (<30 min), affordable, highly robust at room temperature (>1 month), isothermal (42 °C) and user-friendly, making it an excellent assay for broad-based testing.


Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , RNA Viral/isolamento & purificação , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , COVID-19/virologia , Teste para COVID-19 , Humanos , RNA Viral/genética , Recombinação Genética
10.
Chemistry ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34431146

RESUMO

Two dithienocyclopentafluorene-based small-molecule acceptors (SMAs) were developed that feature methylene-functionalized conjugated side chains, to study the effect of arylmethylene substitution and its number on structure, optoelectronic properties and device performance. Results showed that two SMAs have better absorption properties and planarity, lower bandgaps and higher LUMOs compared with the control SMA without conjugated side chains. The synthesized SMAs were tested in polymer solar cells for examples of their applicability. This work argues that the introduction of methylene-functionalized conjugated side chains has great potential in tuning molecular structure, optoelectronic properties, device physics and photovoltaic performance of SMAs.

11.
Comput Biol Med ; 136: 104749, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34388467

RESUMO

Segmentation of adrenal glands from CT images is a crucial step in the AI-assisted diagnosis of adrenal gland-related disease. However, highly intrasubject variability in shape and adhesive boundaries with surrounding tissues make accurate segmentation of the adrenal gland a challenging task. In the current study, we proposed a novel two-stage deep neural network for adrenal gland segmentation in an end-to-end fashion. In the first stage, a localization network that aims to determine the candidate volume of the target organ was used in the preprocessing step to reduce class imbalance and computational burden. Then, in the second stage, a Small-organNet model trained with a novel boundary attention focal loss was designed to refine the boundary of the organ within the screened volume. The experimental results show that our proposed cascaded framework outperforms the state-of-the-art deep learning method in segmenting the adrenal gland with respect to accuracy; it requires fewer trainable parameters and imposes a smaller demand on computational resources.


Assuntos
Processamento de Imagem Assistida por Computador , Tomografia Computadorizada por Raios X , Redes Neurais de Computação
12.
Anticancer Drugs ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34387599

RESUMO

Circular FOXM1 (circFOXM1) has been demonstrated to participate in the initiation and development of cancers, including prostate cancer (PCa). However, there is no relevant information on the regulation of PCa by circFOXM1. The RNA level of circFOXM1 was detected by qRT-PCR in PCa tissues and cells. The protein expression was performed by western blot and immunohistochemistry assay. Cell proliferation was examined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide, colony formation and flow cytometry assays. The abilities of cell migration and invasion were determined by transwell assay. The relationship between circFOXM1 and miR-515-5p or ADAM10 was predicted by starBaseV2.0 online database, and identified by dual-luciferase reporter assay or RNA pull-down assay. The effects of circFOXM1 silencing and ADAM10 knockdown on PCa growth in vivo were evaluated by in-vivo tumor formation assay. As a result, we found that circFOXM1 and ADAM10 expression were upregulated in PCa tissues and cells. Functional analysis showed that circFOXM1 silencing repressed proliferation, migration and invasion, and induced cell cycle arrest, whereas these effects were partly reversed by miR-515-5p inhibitor. Additionally, circFOXM1 directly sponged miR-515-5p, and miR-515-5p bound to ADAM10. ADAM10 absence also repressed PCa process. Furthermore, in-vivo tumor formation assay revealed that both circFOXM1 silencing and ADAM10 knockdown repressed tumor growth in vivo. Thus, we came a conclusion that circFOXM1 contributed to PCa progression via regulating miR-515-5p/ADAM10 axis. These results may provide a theoretical basis for further studying the progression of PCa.

13.
Int Rev Immunol ; : 1-12, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34355656

RESUMO

Spleen tyrosine kinase (Syk) is a cytoplasmic non-receptor protein tyrosine kinase expressed in a variety of cells and play crucial roles in signal transduction. Syk mediates downstream signaling by recruiting to the dually phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) of the transmembrane adaptor molecule or the receptor chain itself. In gut diseases, Syk is observed to be expressed in intestinal epithelial cells, monocytes/macrophages, dendritic cells and mast cells. Activation of Syk in these cells can modulate intestinal mucosal immune response by promoting inflammatory cytokines and chemokines production, thus regulating gut homeostasis. Due to the restriction of specificity and selectivity for the development of Syk inhibitors, only a few such inhibitors are available in gut diseases, including intestinal ischemia/reperfusion damage, infectious disease, inflammatory bowel disease, etc. The promising outcomes of Syk inhibitors from both preclinical and clinical studies have shown to attenuate the progression of gut diseases thereby indicating a great potential in the development of Syk targeted therapy for treatment of gut diseases. This review depicts the characterization of Syk, summarizes the signal pathways of Syk, and discusses its potential targeted therapy for gut diseases.

14.
Cell Death Dis ; 12(9): 815, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34453041

RESUMO

Crohn's disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.

15.
BMC Pregnancy Childbirth ; 21(1): 586, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429102

RESUMO

BACKGROUND: The ability of a preventive nutritional intervention to reduce the morbidity of gestational diabetes mellitus (GDM) remains controversial. We aim to assess whether GDM can be prevented by an individualised nutritional intervention in pregnant women who are at high risk for the disease based on a prediction model. METHODS/DESIGN: A multicentre randomised controlled trial was designed to assess the efficacy of an individualised nutritional intervention for the prevention of GDM in a high-risk population screened by a novel prediction model in the first trimester. Pregnant women evaluated to be at high risk for GDM by the prediction model at less than 14 gestational weeks will be included. Women with pre-existing chronic diseases, including pregestational diabetes, or who are currently prescribed medicines that affect glucose values will be excluded. Allocation to intervention/control at a ratio of 1:1 will be conducted by a computerized randomisation system. The intervention group will complete 3-day food records and receive 3 individualised nutritional consultations with professional dieticians before the oral glucose tolerance test. The primary intention of the intervention is to promote a long-term healthy dietary pattern and prevent excessive gestational weight gain throughout pregnancy. The control group will complete 3-day food records at designated gestational weeks and receive standard antenatal care according to local health care provisions. The primary outcome is the incidence of GDM according to the criteria of the International Association of Diabetes and Pregnancy Study Group (IADPSG). A sample of 464 participants will provide 80% power to detect a 30% reduction in GDM incidence (α = 0.05 two tailed, 10% dropout). A total of 500 participants will be recruited. DISCUSSION: To date, this is the first randomised controlled trial aimed to evaluate the protective effect of an individualised nutritional intervention against GDM based on a logistic regression prediction model. Eligibility is not limited to obese women or singleton pregnancies, as in previous studies. This pragmatic trial is expected to provide valuable information on early screening and effective GDM prevention methods. TRIAL REGISTRATION NUMBER: ChiCTR, ChiCTR1900026963 . Registered 27 October 2019.

16.
J Matern Fetal Neonatal Med ; : 1-8, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34344279

RESUMO

BACKGROUND AND OBJECTIVE: Association of interleukin-10 (IL-10) polymorphism with diabetes and its complication was recently established, while there were few kinds of research considering the potential role of IL-10 in gestational diabetes (GDM). This study aimed to systematically review the association between serum IL-10 level and GDM susceptibility. METHODS: A comprehensive literature search for the published studies in PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials), and Google Scholar databases was performed for English language papers published up to 31st July 2020. Following key terms were used: "Cytokine level" OR "Interleukin-10" OR "IL-10," OR "Pro-inflammatory Cytokines" OR "gestational diabetes mellitus" OR "GDM." Fixed or random-effects models were used to estimate the pooled SDM and 95% confidence intervals (CIs). Begg's funnel plot was used to assess the potential for publication bias. RESULTS: In our meta-analysis, a total of ten studies for the risk of GDM involving 609 GDM cases and 664 controls were included. No significant association between IL-10 levels and risk of GDM as compared to control subjects (SMD = -0.09, 95% CI = -0.73 to 0.55). Subgroup analysis based on ethnicity also does not reveal any association between IL-10 levels and risk of GDM as compared to control subjects has more or less similar trends in Caucasian (SMD = -0.07, 95% CI = -0.58 to 0.45) as well as Asian population (SMD = -0.03, 95% CI = -1.56 to 1.49). CONCLUSION: Our findings suggest that the serum IL-10 level may not be significantly associated with an increased risk of susceptibility to GDM. Further well-designed prospective studies embedded with a large sample size are needed to confirm these findings.

17.
Acta Pharmacol Sin ; 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462561

RESUMO

Helichrysetin (HEL), a chalcone isolated from Alpinia katsumadai Hayata, has an antitumor activity in human lung and cervical cancers. However, the inhibitory effect and underlying mechanism of HEL in gastric cancer have not been elucidated. Here, HEL significantly inhibited the growth of gastric cancer MGC803 cells in vitro and in vivo. HEL decreased expression and transcriptional regulatory activity of c-Myc and mRNA expression of c-Myc target genes. HEL enhanced mitochondrial oxidative phosphorylation (OXPHOS) and reduced glycolysis as evidenced by increased mitochondrial adenosine triphosphate (ATP) production and excessive reactive oxygen species (ROS) accumulation, and decreased the pPDHA1/PDHA1 ratio and Glyco-ATP production. Pyruvate enhanced OXPHOS after HEL treatment. c-Myc overexpression abolished HEL-induced inhibition of cell viability, glycolysis, and protein expression of PDHK1 and LDHA. PDHK1 overexpression also counteracted inhibitory effect of HEL on cell viability. Conversely, c-Myc siRNA decreased cell viability, glycolysis, and PDHK1 expression. NAC rescued the decrease in viability of HEL-treated cells. Additionally, HEL inhibited the overactivated mTOR/p70S6K pathway in vitro and in vivo. HEL-induced cell viability inhibition was counteracted by an mTOR agonist. mTOR inhibitor also decreased cell viability. Similar results were obtained in SGC7901 cells. HEL repressed lactate production and efflux in MGC803 cells. These results revealed that HEL inhibits gastric cancer growth by targeting mTOR/p70S6K/c-Myc/PDHK1-mediated energy metabolism reprogramming in cancer cells. Therefore, HEL may be a potential agent for gastric cancer treatment by modulating cancer energy metabolism reprogramming.

18.
Autophagy ; : 1-18, 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34403298

RESUMO

Thiel-Behnke corneal dystrophy (TBCD) is an epithelial-stromal TGFBI dystrophy caused by mutations in the TGFBI (transforming growth factor beta induced) gene, though the underlying mechanisms and pathogenesis of TBCD are still obscure. The study identifies a novel mutation in the TGFBI gene (p.Gly623_His626del) in a TBCD pedigree. Characteristics of the typical vacuole formation, irregular corneal epithelial thickening and thinning, deposition of eosinophilic substances beneath the epithelium, and involvement of the anterior stroma were observed in this pedigree via transmission electron microscopy (TEM) and histological staining. Tgfbi-p.Gly623_Tyr626del mouse models of TBCD were subsequently generated via CRISPR/Cas9 technology, and the above characteristics were further verified via TEM and histological staining. Lysosomal dysfunction and downregulation of differential expression protein CTSD (cathepsin D) were observed using LysoTracker Green DND-26 and proteomic analysis, respectively. Hence, lysosomal dysfunction probably leads to autophagic flux obstruction in TBCD; this was supported by enhanced LC3-II and SQSTM1 levels and decreased CTSD. TFEB (transcription factor EB) was prominently decreased in TBCD corneal fibroblasts and administration of ATP-competitive MTOR inhibitor torin 1 reversed this decline, resulting in the degradation of accumulated mut-TGFBI (mutant TGFBI protein) via the ameliorative lysosomal function and autophagic flux owing to elevated TFEB activity as measured by western blot, confocal microscopy, and flow cytometry. Transfected HEK 293 cells overexpressing human full-length WT-TGFBI and mut-TGFBI were generated to further verify the results obtained in human corneal fibroblasts. Amelioration of lysosome dysfunction may therefore have therapeutic efficacy in the treatment of TBCD.

19.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3605-3613, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402284

RESUMO

A novel HPLC method with the quantitative analysis of multi-components by single marker( QAMS) combined with the dual-wavelength method was developed for simultaneous determination of six flavonoids in Dendrobium officinale stems from different producing areas,cultivation and processing methods to clarify the main factors contributing to the different composition of flavonoids.The separation of six flavonoids was performed on a Shiseido Capcell PAK MGⅡ C18 column( 4. 6 mm×250 mm,5 µm) using a linear gradient elution system of acetonitrile-0. 1% formic acid aqueous solution. Schaftoside,isoschaftoside,vicenin-2,and glucosylvitexin were simultaneously analyzed using rutin as a reference standard at detection wavelength of 340 nm,and naringenin was determined at290 nm. The credibility and feasibility of QAMS method were validated and the results demonstrated that no significant differences were observed as compared with the external standard method. Finally,a total of 82 batches of D. officinale samples were analyzed and principal component analysis( PCA) and discriminant analysis were applied to distinguish and compare D. officinale samples from different producing areas,cultivation and processing methods. The results showed that the total flavonoid content of D. officinale stems cultivated in the simulated wild( attached tree cultivation or attached stone cultivation) was significantly higher than that in greenhouse bed cultivation. The content of flavonoids in simulated-wild D. officinale stems was higher in Jiangxi,Guizhou,Zhejiang,and Fujian provinces,while that in greenhouse bed cultivation was higher in Fujian and Zhejiang provinces. The content of naringenin was positively correlated with processing temperature,and that of the other five flavonoids was negatively correlated with processing temperature. PCA showed that wild-simulated D. officinale and greenhouse bed-cultivated D. officinale could be roughly divided into two clusters. The samples cultivated in the greenhouse bed were divided into four categories according to the geographical habitats. Wild-simulated D. officinale samples from Guizhou gathered together,and there was no obvious rule in samples from other producing areas. The established method simplified the determination method of flavonoids in D. officinale,and could provide the basis for effective quality control,cultivation and processing of D. officinale.


Assuntos
Dendrobium , Medicamentos de Ervas Chinesas , Cromatografia Líquida de Alta Pressão , Flavonoides , Controle de Qualidade
20.
Phytomedicine ; 90: 153625, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34256329

RESUMO

BACKGROUND: Ulcerative colitis is a subtype of inflammatory bowel disease, characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. Previous studies suggested that the natural compound tricin, a flavone isolated from rice bran, could suppress chemically-induced colitis in mice, while our recent study also demonstrated the anti-metastatic effect of tricin in colon tumor-bearing mice. HYPOTHESIS/PURPOSE: Here we further investigated the underlying mechanism of the inhibitory effects of tricin on lipopolysaccharides-activated macrophage RAW264.7 cells and explored the efficacy of tricin in acute colitis mouse model induced by 4.5% dextran sulfate sodium (DSS) for 7 days. METHODS: Tricin (75, 100, and 150 mg/kg) or the positive control drug sulfasalazine (200 mg/kg) were orally administered to mice for 7 days. Stool consistency scores, stool blood scores, and body weight were recorded daily. Disease activity index (DAI) was examined on day 7, and colon tissues were collected for biochemical analyses. The fecal microbiome of colitis mice after tricin treatment was characterized for the first time in this study using 16S rDNA amplicon sequencing. RESULTS: Results showed that tricin (50 µM) remarkably reduced nitric oxide production in lipopolysaccharides-activated RAW264.7 cells and the anti-inflammatory activity of tricin was shown to act through the NF-κB pathway. Besides, tricin treatment at 150 mg/kg significantly reversed colon length reduction, reduced myeloperoxidase activities and DAI scores, as well as restored the elevated myeloid-derived suppressive cells population in acute colitis mice. The influence from DSS on gut microbiota, such as the increased population of Proteobacteria phylum and Ruminococcaceae family, was shown to be relieved after tricin treatment. CONCLUSION: Our present study firstly demonstrated that tricin ameliorated acute colitis by improving colonic inflammation and modulating gut microbiota profile, which supports the potential therapeutic use of tricin for colitis treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa , Colite , Flavonas , Macrófagos/citologia , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Flavonas/farmacologia , Flavonoides/farmacologia , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7
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