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1.
J Am Chem Soc ; 146(5): 3405-3415, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38282378

RESUMO

Metal-hydride-catalyzed alkene hydroalkylation has been developed as an efficient method for C(sp3)-C(sp3) coupling with broad substrate availability and high functional group compatibility. However, auxiliary groups, a conjugated group or a chelation-directing group, are commonly required to attain high regio- and enantioselectivities. Herein, we reported a ligand-controlled cobalt-hydride-catalyzed regio-, enantio-, and diastereoselective oxyheterocyclic alkene hydroalkylation without chelation-directing groups. This reaction enables the hydroalkylation of conjugated and unconjugated oxyheterocyclic alkenes to deliver C2- or C3-alkylated tetrahydrofuran or tetrahydropyran in uniformly good yields and with high regio- and enantioselectivities. In addition, hydroalkylation of C2-substituted 2,5-dihydrofuran resulted in the simultaneous construction of 1,3-distereocenters, providing convenient access to polysubstituted tetrahydrofuran with multiple enantioenriched C(sp3) centers.

2.
Hepatology ; 72(3): 923-939, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31867749

RESUMO

BACKGROUND AND AIMS: Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB-EGF to promote angiogenesis and HCC progression. APPROACH AND RESULTS: A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB-EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia-inducible factor 1 α signaling pathway. In addition, HB-EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3-kinase/Akt signaling pathway. The level of HB-EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence-free survival, which suggests that HB-EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB-EGF inhibitor cross-reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. CONCLUSIONS: HB-EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB-EGF inhibitor cross-reacting material 197 with sorafenib might be used for individualized treatment of HCC.


Assuntos
Proteínas de Bactérias/farmacologia , Carcinoma Hepatocelular , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Neoplasias Hepáticas , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Inibidores da Angiogênese/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/prevenção & controle , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Transdução de Sinais , Sorafenibe/farmacologia
3.
J Gastroenterol Hepatol ; 36(6): 1487-1496, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33393670

RESUMO

BACKGROUND AND AIM: The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS: A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS: Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION: Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/genética , Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Prognóstico , Taxa de Sobrevida
5.
BMC Gastroenterol ; 19(1): 142, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395026

RESUMO

BACKGROUND: Paragangliomas, also known as chemodectomas, are rare tumors arise from chemoreceptor tissue, and most commonly locate at the bifurcation of the common carotid, the jugular foramen, aortic arch, and retroperitoneum. Paragangliomas generally are considered to be benign tumors, and rarely produce local or distant metastases. Metastasis to liver is extremely rare. CASE PRESENTATION: We report the case of a 39-year-old woman, who had undergone resection of a retroperitoneal paraganglioma at her local hospital for 12 years. She was referred to our hospital for further evaluation of a hepatic mass, which was misdignosed as hepatocellular carcinoma (HCC) and was treated by transarterial chemoembolization (TACE) in the local hospital 6 years ago. At admission, CT scan revealed a huge hypervascular mass with many feeding arteries, almost the same size as 5 years ago. Ultrasound-guided biopsy of the liver tumor was performed and immunohistochemical examination confirmed the diagnosis of hepatic metastatic paraganglioma. Though liver metastasis failed to achieve complete response or partial response to TACE treatment, it remained stable without progression during the 7-year follow-up. CONCLUSION: Paragangliomas are slow growing tumors and metastasis may develop decades after resection of the primary lesion. Long-term follow-up is necessary, and curative or palliative treatment should be considered to control symptoms, improve life quality, reduce complications and prolong survival.


Assuntos
Neoplasias Hepáticas/diagnóstico , Paraganglioma/diagnóstico , Neoplasias Retroperitoneais/diagnóstico , Adulto , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Paraganglioma/secundário , Paraganglioma/terapia , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/terapia
6.
J Phys Chem Lett ; 15(16): 4422-4429, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38626393

RESUMO

Heterocycles with saturated N atoms (HetSNs) are widely used electron donors in organic light-emitting diode (OLED) materials. Their relatively low bond dissociation energy (BDE) of exocyclic C-N bonds has been closely related to material intrinsic stability and even device lifetime. Thus, it is imperative to realize fast prediction and precise regulation of those C-N BDEs, which demands a deep understanding of the relationship between the molecular structure and BDE. Herein, via machine learning (ML), we rapidly and accurately predicted C-N BDEs in various HetSNs and found that five-membered HetSNs (5-HetSNs) have much higher BDEs than almost all 6-HetSNs, except emerging boron-N blocks. Thorough analysis disclosed that high aromaticity is the foremost factor accounting for the high BDE of 5-HetSNs, and introducing intramolecular hydrogen-bond or electron-withdrawing moieties could also increase BDE. Importantly, the ML models performed well in various realistic OLED materials, showing great potential in characterizing material intrinsic stability for high-throughput virtual-screening and material design efforts.

7.
Nat Commun ; 14(1): 3927, 2023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37400475

RESUMO

The 3rd-Gen OLED materials employing thermally-activated delayed fluorescence (TADF) combine advantages of first two for high-efficiency and low-cost devices. Though urgently needed, blue TADF emitters have not met stability requirement for applications. It is essential to elucidate the degradation mechanism and identify the tailored descriptor for material stability and device lifetime. Here, via in-material chemistry, we demonstrate chemical degradation of TADF materials involves critical role of bond cleavage at triplet state rather than singlet, and disclose the difference between bond dissociation energy of fragile bonds and first triplet state energy (BDE-ET1) is linearly correlated with logarithm of reported device lifetime for various blue TADF emitters. This significant quantitative correlation strongly reveals the degradation mechanism of TADF materials have general characteristic in essence and BDE-ET1 could be the shared "longevity gene". Our findings provide a critical molecular descriptor for high-throughput-virtual-screening and rational design to unlock the full potential of TADF materials and devices.

8.
Biomed Res Int ; 2020: 2403595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724797

RESUMO

Gastric cancer is one of the most common malignancies worldwide, with high morbidity and poor survival rate. Its prognosis remains unsatisfactory, with a 5-year survival rate of <30%. Studies have indicated that Huaier granules have good antitumor efficacy and safety in several solid malignant tumors. Recent studies have also found that Huaier polysaccharides can promote apoptosis in numerous tumor cells, although only few studies have focused on the effects of Huaier granules on gastric cancers and the mechanisms underlying their antitumor role. We retrospectively evaluated stage IIb gastric cancer patients at Xiangya Hospital, Central South University, through our outpatient system from January 2013 to December 2015. Fifty-four patients were in the Huaier+Tegafur Gimeracil Oteracil Potassium (TGOP) group and 72 in the TGOP group. Further, we conducted CCK8, colony formation, Annexin V-FITC/PI, Western blot, RT-PCR, and plasmid transfection assays to analyze the mechanism by which Huaier polysaccharides play an antitumor role. We confirmed that Huaier granules combined with Tegafur Gimeracil Oteracil Potassium could promote patient prognosis, with a better disease-free survival rate (51.32 ± 2.23 vs. 44.19 ± 2.26, p = 0.034) and overall survival rate (56.81 ± 1.32 vs. 51.32 ± 1.69, p = 0.020). Moreover, through cell proliferation assays, Western blot, RT-PCR, and detection of Livin expression at the mRNA and protein levels, we found that Huaier polysaccharides could promote gastric cancer cell apoptosis and inhibit gastric cancer cell proliferation in a time- and dose-dependent manner. Finally, we demonstrated that Huaier polysaccharides promote gastric cancer cell apoptosis through the regulation of Livin expression. Overexpression of Livin reversed the gastric cell apoptosis induced by Huaier polysaccharides. Huaier granules combined with Tegafur Gimeracil Oteracil Potassium ameliorated stage IIb gastric cancer prognosis and induced gastric cancer cell apoptosis by regulating Livin.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Misturas Complexas/uso terapêutico , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas de Neoplasias/metabolismo , Piridinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Potássio/uso terapêutico , Prognóstico , Estudos Retrospectivos , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Trametes
9.
Biol Pharm Bull ; 29(6): 1126-31, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16755004

RESUMO

The protein from Thai bitter gourd (Momordica charantia) fruit pulp was extracted and studied for its hypoglycemic effect. Subcutaneous administration of the protein extract (5, 10 mg/kg) significantly and markedly decreased plasma glucose concentrations in both normal and streptozotocin-induced diabetic rats in a dose-dependent manner. The onset of the protein extract-induced antihyperglycemia/hypoglycemia was observed at 4 and 6 h in diabetic and normal rats, respectively. This protein extract also raised plasma insulin concentrations by 2 fold 4 h following subcutaneous administration. In perfused rat pancreas, the protein extract (10 microg/ml) increased insulin secretion, but not glucagon secretion. The increase in insulin secretion was apparent within 5 min of administration and was persistent during 30 min of administration. Furthermore, the protein extract enhanced glucose uptake into C2C12 myocytes and 3T3-L1 adipocytes. Time course experiments performed in rat adipocytes revealed that M. charantia protein extract significantly increased glucose uptake after 4 and 6 h of incubation. Thus, the M. charantia protein extract, a slow acting chemical, exerted both insulin secretagogue and insulinomimetic activities to lower blood glucose concentrations in vivo.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Momordica charantia/química , Proteínas de Plantas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Glicemia/análise , Técnicas de Cultura de Células , Diabetes Mellitus Experimental/sangue , Frutas/química , Glucagon/metabolismo , Glucose/metabolismo , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Secreção de Insulina , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Perfusão , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/uso terapêutico , Ratos , Ratos Wistar , Estreptozocina
10.
Regul Pept ; 129(1-3): 79-84, 2005 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15927701

RESUMO

Somatostatin (SST) inhibits pancreatic endocrine secretion. It is generally accepted that SSTR2 and SSTR5 mediate the inhibition of glucagon and insulin release, respectively. The present study was performed to test the hypothesis that SSTR2, but not SSTR5, mediates SST-induced inhibition of insulin release in hamster beta-cells. Both hamster clonal beta-cells HIT-T15 and pancreatic islets were used to test this hypothesis. Both SST and a nonpeptide SSTR2 agonist L-779,976 (1-100 nM) inhibited insulin release from HIT-T15 and islets in a concentration-dependent manner. In contrast, nonpeptide agonists for SSTR1, 3, 4 and 5 at the highest concentration studied (1 microM) failed to inhibit insulin release. PRL-2903, a peptide SSTR2 antagonist (0.1-1 muicroM), antagonized SST-induced inhibition of insulin release in a concentration-dependent manner. Taken together, we conclude that, in hamster beta-cells, SST inhibits insulin release via SSTR2 but not SSTR5.


Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/farmacologia , Amidas/farmacologia , Animais , Linhagem Celular , Cricetinae , Relação Dose-Resposta a Droga , Indóis/farmacologia , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Peptídeos Cíclicos/farmacologia , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/antagonistas & inibidores
11.
Regul Pept ; 122(3): 157-62, 2004 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-15491785

RESUMO

The purpose of this study was to investigate the role of arginine vasopressin (AVP) on glucagon secretion in both normal and diabetic rats. Diabetes was induced by intravenous administration of 50 mg/kg streptozotocin, 14 days before pancreatic perfusion. Diabetic rats were maintained on insulin replacement therapy until approximately 48 h before the perfusion experiments. Both glucagon and AVP were determined in the effluent of the perfused pancreas using RIA. Both normal and diabetic rats had similar basal glucagon secretion. AVP (3-30 pM) increased glucagon secretion from both normal and diabetic rats in a concentration-dependent manner. However, diabetic subjects were more sensitive to AVP administration than normal subjects with regard to glucagon secretion. By comparison of the areas under the curves, AVP-induced glucagon secretion in diabetic rats was approximately 2-fold that of the normal rats. In addition, immunoreactive AVP was detected in the effluent of the perfused pancreas, and diabetic rats had 70% higher AVP concentrations in the pancreatic effluent than normal rats. We conclude that AVP is secreted from the pancreas and diabetic rats can secrete more AVP from the pancreas than normal rats. Consequently, AVP may have a greater impact on glucagon secretion in diabetic subjects than normal ones. AVP might play an important role in the hypersecretion of glucagon in diabetic subjects.


Assuntos
Arginina Vasopressina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucagon/metabolismo , Pâncreas/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Técnicas In Vitro , Insulina/administração & dosagem , Masculino , Perfusão , Ratos , Ratos Sprague-Dawley
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