RESUMEN
Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. Sanghuangporus (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched Alistipes, especially Alistipes onderdonkii, and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live A. onderdonkii or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of A. onderdonkii and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota.
RESUMEN
A mild and effective strategy for the asymmetric synthesis of C2-quaternary indolin-3-ones from 2-alkynyl arylazides and ketones by gold/chiral amine relay catalysis is described. In this reaction, 2-alkynyl arylazides undergo gold-catalyzed cyclization, nucleophilic attack, and oxidation to form intermediate 2-phenyl-3H-indol-3-ones, followed by an l-proline-catalyzed asymmetric Mannich reaction with ketones, to afford corresponding products in satisfactory yields with excellent enantio- and diastereoselectivities.
RESUMEN
A gold-catalyzed, nucleophile-controlled cascade reaction of N-(2-azidophenyl-ynyl)methanesulfonamides with nitriles and water is described that provides structurally diverse 5H-pyrimido[5,4-b]indoles and 2-benzylidene-3-indolinones in good to excellent yields. Mechanistic studies indicate that the ß-sulfonamido-α-imino gold carbene is the key intermediate which is generated through the gold-catalyzed cyclization of N-(2-azidophenyl-ynyl)methanesulfonamides and undergoes formal [4 + 2] cascade annulation with nitriles and intramolecular SN2' type reaction with water, respectively.
RESUMEN
An asymmetric double oxidative [3 + 2] cycloaddition is reported. Oxidation of 3-((2,2,2-trifluoroethyl)amino)indolin-2-ones and ß-aryl-substituted aldehydes simultaneously and subsequent asymmetric cycloaddition in the presence of the chiral amino catalyst generated highly functionalized chiral CF3-containing spiro[pyrrolidin-3,2'-oxindole] with four contiguous stereocenters stereoselectively, which is characterized by directly constructing two C-C bonds from four C(sp3)-H bonds. This new method features mild conditions, broad substrate scope, and excellent functional group compatibility.
RESUMEN
α-(3-Indolyl)ketones are essential building blocks for the generation of biologically active molecules. We described a new method for the direct assembly of α-(3-indolyl)ketones through the cascade reaction of 2-alkynyl aryl azides with enecarbamates, in which the in situ generated α-imino gold carbene intermediate was trapped by enecarbamate to achieve umpolung reactivity of indole at the 3-position.
RESUMEN
We describe a gold-catalyzed cyclization of 1-(2'-azidoaryl)propargylsulfonamides for the synthesis of 3-sulfonamidoquinolines, featuring a rare and highly selective 1,2-N migration. The key α-imino gold carbene intermediate is generated through an intramolecular nucleophilic attack of the azide group to the Au-activated triple bonds in a 6-endo-dig manner.
RESUMEN
A chemoselective and diastereoselective synthesis of fused oxazolidines was achieved by a three-component cascade reaction of tetrahydroisoquinolines (THIQs), α,ß-unsaturated aldehydes, and diethyl 2-oxomalonate. Probably due to the reactivity difference between the aldehyde and the ketone, the reaction proceeded through the condensation of THIQs with α,ß-unsaturated aldehydes and 1,3-dipolar cycloaddition of the generated azomethine ylide intermediate with 2-oxomalonate. The key features are easily available starting materials, mild reaction conditions, broad substrate scope, and high chemo- and diastereoselectivity.
Asunto(s)
Aldehídos , Tetrahidroisoquinolinas , Aminas , Ciclización , Reacción de Cicloadición , Malonatos , Oxazoles , EstereoisomerismoRESUMEN
An unprecedented gold-catalyzed procedure for the synthesis of polysubstituted 4-quinolones from 1-(2'-azidoaryl) propynols is described. The reaction undergoes an intramolecular nucleophilic attack of the azide group to the Au-activated triple bonds in a 6-endo-dig manner and subsequent gold-assisted expulsion of N2 to furnish an α-imino gold carbene intermediate, which triggers a 1,2-carbon migration and finally is converted to 2,3-disubstituted 4-quinolone.
RESUMEN
BACKGROUND: This study aimed to investigate the effect of the Phellinus linteus (Mesima) decoction on podocyte injury in a rat model of focal and segmental glomerulosclerosis (FSGS) and evaluate the potential mechanisms. METHODS: FSGS resembling primary FSGS in humans was established in rats by uninephrectomy and the repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, low-dose group of P. linteus decoction (PLD-LD), medium-dose group of P. linteus decoction (PLD-MD), and high-dose group of P. linteus decoction (PLD-HD). Blood and urine analysis were performed after 12 weeks and the molecular indicators of renal function and the renal pathological changes were examined. RESULTS: FSGS developed within 12 weeks in the test group and showed progressive proteinuria and segmental glomerular scarring. Urinary protein, serum creatinine, urea nitrogen, triglycerides and cholesterol were significantly reduced following the 12-week intervention with P.linteus decoction, especially in the PLD-LD group. Renal nephrin and podocin were markedly increased. Moreover, the pathological damage in the renal tissue was alleviated by the PLD-LD intervention. CONCLUSION: The P. linteus decoction alleviated the podocyte injury in the FSGS rat model, thus minimizing the progression of glomerular sclerosis and improving renal function.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Podocitos/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Proteínas de la Membrana/metabolismo , Phellinus , Podocitos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation process. This straightforward transformation of sp3-sp3 (C-C) bonds to sp-sp (C≡C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild conditions. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations, as illustrated by regioselective Huisgen alkyne-azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield).
RESUMEN
Ru-catalyzed tandem amine oxidative dehydrogenation/formal aza-Dielsâ»Alder reaction for enantio- and diastereoselective synthesis of indoloquinolizidine-2-ones from tetrahydro-ß-carbolines and α,ß-unsaturated ketones is described. The reaction proceeds via tandem ruthenium-catalyzed amine dehydrogenation using tert-butyl hydroperoxide (TBHP) as the oxidant and a chiral thiourea-catalyzed formal aza-[4 + 2] cycloaddition, providing a step-economical strategy for the synthesis of these valuable heterocyclic products.
Asunto(s)
Carbolinas/química , Reacción de Cicloadición , Cetonas/química , Quinolizidinas/síntesis química , Alcaloides Indólicos/química , Oxidación-Reducción , Quinolizidinas/químicaRESUMEN
An asymmetric dehydrogenative Diels-Alder reaction of 2-methyl-3-phenylmethylindoles and α,ß-unsaturated aldehydes has been established. The successful in situ generation of the indole ortho-quinodimethane intermediate and the iminium activation of enals are the keys to success, providing various tetrahydrocarbazole derivatives with up to >99% ee.
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Challenging substrates and conditions in homogeneous catalysis pose stringent demands on the ligands used. A novel, bulky, 1-adamantyl-substituted disulfoxide ligand designed after a systematic evaluation of the electronic and steric properties of disulfoxide substituents permits the allylic oxidative C-N coupling reaction to proceed at lower catalyst loading while requiring a smaller excess of reagents. Additionally, this ligand improves the yields when TsNHCOOCH2CCl3, a novel reagent that permits deprotection of the products under both acidic and basic conditions, is used.
RESUMEN
Protocatechualdehyde (PCA) extracted from Phellinus gilvus exhibits anti-cancer activity in human colorectal carcinoma cells (HT-29). However, the underlying mechanisms remain poorly understood. We performed an in vitro study involving MTT, flow cytometry, RT-PCR, and western blot analyses to investigate the effects of PCA treatment on cell proliferation, cell cycle distribution, apoptosis, and expression of several cell cycle-related genes in HT-29 cells. The treatment enhanced S-phase cell cycle and apoptosis in HT-29 cells in a dose-dependent manner. Western blot results showed that PCA treatment decreased the expression levels of cyclin A, cyclin D1, and p27(KIP1) but increased those of cyclin-dependent kinase 2 (CDK2) in HT-29 cells. Furthermore, the expression levels of B-cell lymphoma/leukemia-2 (Bcl-2) and B-cell lymphoma/leukemia-xL (Bcl-xL) were down-regulated, whereas the levels of BH3-interacting domain death agonist (Bid), Bcl-2 homologous antagonist/killer (Bak), and cytosolic cytochrome c were significantly upregulated. Thus, the enzymes caspases-9, -3, -8, and -6 were found to be activated in HT-29 cells with PCA treatment. These results indicate that PCA-induced S-phase cell cycle arrest and apoptosis involve p27(KIP1)-mediated activation of the cyclin-A/D1-Cdk2 signaling pathway and the mitochondrial apoptotic pathway.
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Apoptosis/efectos de los fármacos , Benzaldehídos/farmacología , Catecoles/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Benzaldehídos/química , Catecoles/química , Proliferación Celular/efectos de los fármacos , Ciclina A1/metabolismo , Ciclina D1/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Células HT29 , HumanosRESUMEN
Type 2 diabetes mellitus (T2DM) is currently considered a worldwide epidemic and finding effective therapeutic strategies against this disease is highly important. A deoxynojirimycin-polysaccharide mixture (DPM) has previously been shown to exert hypoglycemic effects on alloxan- or streptozotocin (STZ)-induced diabetic mice. The purpose of the present study was to evaluate the therapeutic effects and underlying mechanism(s) of DPM on T2DM induced by high fat diet following low-dose STZ treatment in mice. After daily oral treatment of diabetic mice with DPM (150 mg/kg b.w.) for 90 d, significant decline in blood glucose, pyruvate, triglyceride (TG), aspartate transaminase (AST), alanine transaminase (ALT), creatinine (Cr), lipid peroxide (LPO) and malondialdehyde (MDA) levels as well as evident increases in high density lipoprotein (HDL-c) and hepatic glycogen concentrations were observed. In the first stage, in which DPM was administered for 60 d, blood insulin levels did not undergo significant change but a significant decrease in the HOMA-IR index was detected. By contrast, the HOMA-IR index increased significantly in T2MD controls. In the second stage, in which DPM treatment was continued for another 30 d, insulin levels significantly increased in DPM-treated mice in comparison with T2DM controls. These results indicate that insulin resistance in the pre-diabetic period and the dysfunction of pancreatic ß-cells are ameliorated by DPM treatment. DPM also down-regulated protein levels of insulin receptor (IR) and gluconeogenic enzymes (pyruvate carboxylase, fructose-1, 6-bisphosphatase, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in peripheral tissues (liver and/or muscle), but enhanced the expressions of insulin in pancreas, lipoprotein lipase (LPL) and glycolysis enzymes (glucokinase, phosphofructokinase, private kinase and pyruvate decarboxylase E1) in the liver. Furthermore, deoxynojirimycin (DNJ) and polysaccharide (P) were found to increase proliferation of hepatic LO-2 cells and scavenging of radicals in vitro. These results support the results of our biochemical analyses and underscore possible mechanisms underlying the protective effects of DPM on STZ-induced damage to the pancreas and the liver. Taken together, our findings suggest that DPM may be developed as an antihyperglycemic agent for the treatment of diabetes mellitus.
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Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosamina/análogos & derivados , Hipoglucemiantes/farmacología , Hígado/metabolismo , 1-Desoxinojirimicina/farmacología , 1-Desoxinojirimicina/uso terapéutico , Animales , Glucemia/análisis , Western Blotting , Fructosa-Bifosfatasa/análisis , Fructosa-Bifosfatasa/metabolismo , Glucoquinasa/análisis , Glucoquinasa/metabolismo , Glucosamina/farmacología , Glucosamina/uso terapéutico , Glucosa-6-Fosfatasa/análisis , Glucosa-6-Fosfatasa/metabolismo , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Fosfoenolpiruvato Carboxiquinasa (ATP)/análisis , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Fosfofructoquinasa-1 Tipo Hepático/análisis , Fosfofructoquinasa-1 Tipo Hepático/metabolismo , Piruvato Carboxilasa/análisis , Piruvato Carboxilasa/metabolismo , Piruvato Descarboxilasa/análisis , Piruvato Descarboxilasa/metabolismo , Distribución AleatoriaRESUMEN
Transmetalation is a key elementary reaction of many important catalytic reactions. Among these, 1,4-addition of arylboronic acids to organic acceptors such as α,ß-unsaturated ketones has emerged as one of the most important methods for asymmetric C-C bond formation. A key intermediate for the B-to-Rh transfer arising from quaternization on a boronic acid by a Rh-bound hydroxide (the active catalyst) has been proposed. Herein, DFT calculations (IEFPCM/PBE0/DGDZVP level of theory) establish the viability of this proposal, and characterize the associated pathways. The delivery of phenylboronic acid in the orientation suited for the B-to-Rh transfer from the very beginning is energetically preferable, and occurs with expulsion of Rh-coordinated water molecules. For the bulkier binap ligand, the barriers are higher (particularly for the phenylboronic acid activation step) due to a less favourable entropy term to the free energy, in accordance with the experimentally observed slower transmetalation rate.
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Alcadienos/química , Ácidos Borónicos/química , Cetonas/química , Compuestos Organometálicos/química , Fosfinas/química , Teoría Cuántica , Boro/química , Catálisis , Hidróxidos/química , Ligandos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Rodio/químicaRESUMEN
ETHNOPHARMACOLOGY RELEVANCE: Our previous study showed that the proteoglycan P1 from Phellinus linteus (Mesima) exhibits significant anti-tumor activity against human hepatocellular carcinoma cells (HepG2); however, its molecular mechanism remains unknown. This study aims to provide insights into the mechanism of the anti-tumor activity of P1 against HepG2 cells. METHODS: We examined the effects of P1 on HepG2 cell proliferation in vitro and in vivo. Flow cytometry was used to analyze the cell cycle distribution and apoptosis. Proteomic analysis, real-time (RT)-PCR, and Western blot were carried out to observe the expression of several cell cycle control proteins in HepG2 cells. RESULTS: Both the volume and the weight of solid tumors were significantly decreased in P1-treated mice (200mg/kg) compared with the control. The HepG2 cells in the P1-treated tumors were significantly decreased, irregularly shaped, and smaller. P1 slightly increased the body weight of the tumor-bearing mice, which indicates that P1 is nontoxic to mammals at 200mg/kg. P1 also caused a significant dose-dependent increase in S phase arrest, but no apoptosis was observed in HepG2 cells. The results of the proteomic analysis, RT-PCR, and Western blot analysis showed that significantly downregulated expression of calreticulin, cyclin D1, cyclin E, and CDK2 and upregulated expression of P27 kip1 and cyclin A in the P1-treated HepG2 cells (200 µg/ml). CONCLUSION: These results suggest that calreticulin expression and the P27 kip1-cyclin A/D1/E-CDK2 pathway were involved in P1-induced S-phase cell cycle arrest in HepG2 cells.
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Antineoplásicos/farmacología , Basidiomycota , Polisacáridos Fúngicos/farmacología , Animales , Antineoplásicos/uso terapéutico , Calreticulina/metabolismo , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Ciclinas/metabolismo , Femenino , Polisacáridos Fúngicos/uso terapéutico , Células Hep G2 , Humanos , Ratones , Ratones Desnudos , Proteómica , Fase S/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Our previous study showed that polysaccharide (P1) from Phellinus linteus exhibits a significant inhibitive activity on human colorectal carcinoma cells (HT-29). However its novel molecular mechanism remains unknown. To obtain insights into P1's mechanism of action, we examined its effects on cell proliferation in vitro and in vivo, cell cycle distribution, apoptosis, autophagy, and expression of several cell cycle interrelated proteins in HT-29 cells. Interestingly, we found that volume and weight of the solid tumor significantly decreased in P1 (200mg/kg)-treated mice compared with the control. However, slightly increased the body weight of the P1 treated tumor-bearing mice, with no significant increased ALT, AST levels in serum and LPO concentration in liver and kidney indicated that P1 has no toxicity to mammals at a dose of 200mg/kg. Furthermore, P1 caused a significantly dose-dependent increase in the S-phase cell cycle, but no apoptosis and autophagy in HT-29 cells. RT-PCR and Western blot results showed significantly down-regulated expressions of cyclin D1, cyclin E, and CDK2, as well as increased expressions of P27kip1 in P1 (100 µg/mL)-treated HT-29 cells. These results suggested that the activation of P27kip1-cyclin D1/E-CDK2 pathway is involved in P1-induced S-phase cell cycle arrest in HT-29 cells.
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Hongos/química , Polisacáridos/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Células CACO-2 , Línea Celular , Proliferación Celular/efectos de los fármacos , Ciclina D1/metabolismo , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Células HT29 , Humanos , Ratones , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacosRESUMEN
We had previously shown that deoxynojirimycin-polysaccharide mixture (DPM) not only decreased blood glucose but also reversed the damage to pancreatic ß-cells in diabetic mice, and that the anti-hyperglycemic efficacy of this combination was better than that of 1-deoxynojirimycin (DNJ) or polysachharide alone. However, the mechanisms behind these effects were not fully understood. The present study aimed to evaluate the therapeutic effects of DPM on streptozotocin (STZ)-induced diabetic symptoms and their potential mechanisms. Diabetic mice were treated with DPM (150 mg/kg body weight) for 90 days and continued to be fed without DPM for an additional 30 days. Strikingly, decrease of blood glucose levels was observed in all DPM treated diabetic mice, which persisted 30 days after cessation of DPM administration. Significant decrease of glycosylated hemoglobin and hepatic pyruvate concentrations, along with marked increase of serum insulin and hepatic glycogen levels were detected in DPM treated diabetic mice. Results of a labeled (13)C6-glucose uptake assay indicated that DPM can restrain glucose absorption. Additionally, DPM down-regulated the mRNA and protein expression of jejunal Na(+)/glucose cotransporter, Na(+)/K(+)-ATPase and glucose transporter 2, and enhanced the activities as well as mRNA and protein levels of hepatic glycolysis enzymes (glucokinase, phosphofructokinase, private kinase and pyruvate decarboxylas E1). Activity and expression of hepatic gluconeogenesis enzymes (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) were also found to be attenuated in diabetic mice treated with DPM. Purified enzyme activity assays verified that the increased activities of glucose glycolysis enzymes resulted not from their direct activation, but from the relative increase in protein expression. Importantly, our histopathological observations support the results of our biochemical analyses and validate the protective effects of DPM on STZ-induced damage to the pancreas. Thus, DPM has significant potential as a therapeutic agent against diabetes.
Asunto(s)
1-Desoxinojirimicina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Polisacáridos/uso terapéutico , Estreptozocina/toxicidad , Animales , Glucemia/efectos de los fármacos , Western Blotting , Glucosa/metabolismo , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
We investigated the role of 1-deoxynojirimycin (DNJ) on glucose absorption and metabolism in normal and diabetic mice. Oral and intravenous glucose tolerance tests and labeled (13)C6-glucose uptake assays suggested that DNJ inhibited intestinal glucose absorption in intestine. We also showed that DNJ down-regulated intestinal SGLT1, Na(+)/K(+)-ATP and GLUT2 mRNA and protein expression. Pretreatment with DNJ (50â mg/kg) increased the activity, mRNA and protein levels of hepatic glycolysis enzymes (GK, PFK, PK, PDE1) and decreased the expression of gluconeogenesis enzymes (PEPCK, G-6-Pase). Assays of protein expression in hepatic cells and in vitro tests with purified enzymes indicated that the increased activity of glucose glycolysis enzymes was resulted from the relative increase in protein expression, rather than from direct enzyme activation. These results suggest that DNJ inhibits intestinal glucose absorption and accelerates hepatic glucose metabolism by directly regulating the expression of proteins involved in glucose transport systems, glycolysis and gluconeogenesis enzymes.