Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 83
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Biosci Rep ; 40(3)2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32154555

RESUMO

BACKGROUND: The present study investigated the effects of microvascular endothelial cells (MECs) on the chemotaxis, adhesion and proliferation of bone marrow hematopoietic stem cells (HSCs) ex vivo. METHODS AND RESULTS: MECs were collected from the lung tissue of C57BL/6 mice, and HSCs were isolated with immunomagnetic beads from bone marrow of GFP mice. MECs and HSCs were co-cultured with or without having direct cell-cell contact in Transwell device for the measurement of chemotaxis and adhesion of MECs to HSCs. Experimental results indicate that the penetration rate of HSCs from the Transwell upper chamber to lower chamber in 'co-culture' group was significantly higher than that of 'HSC single culture' group. Also, the HSCs in co-culture group were all adherent at 24 h, and the co-culture group with direct cell-cell contact had highest proliferation rate. The HSC number was positively correlated with vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) levels in supernatants of the culture. CONCLUSIONS: Our study reports that MECs enhance the chemotaxis, adhesion and proliferation of HSCs, which might be related to cytokines SDF-1 and VEGF secreted by MECs, and thus MECs enhance the HSC proliferation through cell-cell contact. The present study revealed the effect of MECs on HSCs, and provided a basis and direction for effective expansion of HSCs ex vivo.

3.
Genome Biol ; 21(1): 51, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32102684

RESUMO

BACKGROUND: CRISPR-Cas9 has been developed as a therapeutic agent for various infectious and genetic diseases. In many clinically relevant applications, constitutively active CRISPR-Cas9 is delivered into human cells without a temporal control system. Excessive and prolonged expression of CRISPR-Cas9 can lead to elevated off-target cleavage. The need for modulating CRISPR-Cas9 activity over time and dose has created the demand of developing CRISPR-Cas off switches. Protein and small molecule-based CRISPR-Cas inhibitors have been reported in previous studies. RESULTS: We report the discovery of Cas9-inhibiting peptides from inoviridae bacteriophages. These peptides, derived from the periplasmic domain of phage major coat protein G8P (G8PPD), can inhibit the in vitro activity of Streptococcus pyogenes Cas9 (SpCas9) proteins in an allosteric manner. Importantly, the inhibitory activity of G8PPD on SpCas9 is dependent on the order of guide RNA addition. Ectopic expression of full-length G8P (G8PFL) or G8PPD in human cells can inactivate the genome-editing activity of SpyCas9 with minimum alterations of the mutation patterns. Furthermore, unlike the anti-CRISPR protein AcrII4A that completely abolishes the cellular activity of CRISPR-Cas9, G8P co-transfection can reduce the off-target activity of co-transfected SpCas9 while retaining its on-target activity. CONCLUSION: G8Ps discovered in the current study represent the first anti-CRISPR peptides that can allosterically inactivate CRISPR-Cas9. This finding may provide insights into developing next-generation CRISPR-Cas inhibitors for precision genome engineering.

4.
J Proteome Res ; 19(4): 1423-1434, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32090575

RESUMO

Endogenous glycopeptides in serum are an invaluable resource for biomarker discovery. Due to the low abundance and the poor fragmentation in tandem mass spectrometry, the identification of endogenously intact glycopeptides still faces many challenges. Herein, an integrated platform is fabricated for the identification of N-linked and O-linked endogenously intact glycopeptides. In this platform, the high-temperature acid denaturation, ultrafiltration, and hydrophilic interaction chromatography steps are combined together for the highly efficient extraction of the endogenously intact glycopeptides from a small amount of serum. Additionally, the twin-spectra scheme and in silico deglycosylation strategy were applied for the identification of N-linked and O-linked endogenous glycopeptides, respectively. In total, 223 intact N-glycopeptides and 51 intact O-glycopeptides are identified from only 40 µL of the human serum sample. This is the first study reporting the identification of endogenously intact N-linked and O-linked glycopeptide and is also the largest data set of endogenously intact glycopeptides reported so far. The distributions of glycans among peptides and proteins and cleavage sites on peptides are further analyzed to seek the regulation of endogenous glycosylation for disease mechanism. The developed strategy provides a novel platform for the disease biomarker discovery.

5.
Biomed Chromatogr ; 34(4): e4794, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31944362

RESUMO

Just as natural saponins transform into aglycones, secondary glycosides and their derivatives using biotransformation technology, steroidal saponins may also undergo similar transformation after stir-frying. The purpose of this study was to elucidate the variations and the reasons for these variations in the contents of steroidal saponins in Fructus Tribuli (FT) during a stir-frying treatment. Stir-fried FT was processed in different time-temperature conditions. An UHPLC-MS/MS method was established and fully validated for quantitative analysis. In addition, the simulation processing products of tribuluside A, terrestroside B, terrestrosin K, terrestrosin D and 25R-tribulosin were determined by qualitative analysis using UHPLC-Q-TOF-MS. The established UHPLC-MS/MS method provides a rapid, flexible, and reliable method for the quality assessment of FT. The present study revealed that furostanol saponins with a C22-OH group could transform into corresponding furostanol saponins with a C-20-C-22 double bond (FSDB) via dehydroxylation. Additionally, FSDB could be successively converted into its secondary glycosides via a deglycosylation reaction. The transformation of spirostanol saponins into corresponding aglycones via deglycosylation led to a decrease in spirostanol saponins and an increase in aglycones. The results of this research provided scientific evidence of variation and structural transformation among steroidal saponins. These findings might be helpful for elucidating the processing mechanism of FT.

6.
Pharmacol Res ; 153: 104657, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982488

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and constitutes a major risk factor for progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC). The occurrence of NAFLD is closely associated with abnormal lipid metabolism and implies a high risk of type 2 diabetes and cardiovascular disease. Therefore, specific and effective drugs for the prevention and treatment of NAFLD are necessary. Hypericin (HP) is one of the main active ingredients of Hypericum perforatum L., and we previously revealed its protective role in islet ß-cells and its effects against type 2 diabetes. In this study, we aimed to explore the preventive and therapeutic effects of HP against NAFLD and the underlying mechanisms in vitro and in vivo. Here, we demonstrated that HP improved cell viability by reducing apoptosis and attenuated lipid accumulation in hepatocytes both in vitro and in vivovia attenuating oxidative stress, inhibiting lipogenesis and enhancing lipid oxidization. Thus, HP exhibited significant preventive and therapeutic effects against HFHS-induced NAFLD and dyslipidemia in mice. Furthermore, we demonstrated that HP directly bound to PKACα and activated PKA/AMPK signaling to elicit its effects against NAFLD, suggesting that PKACα is one of the drug targets of HP. In addition, the enhancing effect of HP on lipolysis in adipocytes through the activation of PKACα was also elucidated. Together, the conclusions indicated that HP, of which one of the targets is PKACα, has the potential to be used as a preventive or therapeutic drug against NAFLD or abnormal lipid metabolism in the future.

7.
J Magn Reson Imaging ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31981400

RESUMO

BACKGROUND: The degeneration of the corticospinal tract (CST) in chronic stroke has been widely described using diffusion tensor imaging and correlates with the extent of motor deficits. However, only a few studies have reported the early degeneration in the distal CST during the acute stage of stroke and pathological changes in the distal CST have not been described. PURPOSE: To study the microstructural changes along the CST beyond the ischemic lesion in acute stroke using diffusion kurtosis imaging (DKI). STUDY TYPE: Prospective. POPULATION: In all, 48 patients (26 males, 22 females; mean age 58.27 ± 12.89 years) with acute ischemic stroke. SEQUENCE: A DKI sequence with three b-values (0, 1000, and 2000 s/mm2 ) at 3.0T MRI. ASSESSMENT: The kurtosis and tensor parameters were derived from DKI and were compared along the length of the CST beyond the ischemic lesion between the affected and unaffected hemispheres using both voxelwise and slicewise analysis. The degree of neurological deficits was evaluated using the National Institute of Health Stroke Score (NIHSS) and the Barthel index and the clinical outcome at 3 months was evaluated using a modified Rankin scale. STATISTICAL TESTS: Paired t-tests, a linear mixed model, and multivariate linear regression. RESULTS: Voxelwise analysis demonstrated increased mean kurtosis, increased axial kurtosis, and decreased axial diffusivity in the affected CST, which were seen only at the level of the cerebral peduncle (all corrected P < 0.05). Slicewise analysis also demonstrated increased axial kurtosis in the cerebral peduncle of the affected CST (corrected P < 0.05). The axial kurtosis from slicewise analysis independently correlated with the motor component of NIHSS (ß = 0.297, P = 0.040). DATA CONCLUSION: Our findings suggest that early anterograde degeneration occurs along the axon direction in the distal CST in acute stroke, and can be detected using DKI. Moreover, acute axonal degeneration along the CST correlated with motor deficits. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

8.
Hum Brain Mapp ; 41(3): 605-616, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31675160

RESUMO

Cognitive processing speed is crucial for human cognition and declines with aging. White matter hyperintensity (WMH), a common sign of WM vascular damage in the elderly, is closely related to slower psychomotor processing speed. In this study, we investigated the association between WMH and psychomotor speed changes through a comprehensive assessment of brain structural and functional features. Multi-modal MRIs were acquired from 60 elderly adults. Psychomotor processing speeds were assessed using the Trail Making Test Part A (TMT-A). Linear regression analyses were performed to assess the associations between TMT-A and brain features, including WMH volumes in five cerebral regions, diffusivity parameters in the major WM tracts, regional gray matter volume, and brain activities across the whole brain. Hierarchical regression analysis was used to demonstrate the contribution of each index to slower psychomotor processing speed. Linear regression analysis demonstrated that WMH volume in the occipital lobe and fractional anisotropy of the forceps major, an occipital association tract, were associated with TMT-A. Besides, resting-state brain activities in the visual cortex connected to the forceps major were associated with TMT-A. Hierarchical regression showed fractional anisotropy of the forceps major and regional brain activities were significant predictors of TMT-A. The occurrence of WMH, combined with the disruption of passing-through fiber integrity and altered functional activities in areas connected by this fiber, are associated with a decline of psychomotor processing speed. While the causal relationship of this WMH-Tract-Function-Behavior link requires further investigation, this study enhances our understanding of these complex mechanisms.

9.
Anal Chem ; 92(1): 1363-1371, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31794197

RESUMO

High-throughput drug discovery is highly dependent on the targets available to accelerate the process of candidates screening. Traditional chemical proteomics approaches for the screening of drug targets usually require the immobilization/modification of the drug molecules to pull down the interacting proteins. Recently, energetics-based proteomics methods provide an alternative way to study drug-protein interaction by using complex cell lysate directly without any modification of the drugs. In this study, we developed a novel energetics-based proteomics strategy, the solvent-induced protein precipitation (SIP) approach, to profile the interaction of drugs with their target proteins by using quantitative proteomics. The method is easy to use for any laboratory with the common chemical reagents of acetone, ethanol, and acetic acid. The SIP approach was able to identify the well-known protein targets of methotrexate, SNS-032, and a pan-kinase inhibitor of staurosporine in cell lysate. We further applied this approach to discover the off-targets of geldanamycin. Three known protein targets of the HSP90 family were successfully identified, and several potential off-targets including NADH dehydrogenase subunits NDUFV1 and NDUFAB1 were identified for the first time, and the NDUFV1 was validated by using Western blotting. In addition, this approach was capable of evaluating the affinity of the drug-target interaction. The data collectively proved that our approach provides a powerful platform for drug target discovery.

10.
Biomed Pharmacother ; 121: 109615, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707343

RESUMO

Psoriasis is considered an immune-mediated inflammatory skin disorder that affects the quality of life of nearly four percent of the world population. Considering the side effects of existing therapeutic drugs and the urgent need for new drug development, we screened more than 250 traditional Chinese medicine compounds to identify drugs that significantly reduced the viability of human HaCaT keratinocytes, a psoriasis-related model cell line. Convallatoxin (CNT) was found to be a highly effective inhibitor of HaCaT cell viability. Subsequent mechanistic studies revealed that CNT induced HaCaT cell death by necroptosis rather than by apoptosis. CNT destroyed the membrane integrity of HaCaT cells, as detected by nuclear propidium iodide (PI) staining and lactate dehydrogenase (LDH) release. Additionally, the intercellular levels of adenosine triphosphate (ATP) were lower in HaCaT cells treated with CNT than in control HaCaT cells, and typical necroptosis-associated characteristics were observed by electron microscopy in cells treated with CNT. Furthermore, compared with control HaCaT cells, CNT-treated HaCaT cells produced more reactive oxygen species (ROS), but this effect was inhibited by the antioxidants N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and apocynin and the necroptosis inhibitor Nec-1. In addition, antioxidant treatment attenuated necroptotic cell death, suggesting that CNT-induced HaCaT necroptosis is mediated by oxidative stress. More importantly, CNT ameliorated skin lesions and inflammation in imiquimod (IMQ)- and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced psoriasis-like mouse models. In conclusion, our results demonstrate that CNT is cytotoxic against HaCaT cells in vitro and exerts antipsoriatic activities in two mouse models of psoriasis in vivo, making CNT a potential promising candidate drug for future research.

11.
Adv Sci (Weinh) ; 6(23): 1901551, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31832315

RESUMO

Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp2)-C(sp2), C(sp2)-C(sp), and C(sp2)-N bonds are highly amenable to synthesis of DNA-encoded libraries with great molecular diversity.

12.
Sci Rep ; 9(1): 19064, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836777

RESUMO

Though sleep disturbance constitutes the risk factor for Alzheimer's disease (AD), the underlying mechanism is still unclear. This study aims to explore the interaction between sleep disturbances and AD on brain function. We included 192 normal controls, 111 mild cognitive impairment (MCI), and 30 AD patients, with either poor or normal sleep (PS, NS, respectively). To explore the strength and stability of brain activity, we used static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance. Further, we examined white matter hyperintensities (WMH) and amyloid PET deposition, representing the vascular risk factor and AD-related hallmark, respectively. We observed that sleep disturbance significantly interacted with disease severity, exposing distinct effects on sALFF and dALFF variance. Interestingly, PS groups showed the dALFF variance trajectory of initially increased, then decreased and finally increased along the AD spectrum, while showing the opposite trajectory of sALFF. Further correlation analysis showed that the WMH burden correlates with dALFF variance in PS groups. Conclusively, our study suggested that sleep disturbance interacts with AD severity, expressing as effects of compensatory in MCI and de-compensatory in AD, respectively. Further, vascular impairment might act as important pathogenesis underlying the interaction effect between sleep and AD.

14.
Front Neurosci ; 13: 904, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551678

RESUMO

Background The biological diagnosis criteria of the Alzheimer's disease (AD) suggests that previous work may misclassify the cognitive impairment caused by other factors into AD. Consequently, re-assessing the imaging profile of AD continuum is needed. Considering the high vulnerability of cortical association fibers, we aimed to elucidate the cortical demyelination process in the AD continuum biologically defined. Methods According to the biological diagnosis criteria, we determined the positive amyloid status (A+) as cerebrospinal fluid (CSF) amyloid1 - 42 < 192 pg/ml, Florbetapir Positron emission tomography (PET) composite standardized uptake value ratio (SUVR) >1.11. Also, the positive Tau status (T+) was determined as p-Tau181 > 23 pg/ml. Based on the cognitive characterization, we further categorized 252 subjects into 27 cognitively unimpaired with normal AD biomarkers (A-T-, controls), 49 preclinical AD (A+T+), 113 AD with mild cognitive impairment (MCI) (A+T+), and 63 AD dementia (A+T+). We estimated the intracortical myelin content used the T1- and T2-weighted (T1W/T2W) ratio mapping. To investigate the sensitivity of the ratio mapping, we also utilized well-validated AD imaging biomarkers as the reference, including gray matter volume and Fludeoxyglucose PET (FDG-PET). Based on the general linear model, we conducted the voxel-wise two-sample T-tests between the controls and each group in the AD continuum. Results Compared to the controls, the results showed that the preclinical AD patients exhibited decreased T1W/T2W ratio value in the right inferior parietal lobule (IPL); as the disease progresses, the prodromal AD patients demonstrated lower ratio value in bilateral IPL, with hippocampus (HP) atrophy. Lastly, the AD dementia patients exhibited decreased ratio value in bilateral IPL and hippocampus; also, we observed the bilateral temporal cortices atrophy and widespread decreased metabolism in the AD dementia patients. After corrected with gray volume, the results remained mostly unchanged. Conclusion Our study implied the decreased right IPL T1W/T2W ratio might represent early AD-related demyelination in disease continuum. Additionally, we demonstrated that the T1W/T2W ratio mapping is an easy-to-implement and sensitive metric to assess the intracortical myelin content in AD, particularly in the early stage.

15.
Am J Physiol Endocrinol Metab ; 317(5): E911-E924, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526292

RESUMO

In the context of hepatic insulin resistance, hepatic gluconeogenesis is abnormally increased, which results in increased hepatic glucose production and hyperglycemia, but the underlying mechanisms remain to be fully elucidated. Micro-RNAs (miRNAs) have been identified as critical regulators of diabetes and other metabolic disorders. In this study, we found that the expressions of miRNA-27 family members miRNA-27a and miRNA-27b (miR-27a/b) decreased significantly in the livers of diabetic mice. Moreover, the levels of miR-27a/b increased in the serum of patients with type 2 diabetes. Our present results showed that inhibition of miR-27a/b expression led to increased hepatic protein levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase and enhanced hepatic gluconeogenesis in vitro and in vivo. Overexpression of miR-27a/b suppressed hepatic glucose output and alleviated hyperglycemia in diabetic mice. Further study revealed that forkhead box O1 (FOXO1) is a downstream target of miR-27a/b. Taken together, we found novel evidence suggesting that miR-27a/b contributes to hepatic gluconeogenesis through targeting FOXO1 and provided novel mechanistic insight into the pathophysiology of insulin resistance.

16.
Ecotoxicol Environ Saf ; 184: 109611, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31491605

RESUMO

Mono-2-ethylhexyl phthalate (MEHP), as the major metabolite of Di-(2-ethylhexyl) phthalate (DEHP), can induce lipid accumulation in hepatocytes and further leads to non-alcoholic fatty liver disease (NAFLD), while the underlying mechanism is unclear. We aim to clarify the effects of JAK2/STAT5 pathway on lipid accumulation induced by MEHP and the role of oxidation stress in NAFLD. BRL-3A hepatocytes were exposed to MEHP (0, 10, 50, 100 and 200 µM) for 24 h and 48 h. Then the lipid droplets in cells were observed by Oil-Red-O staining and quantified by isopropyl alcohol. The levels of TG, SOD, TBARS, AST and ALT were all detected by commercial kits. RT-PCR was used to detect mRNA expression, and western blotting was used to detect the expression of proteins encoded by JAK2/STAT5 pathway genes and lipid metabolism-related genes. As a result, MEHP promoted the lipid synthesis and accumulation in BRL-3A cells. MEHP down-regulated the expression and inhibited the activation of JAK2/STAT5. Moreover, the lipid metabolism-related kinases levels were elevated after MEHP exposure. In addition, the SOD levels were gradually decreased and the TBARS levels were increased in MEHP-treated groups. The lipid metabolism-related proteins levels were correlated with the oxidation stress levels. Furthermore, the ALT and AST levels were elevated after MEHP exposure. Therefore, we concluded that MEHP led to lipid accumulation through inhibiting JAK2/STAT5 pathway, resulted in damaging liver parenchyma and NAFLD by aggravating oxidation stress.


Assuntos
Dietilexilftalato/análogos & derivados , Janus Quinase 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Dietilexilftalato/toxicidade , Regulação para Baixo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Janus Quinase 2/genética , Metabolismo dos Lipídeos/genética , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/genética
17.
Chem Pharm Bull (Tokyo) ; 67(10): 1076-1081, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31406093

RESUMO

Histone deacetylases (HDACs) are enzymes that play a key role in structural modification and gene expression. The overexpression of HDAC is associated with cancer, and thus inhibiting the enzyme could be an efficient cancer therapy. To discover new HDAC inhibitors (HDACis), we proposed an improved protocol combining a hierarchical pharmacophore search, molecular docking, and molecular dynamic simulations. The test results showed that the improved screening protocol effectively reduced the false-positive rates of drug-like chemicals. Based on the protocol, we obtained 16 hit compounds as potential HDACis from the Life Chemicals database. Enzyme inhibition experiments showed that two of the hit chemical compounds had HDAC-inhibitory effects. In vitro assays showed that Z165155756 could selectively inhibit the proliferation of cancer cells and specifically promoted apoptosis and induced G1/S phase arrest in A2780 cells. It may have potential therapeutic effects in ovarian cancer and is worthy of further investigation.


Assuntos
Antineoplásicos/análise , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Histona Desacetilases/análise , Inibidores de Histona Desacetilases/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade
18.
Int J Biol Sci ; 15(7): 1472-1487, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337977

RESUMO

A decrease in islet ß-cell mass is closely associated with the development and progression of diabetes. Therefore, protection against ß-cell loss is an essential measure to prevent and treat diabetes. In this study, we investigated the protective effects of non-photoactivated hypericin, a natural compound, on ß-cells both in vitro and in vivo. In vitro, hypericin greatly improved INS-1 cell viability under high-glucose and high-fatty-acid conditions by inhibiting glucotoxicity- and lipotoxicity-induced apoptosis and nitric oxide (NO) production. Then, we further demonstrated that hypericin elicited its protective effects against glucotoxicity and lipotoxicity in INS-1 cells by attenuating the reduction in pancreatic duodenal homeobox-1 (PDX1) expression and Erk activity. In vivo, prophylactic or therapeutic use of hypericin inhibited islet ß-cell apoptosis and enhanced the anti-oxidative ability of pancreatic tissue in high-fat/high-sucrose (HFHS)-fed mice, thus alleviating ß-cell loss and maintaining or improving ß-cell mass and islet size. More importantly, hypericin treatment decreased fasting blood glucose, improved glucose intolerance and insulin intolerance, and alleviated hyperinsulinaemia in HFHS-fed mice. Therefore, hypericin showed preventive and therapeutic effects against HFHS-induced onset of type II diabetes in mice. Hypericin possesses great potential for development as an anti-diabetes drug in the future.

19.
FEBS J ; 286(18): 3718-3736, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31349381

RESUMO

Glucotoxicity or lipotoxicity leads to hyperglycemia and insulin secretion deficiency, which are important causes for the onset of type 2 diabetes mellitus (T2DM). Thus, the restoration of ß-cell function is a long-sought goal in diabetes research. Previous studies have implicated pancreatic and duodenal homeobox 1 gene (Pdx1) in ß-cell function and insulin secretion. In this study, we established a Pdx1 promoter-dependent luciferase system and identified the natural compound dracorhodin perchlorate (DP) as an effective promotor of Pdx1 expression. We further demonstrated that DP could significantly inhibit ß-cell apoptosis induced by 33 mm glucose or 200 µm palmitate by interfering with endoplasmic reticulum stress and mitochondrial pathways and enhance insulin secretion as well. These effects were associated with enhanced activities of Erk1/2, which in turn promoted Pdx1 expression and increased the ratio of Bcl2/Bax, since inhibition of the Erk1/2 pathway abolished the DP-induced expression of Pdx1 and suppression of apoptosis. In addition, our in vivo results in diabetic mice indicated that DP treatment lowered blood glucose, raised insulin levels, enhanced Pdx1 expression and increased islet size and number in the pancreas of diabetic mice. Our findings suggest that Pdx1 is a potential target molecule of DP in the treatment of T2DM via the inhibition of glucotoxicity- or lipotoxicity- induced ß-cell apoptosis and the attenuation of insulin secretion dysfunction.

20.
Angew Chem Int Ed Engl ; 58(27): 9254-9261, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31020752

RESUMO

DNA encoded chemical libraries (DELs) link the powers of genetics and chemical synthesis via combinatorial optimization. Through combinatorial chemistry, DELs can grow to the unprecedented size of billions to trillions. To take full advantage of the DEL approach, linking the power of genetics directly to chemical structures would offer even greater diversity in a finite chemical world. Natural products have evolved an incredible structural diversity along with their biological evolution. Herein, we used traditional Chinese medicines (TCMs) as examples in a late-stage modification toolbox approach to annotate these complex organic compounds with amplifiable DNA barcodes, which could be easily incorporated into a DEL. The method of end-products labeling also generates a cluster of isomers with a single DNA tag at different sites. These isomers provide an additional spatial diversity for multiple accessible pockets of targeted proteins. Notably, a novel PARP1 inhibitor from TCM has been identified from the natural products enriched DEL (nDEL).

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA