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1.
Phytochemistry ; 193: 112970, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34689099

RESUMO

Hypericum monogynum L. (Hypericaceae) has been used as a folk Chinese medicine for the treatment of inflammatory related diseases. Cyclooxygenase-2 (COX-2) is a crucial target for the development of agents to treat inflammation. To search for anti-inflammatory compounds from traditional Chinese medicines, a chemical constituent study along with COX-2 inhibitory activity analysis was performed for this plant. In this study, sixteen chemical monomers, including three undescribed oxidative degradation polycyclic polyprenylated acylphloroglucinols (PPAPs, hypemoins C-E), two undescribed PPAPs (hypemoins A and B), and 11 known compounds, were identified from the flowers of H. monogynum. Their structures were characterized by HRESIMS, NMR techniques, ECD, and single crystal X-ray diffraction. Four flavonoid derivatives showed remarkable COX-2 inhibitory activities, with IC50 values ranging from 0.220 ± 0.006 to 1.655 ± 0.098 µM. Among these compounds, the possible recognition mechanism between quercetin 3-(6″-O-caffeoyl)-ß-3-D-galactoside and COX-2 was predicted by molecular docking analysis. Moreover, the multidrug resistance reversal activities for the selected compounds were evaluated.


Assuntos
Hypericum , Ciclo-Oxigenase 2 , Flores , Simulação de Acoplamento Molecular , Estrutura Molecular , Floroglucinol/farmacologia
2.
Aging Dis ; 12(8): 1898-1919, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34881076

RESUMO

Cerebral microbleeds (CMBs) are a disorder of cerebral microvessels that are characterized as small (<10 mm), hypointense, round or ovoid lesions seen on T2*-weighted gradient echo MRI. There is a high prevalence of CMBs in community-dwelling healthy older people. An increasing number of studies have demonstrated the significance of CMBs in stroke, dementia, Parkinson's disease, gait disturbances and late-life depression. Blood-brain barrier (BBB) dysfunction is considered to be the event that initializes CMBs development. However, the pathogenesis of CMBs has not yet been clearly elucidated. In this review, we introduce the pathogenesis of CMBs, hypertensive vasculopathy and cerebral amyloid angiopathy, and review recent research that has advanced our understanding of the mechanisms underlying BBB dysfunction and CMBs presence. CMBs-associated risk factors can exacerbate BBB breakdown through the vulnerability of BBB anatomical and functional changes. Finally, we discuss potential pharmacological approaches to target the BBB as therapy for CMBs.

3.
Zhen Ci Yan Jiu ; 46(11): 929-34, 2021 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-34865329

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture(EA) at "Fengfu" (GV16) and "Taichong"(LR3) on the expression of tyrosine hydroxylase (TH), α-synuclein (α-syn) and microglial-related microglial (MG), Toll-like receptor 4(TLR4)/nuclear factor kappa B (NF-κB) signaling pathway in the substantia nigra (SN) of midbrain in Rotenone-induced Parkinson's disease (PD) rats, so as to explore its mechanisms underlying improvement of PD. METHODS: SD male rats were randomly divided into normal control, PD model and EA groups (n=12 in each group). The PD model was established by subcutaneous injection of rotenone (1 mg/kg) at the back of neck. EA (2 Hz, 1 mA) was applied to bilateral GV16 and LR3, once daily for 2 weeks. The rats' behavior(hair color, reaction capacity, locomotion and gait state)scores (0-10 points) were given and the autonomic movement state (trajectory of autonomous motion, total distance, average speed and duration of motion in 8 min) was detected by using open field tests. The immunoactivity of TH and α-syn in the SN tissue were determined by using immunohistochemistry staining, and the number of Iba-1-labelled microglia (MG) was detected by using immunofluorescence staining. The expression levels of TLR4 and NF-κB P65 proteins in the SN were detected by Western blot, and the contents of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the SN were determined by using enzyme-linked immunosorbent assay. RESULTS: In comparison with the normal group, the behavioral score, α-syn immunoactivity, number of Iba-1 labelled microglia, expression of TLR4 and NF-κB P65 proteins and the contents of TNF-α and IL-6 in the SN were significantly increased (P<0.01), whereas the total distance, average speed, duration of motion of the autonomic movement in 8 min, and the TH immunoactivity were remarkably decreased in the model group (P<0.01). After EA intervention, compared with the model group, the increase of the behavioral score, α-syn immunoactivity, number of Iba-1-labelled microglia, expression of TLR4 and NF-κB P65 proteins, the contents of TNF-α and IL-6 in the SN, and the decrease of the total distance, average speed, duration of motion of the autonomic movement in 8 min, and the TH immunoactivity were reversed (P<0.05, P<0.01). CONCLUSION: EA can improve the behavioral manifestations of PD rats, which may be associated with its functions in down-regulating the abnormal accumulation of pathological α-syn, TLR4/NF-κB signaling, inhibiting activities of microglia and in up-regulating the expression of TH in the SN of midbrain.

4.
Front Immunol ; 12: 757909, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804044

RESUMO

Salmonella Infantis has emerged as a major clinical pathogen causing gastroenteritis worldwide in recent years. As an intracellular pathogen, Salmonella has evolved to manipulate and benefit from the cell death signaling pathway. In this study, we discovered that S. Infantis inhibited apoptosis of infected Caco-2 cells by phosphorylating Akt. Notably, Akt phosphorylation was observed in a discontinuous manner: immediately 0.5 h after the invasion, then before peak cytosolic replication. Single-cell analysis revealed that the second phase was only induced by cytosolic hyper-replicating bacteria at 3-4 hpi. Next, Akt-mediated apoptosis inhibition was found to be initiated by Salmonella SopB. Furthermore, Akt phosphorylation increased mitochondrial localization of Bcl-2 to prevent Bax oligomerization on the mitochondrial membrane, maintaining the mitochondrial network homeostasis to resist apoptosis. In addition, S. Infantis induced pyroptosis, as evidenced by increased caspase-1 (p10) and GSDMS-N levels. In contrast, cells infected with the ΔSopB strain displayed faster but less severe pyroptosis and had less bacterial load. The results indicated that S. Infantis SopB-mediated Akt phosphorylation delayed pyroptosis, but aggravated its severity. The wild-type strain also caused more severe diarrhea and intestinal inflammatory damage than the ΔSopB strain in mice. These findings revealed that S. Infantis delayed the cells' death by intermittent activation of Akt, allowing sufficient time for replication, thereby causing more severe inflammation.

5.
Nat Commun ; 12(1): 6202, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34707103

RESUMO

Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.

6.
Planta Med ; 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34715693

RESUMO

Two new maytansinoids, N-methyltreflorine (1: ) and methyltrewiasine (2: ), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3:  - 5: ). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1: and 2: was determined by X-ray crystallographic analysis. Compounds 1:  - 5: exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 - 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1: and 4: also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1: and 2: significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.

7.
Antonie Van Leeuwenhoek ; 114(10): 1735-1744, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34392432

RESUMO

A Gram-positive, acid-fast and rapidly growing rod, designated S2-37 T, that could form yellowish colonies was isolated from one soil sample collected from cotton cropping field located in the Xinjiang region of China. Genomic analyses indicated that strain S2-37 T harbored T7SS secretion system and was very likely able to produce mycolic acid, which were typical features of pathogenetic mycobacterial species. 16S rRNA-directed phylogenetic analysis referred that strain S2-37 T was closely related to bacterial species belonging to the genus Mycolicibacterium, which was further confirmed by pan-genome phylogenetic analysis. Digital DNA-DNA hybridization and the average nucleotide identity presented that strain S2-37 T displayed the highest values of 39.1% (35.7-42.6%) and 81.28% with M. litorale CGMCC 4.5724 T, respectively. And characterization of conserved molecular signatures further supported the taxonomic position of strain S2-37 T belonging to the genus Mycolicibacterium. The main fatty acids were identified as C16:0, C18:0, C20:3ω3 and C22:6ω3. In addition, polar lipids profile was mainly composed of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. Phylogenetic analyses, distinct fatty aids and antimicrobial resistance profiles indicated that strain S2-37 T represented genetically and phenotypically distinct from its closest phylogenetic neighbour, M. litorale CGMCC 4.5724 T. Here, we propose a novel species of the genus Mycolicibacterium: Mycolicibacterium gossypii sp. nov. with the type strain S2-37 T (= JCM 34327 T = CGMCC 1.18817 T).


Assuntos
Mycobacterium , Solo , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Ácidos Graxos/análise , Genômica , Fosfolipídeos/análise , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Microbiologia do Solo
8.
Chem Commun (Camb) ; 57(68): 8512-8515, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34351332

RESUMO

N-Phenylphenothiazine as an inexpensive, highly reductive and oxygen tolerant organophotocatalyst has exhibited potential in various challenging photochemical transformations. Here we report a general and straightforward method to access structurally diverse N-phenylphenothiazine derivatives by means of a novel electrochemical tool. The introduction of a 2-naphthylamine moiety with an extended π-system and an amine group led to the variation of spectral characterization. Photochemical verification experiments demonstrated that the formed N-arylation products with good efficacy and chemo/site-control displayed competitive catalytic activity in challenging transformations.

9.
Artigo em Inglês | MEDLINE | ID: mdl-34343063

RESUMO

A Gram-negative bacterium, designated S1-65T, was isolated from soil samples collected from a cotton field located in the Xinjiang region of PR China. Results of 16S rRNA gene sequence analysis revealed that strain S1-65T was affiliated to the genus Steroidobacter with its closest phylogenetic relatives being 'Steroidobacter cummioxidans' 35Y (98.4 %), 'Steroidobacter agaridevorans' SA29-B (98.3 %) and Steroidobacter agariperforans KA5-BT (98.3 %). 16S rRNA-directed phylogenetic analysis showed that strain S1-65T formed a unique phylogenetic subclade next to 'S. agaridevorans' SA29-B and S. agariperforans KA5-BT, suggesting that strain S1-65T should be identified as a member of the genus Steroidobacter. Further, substantial differences between the genotypic properties of strain S1-65T and the members of the genus Steroidobacter, including average nucleotide identity and digital DNA-DNA hybridization, resolved the taxonomic position of strain S1-65T and suggested its positioning as representing a novel species of the genus Steroidobacter. The DNA G+C content of strain S1-65T was 62.5 mol%, based on its draft genome sequence. The predominant respiratory quinone was ubiquinone-8. The main fatty acids were identified as summed feature 3 (C16:1ω6c/C16:1ω7c), C16 : 0 and iso-C15 : 0. In addition, its polar lipid profile was composed of aminophospholipid, diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. Here, we propose a novel species of the genus Steroidobacter: Steroidobacter gossypii sp. nov. with the type strain S1-65T (=JCM 34287T=CGMCC 1.18736T).


Assuntos
Gammaproteobacteria/classificação , Gossypium/microbiologia , Filogenia , Microbiologia do Solo , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Gammaproteobacteria/isolamento & purificação , Hibridização de Ácido Nucleico , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Ubiquinona/química
10.
Pharmacol Res ; 171: 105755, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34229049

RESUMO

Diabetic retinopathy (DR) is one of the common complications in diabetic patients. Nowadays, VEGF pathway is subject to extensive research. However, about 27% of the patients have a poor visual outcome, with 50% still having edema after two years' treatment of diabetic macular edema (DME) with ranibizumab. Docosahexaenoic acid (DHA), the primary ω-3 long-chain polyunsaturated fatty acid (LC-PUFA), reduces abnormal neovascularization and alleviates neovascular eye diseases. A study reported that fish oil reduced the incidence of retinopathy of prematurity (ROP) by about 27.5% in preterm infants. Although ω-3 LC-PUFAs protects against pathological retinal neovascularization, the treatment effectiveness is low. It is interesting to investigate why DHA therapy fails in some patients. In human vitreous humor samples, we found that the ratio of DHA and DHA-derived metabolites to total fatty acids was higher in vitreous humor from DR patients than that from macular hole patients; however, the ratio of DHA metabolites to DHA and DHA-derived metabolites was lower in the diabetic vitreous humor. The expression of Mfsd2a, the LPC-DHA transporter, was reduced in the oxygen-induced retinopathy (OIR) model and streptozotocin (STZ) model. In vitro, Mfsd2a overexpression inhibited endothelial cell proliferation, migration and vesicular transcytosis. Moreover, Mfsd2a overexpression in combination with the DHA diet obviously reduced abnormal retinal neovascularization and vascular leakage, which is more effective than Mfsd2a overexpression alone. These results suggest that DHA therapy failure in some DR patients is linked to low expression of Mfsd2a, and the combination of Mfsd2a overexpression and DHA therapy may be an effective treatment.

11.
ACS Appl Mater Interfaces ; 13(30): 35767-35776, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34309354

RESUMO

Methanol electrolysis is a promising strategy to achieve energy-saving and efficient electrochemical hydrogen (H2) production. In this system, the advanced electrocatalysts with high catalytic performance for both the methanol oxidation reaction (MOR) and hydrogen evolution reaction (HER) are highly desirable. Inspired by the complementary catalytic properties of rhodium (Rh) and palladium (Pd) for MOR and HER, herein, several Pd core-RhPd alloy shell nanodendrites (Pd@RhPd NDs) are synthesized through the galvanic replacement reaction between Pd nanodendrites (Pd NDs) and rhodium trichloride. For MOR, Pd@RhPd NDs exhibit Rh content-determined catalytic activity, in which Pd@Rh0.07Pd NDs have an optimal combination of oxidation potential and oxidation current due to the synergistic catalytic process of Pd/Rh double active sites. For HER, the introduction of Rh greatly improves the catalytic activity of Pd@RhPd NDs compared to that of Pd NDs, suggesting that Rh is the main activity site for HER. Unlike MOR, however, the HER activity of Pd@RhPd NDs is not sensitive to the Rh content. Using Pd@Rh0.07Pd NDs as robust bifunctional electrocatalysts, the as-constructed two-electrode methanol electrolysis cell shows a much lower voltage (0.813 V) than that of water electrolysis (1.672 V) to achieve electrochemical H2 production at 10 mA cm-2, demonstrating the application prospect of methanol electrolysis for H2 production.

12.
Exp Ther Med ; 22(3): 933, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34306202

RESUMO

Aberrations in long noncoding RNA (lncRNA) expression have been recognized in numerous human diseases. In the present study, the of role the long noncoding RNA HOX antisense intergenic RNA myeloid 1 variant (HOTAIRM1-1) in regulating the pathological progression of osteoarthritis (OA) was investigated. The aberrant expression of HOTAIRM1-1 in OA was demonstrated, but the molecular mechanisms require further analysis. The aim of the present study was to explore the function of miR-125b in modulating chondrocyte viability and apoptosis, and to address the functional association between HOTAIRM1-1 and miR-125b as potential targets. A miR-125b inhibitor was used, which laid the foundation for the following investigation. The study confirmed that HOTAIRM1-1 and miR-125b are inversely expressed in chondrocytes. The expression of HOTAIRM1-1 was downregulated and the expression of miR-125b was upregulated in tissues from patients with OA. HOTAIRM1-1 directly interacted with miR-125b in chondrocytes. HOTAIRM1-1 knockdown was associated with chondrocyte proliferation and extracellular matrix degradation. Furthermore, miR-125b reversed the effect of HOTAIRM1-1 on cell proliferation and apoptosis. In conclusion, the present study indicates that the loss of HOTAIRM1-1 function leads to aberrant increases in the proliferation and apoptosis of chondrocytes. miR-125b may be a potential downstream mechanism that regulates the function of HOTAIRM1-1, and this finding provides a therapeutic strategy for OA.

13.
Front Immunol ; 12: 678744, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248961

RESUMO

Blood-Brain Barrier (BBB) disruption is an important pathophysiological process of acute ischemic stroke (AIS), resulting in devastating malignant brain edema and hemorrhagic transformation. The rapid activation of immune cells plays a critical role in BBB disruption after ischemic stroke. Infiltrating blood-borne immune cells (neutrophils, monocytes, and T lymphocytes) increase BBB permeability, as they cause microvascular disorder and secrete inflammation-associated molecules. In contrast, they promote BBB repair and angiogenesis in the latter phase of ischemic stroke. The profound immunological effects of cerebral immune cells (microglia, astrocytes, and pericytes) on BBB disruption have been underestimated in ischemic stroke. Post-stroke microglia and astrocytes can adopt both an M1/A1 or M2/A2 phenotype, which influence BBB integrity differently. However, whether pericytes acquire microglia phenotype and exert immunological effects on the BBB remains controversial. Thus, better understanding the inflammatory mechanism underlying BBB disruption can lead to the identification of more promising biological targets to develop treatments that minimize the onset of life-threatening complications and to improve existing treatments in patients. However, early attempts to inhibit the infiltration of circulating immune cells into the brain by blocking adhesion molecules, that were successful in experimental stroke failed in clinical trials. Therefore, new immunoregulatory therapeutic strategies for acute ischemic stroke are desperately warranted. Herein, we highlight the role of circulating and cerebral immune cells in BBB disruption and the crosstalk between them following acute ischemic stroke. Using a robust theoretical background, we discuss potential and effective immunotherapeutic targets to regulate BBB permeability after acute ischemic stroke.


Assuntos
Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Suscetibilidade a Doenças/imunologia , AVC Isquêmico/etiologia , AVC Isquêmico/metabolismo , Animais , Biomarcadores , Barreira Hematoencefálica/patologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Comunicação Celular , Gerenciamento Clínico , Modelos Animais de Doenças , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Imunoterapia/métodos , AVC Isquêmico/patologia , AVC Isquêmico/terapia
14.
Therap Adv Gastroenterol ; 14: 17562848211010675, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104207

RESUMO

Background: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) in the immune-tolerant (IT) phase is significantly associated with high risk for hepatocellular carcinoma, suggesting requirement for antiviral therapy, particularly for those with histological liver injury. This study aimed to establish a non-invasive panel to assess significant liver fibrosis in IT chronic hepatitis B. Patients and methods: One hundred and thirteen IT-phase CHB patients were retrospectively recruited and divided into two histopathological groups according to their histological profiles: necroinflammatory score <4 (N <4)/fibrosis score ⩽1 (F0-1), and necroinflammatory score ⩾4 (N ⩾4)/fibrosis score ⩾2 (F2-4). Multivariate analysis was conducted to assess the predictive value of the non-invasive model for significant liver fibrosis. Results: IT-phase CHB patients with N <4/F0-1 had significantly higher HBsAg levels than those with N ⩾4/F2-4. The optimal HBsAg level of log 4.44 IU/mL for significant liver fibrosis (F ⩾2) gave an area under the curve (AUC) of 0.83, sensitivity of 81.1%, specificity of 81.6%, positive predictive value (PPV) of 68.2%, and negative predictive value (NPV) of 89.9%. An IT model with HBsAg and gamma glutamyl transpeptidase (GGT) in combination was established, and it had an AUC of 0.86, sensitivity of 86.5%, specificity of 81.6%, PPV of 69.6, NPV of 92.5, and accuracy of 83.2% to predict F ⩾2 in the IT-phase CHB patients. Notably, the IT model exhibited higher predictive value than the existing aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 score, and GGT to platelet ratio. Conclusion: The established IT model combining HBsAg and GGT has good performance in predicting significant liver fibrosis in IT-phase CHB patients.

15.
Front Mol Biosci ; 8: 559800, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34109209

RESUMO

Background: Cancer is one of the deadliest diseases at present. Although effective screening and treatment can save lives to a certain extent, our knowledge of the disease is far from sufficient. KIF18B is a member of the kinesin-8 superfamily and plays a conserved regulatory role in the cell cycle. KIF18B reportedly functions as an oncogene in some human cancers, but the correlations between KIF18B and prognosis and immune-infiltrates in different cancers remain unclear. Methods: Data were collected from the TCGA, GTEx, CCLE, TIMER, and GSEA databases. The expression difference, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repairs (MMRs), tumor microenvironment (TME), immune cell infiltration, and gene co-expression of KIF18B were analyzed using the R language software. Results: KIF18B was widely upregulated in cancers, compared with normal tissues, and high KIF18B expression was associated with unfavorable prognoses. TMB, MSI, MMRs, and DNA methylation correlated with KIF18B dysregulation in cancers. KIF18B correlated closely with tumor immunity and interacted with different immune cells and genes in different cancer types. Conclusion: KIF18B could be used as a prognostic biomarker for determining prognosis and immune infiltration in pan-cancer.

16.
Stem Cell Res Ther ; 12(1): 278, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962658

RESUMO

BACKGROUND: Long-QT syndrome type 2 (LQT2) is a common malignant hereditary arrhythmia. Due to the lack of suitable animal and human models, the pathogenesis of LQT2 caused by human ether-a-go-go-related gene (hERG) deficiency is still unclear. In this study, we generated an hERG-deficient human cardiomyocyte (CM) model that simulates 'human homozygous hERG mutations' to explore the underlying impact of hERG dysfunction and the genotype-phenotype relationship of hERG deficiency. METHODS: The KCNH2 was knocked out in the human embryonic stem cell (hESC) H9 line using the CRISPR/Cas9 system. Using a chemically defined differentiation protocol, we obtained and verified hERG-deficient CMs. Subsequently, high-throughput microelectrode array (MEA) assays and drug interventions were performed to characterise the electrophysiological signatures of hERG-deficient cell lines. RESULTS: Our results showed that KCNH2 knockout did not affect the pluripotency or differentiation efficiency of H9 cells. Using high-throughput MEA assays, we found that the electric field potential duration and action potential duration of hERG-deficient CMs were significantly longer than those of normal CMs. The hERG-deficient lines also exhibited irregular rhythm and some early afterdepolarisations. Moreover, we used the hERG-deficient human CM model to evaluate the potency of agents (nifedipine and magnesium chloride) that may ameliorate the phenotype. CONCLUSIONS: We established an hERG-deficient human CM model that exhibited QT prolongation, irregular rhythm and sensitivity to other ion channel blockers. This model serves as an important tool that can aid in understanding the fundamental impact of hERG dysfunction, elucidate the genotype-phenotype relationship of hERG deficiency and facilitate drug development.


Assuntos
Células-Tronco Embrionárias Humanas , Síndrome do QT Longo , Animais , Canal de Potássio ERG1/genética , Canais de Potássio Éter-A-Go-Go/genética , Humanos , Síndrome do QT Longo/genética , Miócitos Cardíacos
17.
Org Lett ; 23(8): 3125-3129, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33818113

RESUMO

Hymoins A-D (1-4), two pairs of light-induced transformative polyprenylated acylphloroglucinols with an unprecedented pentacyclic skeleton, were isolated from the flowers of Hypericum monogynum. The first decarbonylative ring contraction of complex natural products was investigated by light irradiation. Their structures were elucidated by nuclear magnetic resonance analysis, X-ray crystallography, and electronic circular dichroism calculations. In addition, compound 3 showed moderate inhibition efficacy of the platelet-activating-factor-induced aggregation of rabbit platelets.


Assuntos
Hypericum/química , Floroglucinol/química , Animais , Dicroísmo Circular , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Floroglucinol/isolamento & purificação , Coelhos
18.
J Ethnopharmacol ; 275: 114095, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33819505

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia fischeriana Steud. (Euphorbiaceae) is a perennial herb distributed in grassland, hill slopes or gravel hillside, with average altitude of 100-600 m. The whole grass of E. fischeriana is toxic with roots used as folk medicine to treat Zhushui, dyspepsia, abdominal distension, abdominal pain, cough, as well as external applications such as cure of scabies and tuberculosis of lymph nodes. AIM OF THE REVIEW: This systematic review aims to provide a detailed and in-depth summary about the reported advances in traditional uses, clinical applications, phytochemistry, pharmacology and toxicity of E. fischeriana, so as to offer fresh ideas and broader vision and insights for subsequent studies. MATERIALS AND METHODS: Various scientific data bases such as CNKI, Elsevier, Google Scholar, Pubmed, Science Direct, SciFinder Scholar and Web of Science were searched to collect information about E. fischeriana. Other relevant literatures were searched in 'Flora of China Editorial Committee', ancient books, Ph.D and Masters' Dissertation to get more data of E. fischeriana. RESULTS: A total of 241 chemical constituents have been identified from the roots of E. fischeriana, including diterpenoids, triterpenoids, meroterpenoids, acetophenones, flavonoids, coumarins, steroids, phenolic acids, tannins, etc. Various pharmacological activities have been demonstrated, especially anti-tumor, antibacterial, anti-inflammatory, antiviral and anti-leukemia activities. Moreover, different investigations about clinical uses and toxicology of E. fischeriana indicated that attention should be paid to its usage and dosage. CONCLUSION: The researches of E. fischeriana are excellent, but gap still remains. As a poisonous traditional Chinese medicine, there are not enough studies on the toxicity of E. fischeriana. In addition, scholars' research on the pharmacological mechanism of E. fischeriana focuses more on the anti-tumor activity, which can be broadened in the future. Presumably, chemical constituents and biological activities of diterpenoids and trace meroterpenoids in E. fischeriana deserve further research in-depth in the future, in order to provide low toxicity and high efficiency lead compounds. Meanwhile, further studies on other medicinal aspects may lay a foundation for the comprehensive development and utilization of E. fischeriana.


Assuntos
Euphorbia/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Euphorbia/toxicidade , Humanos , Medicina Tradicional Chinesa/métodos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/toxicidade
19.
J Org Chem ; 86(10): 7021-7027, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881865

RESUMO

Hypermonins A-D (1-4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A-D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1-7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.


Assuntos
Hypericum , Cristalografia por Raios X , Flores , Estrutura Molecular , Floroglucinol/farmacologia
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