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1.
Biochem Pharmacol ; 171: 113694, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706845

RESUMO

Poor bioavailability and limited efficacy are challenges associated with using andrographolide as a therapeutic agent. We recently synthesized AGS-30, a new andrographolide derivative, in our laboratory. In this study we investigated the potential anti-tumor effect of AGS-30 and the underlying mechanisms, particularly those related to angiogenesis. Results from our in vitro experiments showed that AGS-30 exerted anti-angiogenic effects by inhibiting endothelial cell proliferation, migration, invasion, and tube formation. Phosphorylation and activation of angiogenesis-related signaling molecules (e.g., vascular endothelial growth factor [VEGF] receptor 2, mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2, mechanistic target of rapamycin [mTOR], protein kinase B [Akt], and p38) were markedly reduced by AGS-30. Meanwhile, AGS-30 potently inhibited cell proliferation and phosphorylation of cell survival-related proteins (e.g., Akt, mTOR, and ERK1/2) and decreased the expression of VEGF in HT-29 colon cancer cells. AGS-30 blocked microvessel sprouting in a rat aortic ring model and blood vessel formation in zebrafish embryos and a mouse Matrigel plug model. Additionally, AGS-30 suppressed tumor growth and angiogenesis in HT-29 colon cancer cell xenografts in nude mice. These effects were not observed when same concentration of andrographolide, the parent compound of AGS-30, was used. Thus, AGS-30 exerted a strong antitumor effect by inhibiting tumor cell growth and angiogenesis and is a candidate compound for the treatment of cancer.

2.
J Nutr Biochem ; 77: 108268, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31830590

RESUMO

Glycyrrhetinic acid (GA) is a major bioactive compound of licorice. The objective of this study was to investigate the effects of GA on ovarian cancer, particularly those related to angiogenesis and apoptosis, and to elucidate the underlying mechanisms of action. In vitro studies showed that GA significantly inhibited proliferation, migration, invasion and tube formation in human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. GA inhibited the phosphorylation of major receptors and enzymes involved in angiogenesis, such as VEGFR2, mTOR, Akt, ERK1/2, MEK1/2, p38 and JNK1/2 in HUVECs. In addition, GA induced apoptosis, loss of mitochondrial membrane potential and cell cycle arrest in G1 phase in A2780 ovarian cancer cells. The proapoptotic effect of GA involved the increased phosphorylation of p38 and JNK1/2; increased cleavage of caspase 3, caspase 9 and PARP; reduced phosphorylation of mTOR, Akt and ERK1/2; and reduced expressions of survivin and cyclin D1. Ex vivo studies showed that GA significantly inhibited microvessel sprouting in rat aortic ring model. In vivo studies showed that GA inhibited the formation of new blood vessels in zebrafish and mouse Matrigel plug. GA also significantly reduced the size of ovarian cancer xenograft tumors in nude mice. Taken together, GA possesses potential antitumor effects, and the underlying mechanisms may involve the inhibition of signaling pathways related to angiogenesis and the activation of apoptotic pathways in cancer cells. Our findings suggest that GA could serve as an effective regimen in the prevention or treatment of cancer.

3.
Oxid Med Cell Longev ; 2019: 8169125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827703

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer's disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3ß and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

4.
Nat Commun ; 10(1): 4201, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519986

RESUMO

As Charles Darwin anticipated, living fossils provide excellent opportunities to study evolutionary questions related to extinction, competition, and adaptation. Ginkgo (Ginkgo biloba L.) is one of the oldest living plants and a fascinating example of how people have saved a species from extinction and assisted its resurgence. By resequencing 545 genomes of ginkgo trees sampled from 51 populations across the world, we identify three refugia in China and detect multiple cycles of population expansion and reduction along with glacial admixture between relict populations in the southwestern and southern refugia. We demonstrate multiple anthropogenic introductions of ginkgo from eastern China into different continents. Further analyses reveal bioclimatic variables that have affected the geographic distribution of ginkgo and the role of natural selection in ginkgo's adaptation and resilience. These investigations provide insights into the evolutionary history of ginkgo trees and valuable genomic resources for further addressing various questions involving living fossil species.


Assuntos
Evolução Biológica , Genoma de Planta , Ginkgo biloba/genética , Filogenia , Adaptação Fisiológica , China , Fósseis , Genômica , Sementes/genética , Seleção Genética
5.
Neurotherapeutics ; 16(4): 1225-1236, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313223

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized in part by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The main pathological hallmark of PD is the intraneuronal accumulation of misfolded α-synuclein (α-syn) aggregates. Mutations in the SNCA gene (encoding α-syn) and variations in its copy number are associated with some forms of familial PD. In the present study, T-006, a new tetramethylpyrazine (TMP) derivative with recently reported anti-Alzheimer activity, is shown to significantly promote α-syn degradation in a cellular PD model. Moreover, we illustrate that T-006 inhibits the accumulation of both Triton-soluble and -insoluble forms of α-syn and protects against α-syn-induced neurotoxicity in A53T-α-syn transgenic mice. The mechanism of action of T-006 was verified by evaluation of a potential protein degradation pathway. We found that T-006 promotes α-syn degradation in a proteasome-dependent and autophagy-independent manner. We further confirmed that T-006 enhances proteasome activity by upregulating 20S proteasome subunit ß5i (LMP7) protein expression. A functional study revealed that T-006 activates the PKA/Akt/mTOR/p70S6K pathway to trigger LMP7 expression and enhance chymotrypsin-like proteasomal activity. These findings indicate that T-006 is a potent proteasome activator and a potential therapeutic agent for the prevention and treatment of PD and related diseases.

6.
Biomed Res Int ; 2019: 7465272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355279

RESUMO

In parallel with the prevalence metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in most countries. It features a constellation of simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even hepatocellular carcinoma. There are no approved drugs for effective management of NAFLD and NASH. Jianpi Huoxue formula (JPHX) mainly consists of Atractylodes macrocephal (Baizhu), Salvia miltiorrhiza (Danshen), Rasux Paeonia Alba (Baishao), Rhizoma Alismatis (Zexie), and Fructus Schisandrae Chinensis (Wuweizi), which may have beneficial effects on NAFLD. The aim of the study was to identify the effect of JPHX on NAFLD. A NAFLD model was induced by methionine-choline-deficient food (MCD) in Wistar rats and orally administered with simultaneous JPHX, once a day for 8 weeks. Hepatocellular injury, lipid profile, inflammation, fibrosis, and apoptosis were evaluated. The results showed that JPHX significantly decreased the abnormal serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the MCD model (P<0.05). Furthermore, JPHX protected MCD diet-fed rats from accumulation of hepatic triglycerides (TG) and total cholesterol (TC). Histological examination demonstrated that JPHX noticeably normalized the NAFLD activity score (NAS). Moreover, JPHX ameliorated liver inflammation by decreasing TNF-α levels and reduced collagen and matrix metalloproteinases in MCD diet-fed rats. In addition, JPHX prevented rats from MCD-induced cellular apoptosis, as suggested by TUNEL staining, and suppressed the activation of caspase 3 and 7 proteins. JPHX also inhibited the phosphorylation of JNK. In conclusion, JPHX exhibited a hepatoprotective effect against NAFLD in an MCD experimental model.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Alimentos Formulados/efeitos adversos , Fígado , Hepatopatia Gordurosa não Alcoólica , Animais , Colina , Fígado/metabolismo , Fígado/patologia , Masculino , Metionina , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ratos , Ratos Wistar
7.
Arch Toxicol ; 93(6): 1745-1767, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31203412

RESUMO

Venoms from marine animals have been recognized as a new emerging source of peptide-based therapeutics. Several peptide toxins from sea anemone have been investigated as therapeutic leads or pharmacological tools. Venom complexity should be further highlighted using combined strategies of large-scale sequencing and data analysis which integrated transcriptomics and proteomics to elucidate new proteins or peptides to be compared among species. In this work, transcriptomic and proteomic analyses were combined to identify six groups of expressed peptide toxins in Zoanthus natalensis. These include neurotoxin, hemostatic and hemorrhagic toxin, protease inhibitor, mixed function enzymes, venom auxiliary proteins, allergen peptides, and peptides related to the innate immunity. Molecular docking analysis indicated that one expressed Zoanthus Kunitz-like peptide, ZoaKuz1, could be a voltage-gated potassium channels blocker and, hence, it was selected for functional studies. Functional bioassays revealed that ZoaKuz1 has an intrinsic neuroprotective activity in zebrafish model of Parkinson's disease. Since pharmacological blockade of KV channels is known to induce neuroprotective effects, ZoaKuz1 holds the potential to be developed in a therapeutic tool to control neural dysfunction by slowing or even halting neurodegeneration mediated by ion-channel hyperactivity.

8.
Phytomedicine ; 61: 152842, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31048127

RESUMO

BACKGROUND: Parkinson's disease (PD) is an age-dependent progressive movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Accumulation of -synuclein (-syn) positive protein aggregates in the substantia nigra is a pathological hallmark of PD, indicating that protein turnover defect is implicated in PD pathogenesis. PURPOSE: This study aims to identify neuroprotective compounds which can alleviate the accumulation of -syn in neuronal cells and dissect the underlying mechanisms. METHODS: High throughput screening was performed by dot blot assay. The degradation of different forms of -syn by candidate compounds were assessed by western blot. The autophagy lysosome pathway and ubiquitin-proteasome system were examined to dissect the degradation pathway. The UPS activity was assessed by cellular UPS substrates degradation assay and biochemical proteasome activity assay. Q-PCR was performed to test the mRNA level of different proteasome subunits. Furthermore, Neuroprotective effect of candidate compound was tested by LDH assay and PI staining. RESULTS: Through the high throughput screening, harmine was identified as a potent -syn lowering compound. The time-dependent and dose-dependent effects of harmine on the degradation of different forms of -syn were further confirmed. Harmine could dramatically promote the degradation of UPS substrates GFP-CL1, Ub-R-GFP and Ub-G76V-GFP, and activate cellular proteasome activity. Mechanistically, harmine dramatically enhanced PKA phosphorylation to enhance proteasome subunit PSMD1 expression. PKA inhibitor blocked the effects of harmine in activating UPS, up regulating PSMD1 and promoting -syn degradation, indicating that harmine enhances UPS function via PKA activation. Moreover, harmine efficiently rescued cell death induced by over-expression of -syn, via UPS-dependent manner. CONCLUSION: Harmine, as a new proteasome enhancer, may have potential to be developed into therapeutic agent against neurodegenerative diseases associated with UPS dysfunction and aberrant proteins accumulation.


Assuntos
Harmina/farmacologia , Neurônios/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , alfa-Sinucleína/metabolismo , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Camundongos Transgênicos , Neurônios/metabolismo , Células PC12 , Fosforilação/efeitos dos fármacos , Ratos , alfa-Sinucleína/genética
9.
Eur J Pharmacol ; 854: 372-379, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31054273

RESUMO

G-protein coupled receptor 55 (GPR55) is an orphan G-protein coupled receptor, which is activated by endocannabinoids and lipid transmitters. Recently, GPR55 was shown to play a role in glucose and energy homeostasis, and insulin secretion is essential to maintain glucose homeostasis in the body. In Type 2 Diabetes Mellitus (T2DM), chronic insulin resistance and a progressive decline in ß-cell function result in ß-cell dysfunction, this leads to defect in insulin secretion, which is the key process in the development and progression of T2DM. GPR55 agonists were shown to increase insulin secretion, however the underlying mechanisms were not fully understood. Therefore the aim of the present study was to examine the effects of potent GPR55 agonists, O-1602 and abnormal cannabidiol (Abn-CBD), on glucose-induced insulin secretion in a mouse pancreatic ß-cell line, MIN6, and the underlying mechanisms with a focus on intracellular calcium (Ca2+). Our results demonstrated that O-1602 and Abn-CBD increased glucose-induced insulin secretion in MIN6 cells, which was abolished by a PLC inhibitor, U73122. Glucose-induced Ca2+ transients were enhanced by O-1602 and Abn-CBD, and this was significantly reduced by U73122 and inositol trisphosphate (IP3) receptor inhibitors, 2-aminoethoxydiphenyl borate (2-APB) and xestospongin C, as well as by Y-27632, a Rho-associated protein kinase (ROCK) inhibitor. Interestingly, O-1602 and Abn-CBD could directly induce intracellular Ca2+ transients through IP3-mediated Ca2+ release. In conclusion, GPR55 agonists increased insulin secretion through calcium mobilisation from IP3-sensitive ER stores in ß-cells.


Assuntos
Cálcio/metabolismo , Fosfatos de Inositol/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Canabidiol/análogos & derivados , Canabidiol/farmacologia , Linhagem Celular Tumoral , Glucose/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Células Secretoras de Insulina/citologia , Camundongos , Fosfolipase C beta/metabolismo , Resorcinóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Quinases Associadas a rho/metabolismo
10.
Mol Ecol Resour ; 19(5): 1309-1321, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31077549

RESUMO

The black rockfish (Sebastes schlegelii) is a teleost in which eggs are fertilized internally and retained in the maternal reproductive system, where they undergo development until live birth (viviparity). In the present study, we report a chromosome-level black rockfish genome assembly. High-throughput transcriptome analysis (RNA-seq and ATAC-seq) coupled with in situ hybridization (ISH) and immunofluorescence reveal several candidate genes for maternal preparation, sperm storage and release, and hatching. We propose that zona pellucida (ZP) proteins retain sperm at the oocyte envelope, while genes in two distinct astacin metalloproteinase subfamilies serve to release sperm from the ZP and free the embryo from chorion at prehatching stage. We present a model of black rockfish reproduction, and propose that the rockfish ovarian wall has a similar function to the uterus of mammals. Together, these genomic data reveal unprecedented insights into the evolution of an unusual teleost life history strategy, and provide a sound foundation for studying viviparity in nonmammalian vertebrates and an invaluable resource for rockfish ecological and evolutionary research.


Assuntos
Cromossomos , Evolução Molecular , Nascimento Vivo , Perciformes/genética , Perciformes/fisiologia , Animais , Biologia Computacional , Genômica/métodos , Anotação de Sequência Molecular
11.
BMC Genomics ; 20(1): 399, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117933

RESUMO

BACKGROUND: The three epidemiologically important Opisthorchiidae liver flukes Opisthorchis felineus, O. viverrini, and Clonorchis sinensis, are believed to harbour similar potencies to provoke hepatobiliary diseases in their definitive hosts, although their populations have substantially different ecogeographical aspects including habitat, preferred hosts, population structure. Lack of O. felineus genomic data is an obstacle to the development of comparative molecular biological approaches necessary to obtain new knowledge about the biology of Opisthorchiidae trematodes, to identify essential pathways linked to parasite-host interaction, to predict genes that contribute to liver fluke pathogenesis and for the effective prevention and control of the disease. RESULTS: Here we present the first draft genome assembly of O. felineus and its gene repertoire accompanied by a comparative analysis with that of O. viverrini and Clonorchis sinensis. We observed both noticeably high heterozygosity of the sequenced individual and substantial genetic diversity in a pooled sample. This indicates that potency of O. felineus population for rapid adaptive response to control and preventive measures of opisthorchiasis is higher than in O. viverrini and C. sinensis. We also have found that all three species are characterized by more intensive involvement of trans-splicing in RNA processing compared to other trematodes. CONCLUSION: All revealed peculiarities of structural organization of genomes are of extreme importance for a proper description of genes and their products in these parasitic species. This should be taken into account both in academic and applied research of epidemiologically important liver flukes. Further comparative genomics studies of liver flukes and non-carcinogenic flatworms allow for generation of well-grounded hypotheses on the mechanisms underlying development of cholangiocarcinoma associated with opisthorchiasis and clonorchiasis as well as species-specific mechanisms of these diseases.


Assuntos
Cricetinae/parasitologia , Cyprinidae/parasitologia , Genoma Helmíntico , Genômica/métodos , Proteínas de Helminto/genética , Opistorquíase/epidemiologia , Opisthorchis/genética , Sequência de Aminoácidos , Animais , Clonorquíase/epidemiologia , Clonorquíase/genética , Clonorquíase/parasitologia , Clonorchis sinensis/genética , Opistorquíase/genética , Opistorquíase/parasitologia , Homologia de Sequência
12.
Biomed Pharmacother ; 111: 1176-1186, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841431

RESUMO

Insulin resistance and ß-cell dysfunction are the main defects in Type 2 Diabetes Mellitus (T2DM), and ß-cell dysfunction and apoptosis is the critical determinant in the progression of T2DM. G-protein coupled receptor 55 (GPR55) is an orphan G-protein coupled receptor, which is activated by endocannabinoids and lipid transmitters. Recently, GPR55 was shown to regulate glucose and energy homeostasis, however its role in ß-cell apoptosis was not studied. Therefore, in this study, we investigated the novel effect of GPR55 agonists, O-1602 and abnormal cannabidiol (Abn-CBD), on endoplasmic reticulum (ER) stress-induced apoptosis in mouse pancreatic ß-cell lines, MIN6 and Beta-TC-6, and its underlying mechanisms. Our results showed that O-1602 and Abn-CBD reduced ER stress-induced apoptosis in MIN6 and Beta-TC-6 cells. This was through the phosphorylation of 3'-5'-cyclic adenosine monophosphate response element-binding protein (CREB) in ß-cells, hence activating CREB downstream anti-apoptotic genes, Bcl-2 and Bcl-xL. Moreover, O-1602 and Abn-CBD directly activated kinases, CaMKIV, Erk1/2 and PKA, to induce CREB phosphorylation. Therefore, our results indicated that GPR55 agonists protected from ß-cell apoptosis through CREB activation, thus up-regulating anti-apoptotic genes. In conclusion, our study provided a novel protective effect of GPR55 agonists on ER stress-induced apoptosis in ß-cells and its underlying mechanisms mediating this protection, therefore we suggested that GPR55 might be a therapeutic target for T2DM.


Assuntos
Apoptose/efeitos dos fármacos , Canabidiol/análogos & derivados , Canabidiol/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Canabinoides/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Células Secretoras de Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/metabolismo
13.
ACS Chem Neurosci ; 10(5): 2434-2449, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30839193

RESUMO

This study mainly investigated the therapeutic effects of BHDPC on ischemic stroke and its underlying mechanisms. In vivo, the transient middle cerebral artery occlusion (MCAO) was used to induce ischemic model. In vitro, oxygen and glucose deprivation/reperfusion (OGD/R)-induced ischemic stroke in BV-2 microglia and primary neurons, and bEnd.3 mouse cerebral microvascular endothelial cells (ECs) were also used. First, we found that BHDPC exerts considerable neuroprotection against MCAO-induced ischemic injury to mice via alleviating neurological deficits and brain infarcts, inhibiting neuronal cell loss and apoptosis, and attenuating blood-brain barrier disruption and tight junction protein changes. Next, we observed that BHDPC significantly reduced microglial M1 activation but enhanced M2 polarization in MCAO-induced ischemic brain. Further experiments in vitro indicated that BHDPC suppressed microglial activation but promoted M2 microglial polarization in OGD/R-induced BV-2 microglia. In addition, conditioned medium (CM) experiments showed that CM from BHDPC-treated BV-2 microglia provided protections against OGD/R-induced ischemic damage in primary neurons and bEnd.3 ECs. Moreover, we found that BHDPC actions on microglial inflammation were associated with the inactivation of NF-κB signaling. Interestingly, we also found that BHDPC enhanced phosphorylation of protein kinase A (PKA) and cAMP-response element-binding protein (CREB). The pharmacological inhibition or gene knockdown of PKA/CREB signaling diminished BHDPC-promoted microglial M2 polarization. In summary, BHDPC conferred neuroprotection against ischemic injury in experimental stroke models. Modulating microglial activation and polarization contributes to BHDPC-mediated neuroprotective actions, which in part were mediated by nuclear factor kappa B and PKA/CREB signaling pathway.

14.
Int J Syst Evol Microbiol ; 69(5): 1343-1349, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30821673

RESUMO

A Gram-stain-positive, aerobic, motile, non-spore-forming and rod-shaped actinobacterium, designated strain 4Q3S-7T, was isolated from a piece of surface-sterilized bark of Kandelia candel collected at the Cotai Ecological Zone in Macao, China. Colonies were yellowish white, circular, smooth and convex. The 16S rRNA gene sequence of strain 4Q3S-7T exhibited highest similarities to Marmoricola ginsengisoli Gsoil 097T (97.6 %), Marmoricola solisilvae KIS18-7T (97.6 %) and Marmoricola pocheonensis Gsoil 818T (97.3 %). Phylogenetic analysis showed that strain 4Q3S-7T clustered with species of the genus Marmoricola and was clearly affiliated to the genus Marmoricola. Genomic analyses, including average nucleotide identity and DNA-DNA hybridization, clearly separated strain 4Q3S-7T from M. ginsengisoli Gsoil 097T, M. solisilvae KIS18-7T and M. pocheonensis Gsoil 818T with values below the thresholds for species delineation. Strain 4Q3S-7T had ll-2,6-diaminopimelic acid as the diagnostic diamino acid in the cell wall. The major fatty acids (>10 % of total fatty acids) were C18 : 0 10-methyl (TBSA), C18 : 1ω9c, iso-C16 : 0 and iso-C16 : 0 2-OH. The predominant menaquinone was MK-8(H4). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylinositol and an unidentified phospholipid. The DNA G+C content of strain 4Q3S-7T was 72.0 mol% (draft genome sequence). Based on its phylogenetic, phenotypic and chemotaxonomic features, strain 4Q3S-7T is considered to represent a novel species of the genus Marmoricola, for which the name Marmoricola mangrovicus sp. nov. is proposed. The type strain is 4Q3S-7T (=KCTC 39790T=CGMCC 4.7424T).


Assuntos
Actinobacteria/classificação , Filogenia , Casca de Planta/microbiologia , Rhizophoraceae/microbiologia , Actinobacteria/isolamento & purificação , Técnicas de Tipagem Bacteriana , Composição de Bases , Parede Celular/química , China , DNA Bacteriano/genética , Ácido Diaminopimélico/química , Ácidos Graxos/química , Hibridização de Ácido Nucleico , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/química
15.
Food Funct ; 10(2): 1212-1224, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30741293

RESUMO

The aim of the present study was to explore whether the supercritical-carbon dioxide fluid extract from flowers and buds of Chrysanthemum indicum (SEC) exhibits antidepressant-like effects in a chronic unpredictable mild stress (CUMS)-induced mice model. Firstly, SEC was found to reverse a CUMS-induced decrease in the body weight gain in mice. Next, SEC was found to alleviate CUMS-induced depressive-like behavior, evidenced by the reversal of the decrease in the sucrose consumption in the sucrose preference test (SPT), the increase in the locomotor activity in the open field test (OPF), and the alleviation of immobility duration in both the forced swimming test (FST), and tail-suspension test (TST). SEC also attenuated CUMS-induced hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis by decreasing the levels of serum corticosterone and (CORT) and adrenocorticotropic hormone (ACTH), and hypothalamus corticotrophin-releasing hormone (CRH). In addition, SEC was found to suppress the expression of pro-inflammatory cytokines, including the tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in the hippocampal of CUMS mice. Interestingly, further investigations demonstrated that SEC inhibited CUMS-induced activation of the nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasomes pathways but upregulated brain-derived neurotrophic factor (BDNF) expression and promoted phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element-binding protein (CREB) in hippocampal. In summary, SEC was able to alleviate depressive-like behavior in a CUMS-induced mice model, accompanied by inhibitory roles in the hyperactivity of the HPA axis and pro-inflammatory cytokine expression. Modulating the NF-κB/NLRP3 and BDNF/CREB/ERK pathways contributed to SEC-mediated antidepressant-like effects.


Assuntos
Antidepressivos/farmacologia , Chrysanthemum/química , Depressão/tratamento farmacológico , Extratos Vegetais/farmacologia , Estresse Fisiológico , Animais , Antidepressivos/química , Peso Corporal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dióxido de Carbono , Cromatografia com Fluido Supercrítico , Depressão/etiologia , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora , Fitoterapia , Extratos Vegetais/química , Sacarose
16.
J Cachexia Sarcopenia Muscle ; 10(2): 429-444, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30793539

RESUMO

BACKGROUND: Muscle atrophy and weakness are adverse effects of high dose or the sustained usage of glucocorticoids. Loss of mitochondria and degradation of protein are highly correlated with muscle dysfunction. The deacetylase sirtuin 1 (SIRT1) plays a vital role in muscle remodelling. The current study was designed to identify myricanol as a SIRT1 activator, which could protect skeletal muscle against dexamethasone-induced wasting. METHODS: The dexamethasone-induced atrophy in C2C12 myotubes was evaluated by expression of myosin heavy chain, muscle atrophy F-box (atrogin-1), and muscle ring finger 1 (MuRF1), using western blots. The mitochondrial content and oxygen consumption were assessed by MitoTracker staining and extracellular flux analysis, respectively. Muscle dysfunction was established in male C57BL/6 mice (8-10 weeks old, n = 6) treated with a relatively high dose of dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, forced swimming capacity, muscle weight, and muscle histology were assessed. The expression of proteolysis-related, autophagy-related, apoptosis-related, and mitochondria-related proteins was analysed by western blots or immunoprecipitation. RESULTS: Myricanol (10 µM) was found to rescue dexamethasone-induced muscle atrophy and dysfunction in C2C12 myotubes, indicated by increased expression of myosin heavy chain (0.33 ± 0.14 vs. 0.89 ± 0.21, *P < 0.05), decreased expression of atrogin-1 (2.31 ± 0.67 vs. 1.53 ± 0.25, *P < 0.05) and MuRF1 (1.55 ± 0.08 vs. 0.99 ± 0.12, **P < 0.01), and elevated ATP production (3.83 ± 0.46 vs. 5.84 ± 0.79 nM/mg protein, **P < 0.01), mitochondrial content (68.12 ± 10.07% vs. 116.38 ± 5.12%, *P < 0.05), and mitochondrial oxygen consumption (166.59 ± 22.89 vs. 223.77 ± 22.59 pmol/min, **P < 0.01). Myricanol directly binds and activates SIRT1, with binding energy of -5.87 kcal/mol. Through activating SIRT1 deacetylation, myricanol inhibits forkhead box O 3a transcriptional activity to reduce protein degradation, induces autophagy to enhance degraded protein clearance, and increases peroxisome proliferator-activated receptor γ coactivator-1α activity to promote mitochondrial biogenesis. In dexamethasone-induced muscle wasting C57BL/6 mice, 5 mg/kg myricanol treatment reduces the loss of muscle mass; the percentages of quadriceps and gastrocnemius muscle in myricanol-treated mice are 1.36 ± 0.02% and 0.87 ± 0.08%, respectively (cf. 1.18 ± 0.06% and 0.78 ± 0.05% in dexamethasone-treated mice, respectively). Myricanol also rescues dexamethasone-induced muscle weakness, indicated by improved grip strength (70.90 ± 4.59 vs. 120.58 ± 7.93 g, **P < 0.01) and prolonged swimming exhaustive time (48.80 ± 11.43 vs. 83.75 ± 15.19 s, **P < 0.01). Myricanol prevents dexamethasone-induced muscle atrophy and weakness by activating SIRT1, to reduce muscle protein degradation, enhance autophagy, and promote mitochondrial biogenesis and function in mice. CONCLUSIONS: Myricanol ameliorates dexamethasone-induced skeletal muscle wasting by activating SIRT1, which might be developed as a therapeutic agent for treatment of muscle atrophy and weakness.

17.
Sci Rep ; 9(1): 823, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696899

RESUMO

Actinobacteria, a group of gram-positive bacteria, can produce plenty of valuable bioactive secondary metabolites, especially antibiotics. Hence, in order to search for new actinobacteria, actinobacterial isolates were obtained from rhizosphere soil collected from the Futian mangrove ecosystem in Shenzhen, China. According to 16S rRNA sequences, 14 actinobacterial strains of the genus Streptomyces, Rhodococcus, Microbacterium, Micromonospora, Actinoplanes and Mycobacterium were isolated and identified. Among these, strain Mycobacterium sp.13 was described as a potential new species belonging to the genus Mycobacterium within the class of actinobacteria according to the genomic analysis. The genome-based 16S rRNA sequences had 98.48% sequence similarity with Mycobacterium moriokaense DSM 44221T. Meanwhile, the genome sequences of Mycobacterium sp.13 showed an average nucleotide identity (ANI) with the Mycobacterium mageritense DSM 44476, Mycobacterium smegmatis MKD8 and Mycobacterium goodii strain X7B of only 74.79%, 76.12% and 76.42%, respectively. Furthermore, genome-mining results showed that Mycobacterium sp.13 contained 105 gene clusters encoding to the secondary metabolite biosynthesis, where many kinds of terpene, bacteriocin, T1pks, Nrps, saccharide, fatty acid, butyrolactone, ectoine and resorcinol were included. Finally, through LC-MS and HR-MS, analyzing the small molecules from ethyl acetate extract of this strain, asukamycin C and apramycin were for the first time found present to be in Mycobacterium moriokaense strain. Our study provides evidence in support of the potential new Mycobacterium sp.13 isolated from the mangrove environment as a possible novel source of natural products.

18.
J Cell Biochem ; 120(4): 5913-5922, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30304553

RESUMO

Doxorubicin (Dox) is a well-known chemotherapeutic agent used in the treatment of various cancers. However, Dox-induced cardiotoxicity limits its further clinical use. We have previously reported a small molecular named biotin-conjugated ADTM analog (BAA) that exhibits cytoprotective effects against oxidative stress-induced cell injury in cardiomyoblast H9c2 cells. Here, the protective effects of BAA, indexed by attenuation of the cardiotoxicity induced by Dox as well as synergistic antitumor activity that increases the chemotherapeutic efficacy of Dox were investigated. Our results demonstrated that BAA significantly ameliorated Dox-induced toxicity in the H9c2 cells and zebrafish models. In addition, BAA attenuated Dox-induced endoplasmic reticulum (ER) stress in H9c2 cells. An ER stress inhibitor, 4-phenylbutyric acid, reversed the protective effect of BAA in H9c2 cells. In contrast, in human breast tumor MDA-MB-231 cells, BAA significantly enhanced Dox-induced cytotoxicity through upregulating Dox-induced ER stress response. Taken together, our findings indicate that Dox combined with BAA can significantly enhance its antitumor activity in breast cancer cells and reduce its cardiotoxicity, at least in part, by mediating ER stress activation.

19.
Drug Discov Today ; 24(1): 189-197, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30165198

RESUMO

Cnidaria provide the largest source of bioactive peptides for new drug development. The venoms contain enzymes, potent pore-forming toxins and neurotoxins. The neurotoxins can immobilize predators rapidly when discharged via modifying sodium-channel-gating or blocking the potassium channel during the repolarization stage. Most cnidarian neurotoxins remain conserved under the strong influence of negative selection. Neuroactive peptides targeting the central nervous system through affinity with ion channels could provide insight leading to drug treatment of neurological diseases, which arise from ion channel dysfunctions. Although marine resources offer thousands of possible peptides, only one peptide derived from Cnidaria: ShK-186, also named dalazatide, has reached the pharmaceutical market. This review focuses on neuroprotective agents derived from cnidarian neurotoxic peptides.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Cnidários , Canais Iônicos/fisiologia , Fármacos Neuroprotetores , Neurotoxinas , Peptídeos , Animais , Descoberta de Drogas , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/farmacologia , Neurotoxinas/uso terapêutico , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Filogenia
20.
Food Chem ; 270: 305-314, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30174051

RESUMO

Myricanol is a diarylheptanoid isolated from Chinese bayberry. Through virtual docking strategy, myricanol was discovered as an AMP-activated protein kinase (AMPK) activator among a series of structural analogs, with high affinity for the γ subunit of AMPK. Myricanol was also evaluated for regulatory effects on lipid accumulation and insulin sensitivity in 3T3-L1 adipocytes and adiposity in high-fat diet-fed zebrafish. Myricanol suppressed lipid accumulation in 3T3-L1 cells in the initial stage (days 0-2) by suppressing adipogenesis and in the terminal stage (days 4-7) by inducing lipolysis and lipid combustion through activating AMPK. Moreover, myricanol enhanced insulin-stimulated glucose uptake by activating the insulin signaling pathway. In high-fat diet-fed zebrafish, myricanol inhibited lipid accumulation by suppressing adipogenic factors including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). In summary, the results indicate that myricanol could be a potential therapeutic agent against obesity by activating the AMPK signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia , Diarileptanoides/farmacologia , Peixe-Zebra , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Animais , Proteína alfa Estimuladora de Ligação a CCAAT , Dieta Hiperlipídica/efeitos adversos , Lipídeos , Camundongos , PPAR gama
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