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1.
Acta Pharmacol Sin ; 45(1): 112-124, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37731037

RESUMO

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 µg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.


Assuntos
Aterosclerose , Placa Aterosclerótica , Camundongos , Humanos , Animais , Placa Aterosclerótica/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Aterosclerose/metabolismo , Macrófagos/metabolismo , Apolipoproteínas E/metabolismo , Ativação de Macrófagos , Camundongos Endogâmicos C57BL
2.
Pharmaceutics ; 15(12)2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38140054

RESUMO

Gefitinib (GEF) is a clinical medication for the treatment of lung cancer targeting the epidermal growth factor receptor (EGFR). However, its efficacy is remarkably limited by low solubility and dissolution rates. In this study, two cocrystals of GEF with co-formers were successfully synthesized using the recrystallization method characterized via Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and 2D Nuclear Overhauser Effect Spectroscopy. The solubility and dissolution rates of cocrystals were found to be two times higher than those of free GEF. In vitro cytotoxicity studies revealed that the cocrystals enhanced the inhibition of cell proliferation and apoptosis in A549 and H1299 cells compared to free GEF. In mouse models, GEF@TSBO demonstrated targeted, safe, and effective antitumor activity with only one-dose administration. Mechanistically, the GEF cocrystals were shown to increase the cellular levels of damaged DNA, while potentially downregulating PARP, thereby impairing the DNA repair machinery and leading to an imbalance between DNA damage and restoration. These findings suggest that the cocrystallization of GEF could serve as a promising adjunct to significantly enhance the physicochemical and biopharmaceutical performance for lung cancer treatment, providing a facial strategy to improve GEF anticancer efficiency with high bioavailability that can be orally administrated with only one dose.

3.
Org Lett ; 25(26): 4923-4927, 2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37358340

RESUMO

A straightforward strategy for constructing seven-membered carbocycles by employing a Lewis acid catalyzed intramolecular Michael addition of allenones is reported. It offers atom-economic access to synthetically important furan-fused bi- or tricyclic frameworks containing seven-membered carbocycles, which are widely found in natural products possessing various bioactivities. A number of seven-membered carbocycle-containing polycyclic frameworks bearing diverse functional groups were prepared in good to excellent yields. Furthermore, the application potential of this strategy was exemplified by the construction of the key skeletons of Caribenol A and Frondosin B.

4.
Front Immunol ; 14: 1162004, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37090697

RESUMO

Upon migrating into the tissues, hematopoietic stem cell (HSC)-derived monocytes differentiate into macrophages, playing a crucial role in determining innate immune responses towards external pathogens and internal stimuli. However, the regulatory mechanisms underlying monocyte-to-macrophage differentiation remain largely unexplored. Here we divulge a previously uncharacterized but essential role for an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), in monocyte-to-macrophage maturation. FLRT2 is almost undetectable in human monocytic cell lines, human peripheral blood mononuclear cells (PBMCs), and mouse primary monocytes but significantly increases in fully differentiated macrophages. Myeloid-specific deletion of FLRT2 (Flrt2ΔMyel ) contributes to decreased peritoneal monocyte-to-macrophage generation in mice in vivo, accompanied by impaired macrophage functions. Gain- and loss-of-function studies support the promoting effect of FLRT2 on THP-1 cell and human PBMC differentiation into macrophages. Mechanistically, FLRT2 directly interacts with Unc-5 netrin receptor B (UNC5B) via its extracellular domain (ECD) and activates Akt/mTOR signaling. In vivo administration of mTOR agonist MYH1485 reverses the impaired phenotypes observed in Flrt2ΔMyel mice. Together, these results identify FLRT2 as a novel pivotal endogenous regulator of monocyte differentiation into macrophages. Targeting the FLRT2/UNC5B-Akt/mTOR axis may provide potential therapeutic strategies directly relevant to human diseases associated with aberrant monocyte/macrophage differentiation.


Assuntos
Leucócitos Mononucleares , Monócitos , Humanos , Animais , Camundongos , Monócitos/metabolismo , Leucócitos Mononucleares/metabolismo , Fibronectinas/metabolismo , Leucina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Macrófagos/metabolismo , Diferenciação Celular , Serina-Treonina Quinases TOR/metabolismo , Receptores de Netrina/metabolismo , Glicoproteínas de Membrana/metabolismo
5.
Pharm Biol ; 61(1): 362-371, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36740871

RESUMO

CONTEXT: Kazinol B (KB), an isoprenylated flavan derived from Broussonetia kazinoki Sieb. (Moraceae) root, has long been used in folk medicine. OBJECTIVE: This study examines the protective effects of KB and its underlying mechanisms in hypoxia and reoxygenation (H/R)-induced cardiac injury in H9c2 rat cardiac myoblasts. MATERIALS AND METHODS: H9c2 cells were incubated with various concentrations of KB (0, 0.3, 1, 3, 10 and 30 µM) for 2 h and then subjected to H/R insults. The protective effects of KB and its underlying mechanisms were explored. RESULTS: KB significantly elevated cell viability (1 µM, 1.21-fold; 3 µM, 1.36-fold, and 10 µM, 1.47-fold) and suppressed LDH release (1 µM, 0.77-fold; 3 µM, 0.68-fold, and 10 µM, 0.59-fold) in H/R-induced H9c2 cells. Further, 10 µM KB blocked apoptotic cascades, as shown by the Annexin-V/PI (0.41-fold), DNA fragmentation (0.51-fold), caspase-3 (0.52-fold), PARP activation (0.27-fold) and Bax/Bcl-2 expression (0.28-fold) assays. KB (10 µM) downregulated reactive oxygen species production (0.51-fold) and lipid peroxidation (0.48-fold); it upregulated the activities of GSH-Px (2.08-fold) and SOD (1.72-fold). KB (10 µM) induced Nrf2 nuclear accumulation (1.94-fold) and increased ARE promoter activity (2.15-fold), HO-1 expression (3.07-fold), AKT (3.07-fold) and AMPK (3.07-fold) phosphorylation. Nrf2 knockdown via using Nrf2 siRNA abrogated KB-mediated protective effects against H/R insults. Moreover, pharmacological inhibitors of AKT and AMPK also abrogated KB-induced Nrf2 activation and its protective function. DISCUSSION AND CONCLUSIONS: KB prevented H/R-induced cardiomyocyte injury via modulating the AKT and AMPK-mediated Nrf2 induction. KB might be a promising drug candidate for managing ischemic cardiac disorders.


Assuntos
Miócitos Cardíacos , Proteínas Proto-Oncogênicas c-akt , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Apoptose , Estresse Oxidativo
6.
Micromachines (Basel) ; 13(10)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36295924

RESUMO

Exosomes are lipid-bilayer enclosed vesicles with diameters of 30-150 nm, which play a pivotal role in cell communication by transporting their cargoes such as proteins, lipids, and genetic materials. In recent years, exosomes have been under intense investigation, as they show great promise in numerous areas, especially as bio-markers in liquid biopsies. However, due to the high heterogeneity and the nano size of exosomes, the separation of exosomes is not easy. This review will deliver an outline of the conventional methods and the microfluidic-based technologies for exosome separation. Particular attention is devoted to microfluidic devices, highlighting the efficiency of exosome isolation by these methods. Additionally, this review will introduce advances made in the integrated microfluidics technologies that enable the separation and analysis of exosomes.

7.
Front Chem ; 10: 816741, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35211455

RESUMO

Bacteria have developed increasing resistance to currently used antimicrobial agents. New classes of antimicrobial drugs are urgently required to fight drug-resistant pathogens. Here, we designed and synthesized a series of calix[4]arene derivatives as antibacterial agents by biomimicking the structural properties and biological functions of antibacterial peptides. After introducing cationic hydrophilic moieties and preliminary structural optimization, we obtained a lead compound (16) that exhibited excellent antibacterial activity against Gram-positive bacteria, low toxicity toward mammalian cells and poor hemolytic activity. The antibacterial mechanism studies showed that compound 16 can destroy bacterial cell membrane directly, leading to bacterial death and a low tendency to develop bacterial resistance.

8.
Acta Pharmacol Sin ; 43(6): 1408-1418, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34552216

RESUMO

Despite improvements in cardiovascular disease (CVD) outcomes by cholesterol-lowering statin therapy, the high rate of CVD is still a great concern worldwide. Dehydrocorydaline (DHC) is an alkaloidal compound isolated from the traditional Chinese herb Corydalis yanhusuo. Emerging evidence shows that DHC has anti-inflammatory and antithrombotic benefits, but whether DHC exerts any antiatherosclerotic effects remains unclear. Our study revealed that intraperitoneal (i.p.) injection of DHC in apolipoprotein E-deficient (ApoE-/-) mice not only inhibited atherosclerosis development but also improved aortic compliance and increased plaque stability. In addition, DHC attenuated systemic and vascular inflammation in ApoE-/- mice. As macrophage inflammation plays an essential role in the pathogenesis of atherosclerosis, we next examined the direct effects of DHC on bone marrow-derived macrophages (BMDMs) in vitro. Our RNA-seq data revealed that DHC dramatically decreased the levels of proinflammatory gene clusters. We verified that DHC significantly downregulated proinflammatory interleukin (IL)-1ß and IL-18 mRNA levels in a time- and concentration-dependent manner. Furthermore, DHC decreased lipopolysaccharide (LPS)-induced inflammation in BMDMs, as evidenced by the reduced protein levels of CD80, iNOS, NLRP3, IL-1ß, and IL-18. Importantly, DHC attenuated LPS-induced activation of p65 and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Thus, we conclude that DHC ameliorates atherosclerosis in ApoE-/- mice by inhibiting inflammation, likely by targeting macrophage p65- and ERK1/2-mediated pathways.


Assuntos
Aterosclerose , Interleucina-18 , Alcaloides , Animais , Apolipoproteínas E , Aterosclerose/metabolismo , Inflamação/metabolismo , Interleucina-18/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
9.
Chin Med ; 16(1): 116, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34758851

RESUMO

BACKGROUND: Arsenic (As3+) is a carcinogen with considerable environmental and occupational relevancy. Its mechanism of action and methods of prevention remain to be investigated. Previous studies have demonstrated that ROS is responsible for As3+-induced cell transformation, which is considered as the first stage of As3+ carcinogenesis. The NF-E2 p45-related factor-2 (Nrf2) signaling pathway regulates the cellular antioxidant response, and activation of Nrf2 has recently been shown to limit oxidative damage following exposure to As3+ METHODS AND RESULTS: In this study, molecular docking was used to virtually screen natural antioxidant chemical databases and identify molecules that interact with the ligand-binding site of Keap1 (PDB code 4L7B). The cell-based assays and molecular docking findings revealed that curcumin has the best inhibitory activity against Keap1-4L7B. Co-immunoprecipitation (Co-IP) results indicated that curcumin is a potent Keap1 Kelch domain-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. The increased activation of Nrf2 and its target antioxidant genes by curcumin could significantly decrease As3+-generated ROS. Moreover, curcumin induced autophagy in As3+-treated BEAS-2B via inducing autophagy by the formation of a p62/LC-3 complex and increasing autophagic flux by promoting transcription factor EB (TFEB) and lysosome-associated membrane protein 1 (LAMP1) expression. Knockdown of Nrf2 abolished curcumin-induced autophagy and downregulated ROS. Further studies showed that inhibition of autophagosome and lysosome fusion with bafilomycin a1 (BafA1) could block curcumin and prevented As3+-induced cell transformation. These results demonstrated that curcumin prevents As3+-induced cell transformation by inducing autophagy via the activation of the Nrf2 signaling pathway in BEAS-2B cells. However, overexpression of Keap-1 showed a constitutively high level of Nrf2 in As3+-transformed BEAS-2B cells (AsT) is Keap1-independent regulation. Overexpression of Nrf2 in AsT demonstrated that curcumin increased ROS levels and induced cell apoptosis via the downregulation of Nrf2. Further studies showed that curcumin decreased the Nrf2 level in AsT by activating GSK-3ß to inhibit the activation of PI3K/AKT. Co-IP assay results showed that curcumin promoted the interaction of Nrf2 with the GSK-3ß/ß-TrCP axis and ubiquitin. Moreover, the inhibition of GSK-3ß reversed Nrf2 expression in curcumin-treated AsT, indicating that the decrease in Nrf2 is due to activation of the GSK-3ß/ß-TrCP ubiquitination pathway. Furthermore, in vitro and in vivo results showed that curcumin induced cell apoptosis, and had anti-angiogenesis and anti-tumorigenesis effects as a result of activating the GSK-3ß/ß-TrCP ubiquitination pathway and subsequent decrease in Nrf2. CONCLUSIONS: Taken together, in the first stage, curcumin activated Nrf2, decreased ROS, and induced autophagy in normal cells to prevent As3+-induced cell transformation. In the second stage, curcumin promoted ROS and apoptosis and inhibited angiogenesis via inhibition of constitutive expression of Nrf2 in AsT to prevent tumorigenesis. Our results suggest that antioxidant natural compounds such as curcumin can be evaluated as potential candidates for complementary therapies in the treatment of As3+-induced carcinogenesis.

10.
Int J Nanomedicine ; 16: 6003-6016, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34511902

RESUMO

INTRODUCTION: Traditional antitumor chemotherapy faces great challenges, such as multi-drug resistance (MDR) and poor penetration into tumor tissues. The newly emerging nitric oxide (NO)-based gas therapy has been recognized to reduce MDR and has improved permeation into tumor tissue. METHODS: In this study, NO-generating prodrug sodium nitroprusside (SNP) was doped to hollow mesoporous Prussian blue (PB) nanoparticles to fabricate NO-generating nanoparticles (NO-PB), which was further loaded with doxorubicin (DOX). RESULTS: DOX loaded NO-PB (DOX-NO-PB) was released quicker at pH 6 compared with neutral pH, suggesting NO-PB may facilitate the release of loaded drug in acidic tumor tissue. The capacity of NO production by NO-PB was measured, and the results showed the presence of NO in the culture medium from 4T1 cells incubated with NO-PB and inside the cells. NP-PB could be detected by photoacoustic imaging (PAI) in tumor tissue in 4T1 tumor bearing mice, suggesting this nanoparticle may serve as contrast agent for the noninvasive diagnosis of tumor tissues. NO-PB suppressed the growth of tissues in 4T1 tumor bearing mice. DOX-NO-PB showed more potent anti-tumor effects in 4T1 cells and tumor bearing mice compared with free DOX and NO-PB alone, indicating that the combination of DOX and NO-PB exhibited synergistic effects on tumor suppression. CONCLUSION: This study provides a novel nanocarrier for gas therapy with additional PAI imaging capacity. This nanocarrier can be utilized for combination therapy of NO and chemotherapeutics which may serve as theranostic agents.


Assuntos
Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Animais , Doxorrubicina/farmacologia , Ferrocianetos , Camundongos , Óxido Nítrico
11.
Neurotox Res ; 39(4): 1323-1337, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33999357

RESUMO

The present study aimed to evaluate the neuroprotective effects and underlying mechanisms of pinocembrin-7-methylether (PME), a natural bioflavonoid, in 6-hydroxydopamine (6-OHDA)-induced models of Parkinson's disease in vivo and in vitro. First, we found that PME decreased apoptosis in 6-OHDA-intoxicated SH-SY5Y cells. PME also blocked several 6-OHDA-induced mitochondrial apoptotic cascades, including loss of mitochondrial membrane potential, caspase 3 and PARP activation, and a decrease in the Bcl-2/Bax ratio. Also, PME suppressed 6-OHDA-induced oxidative stress while increasing antioxidant enzymatic activity. Further investigations indicated that PME significantly enhanced nuclear accumulation of Nrf2, improved ARE promoter activity, and upregulated HO-1 and NQO1 expression levels. In addition, siRNA-mediated Nrf2 knockdown abolished PME-induced anti-oxidative and anti-apoptotic effects. Interestingly, we found that PME promoted phosphorylation of AKT and ERK, whereas pharmacological inhibition of AKT or ERK pathways diminished PME-induced Nrf2 activation and protective actions. Moreover, PME attenuated 6-OHDA-induced loss of dopaminergic neurons and ameliorated locomotor deficiency in zebrafish, supporting the neuroprotective actions of PME in vivo. In summary, we found that PME conferred neuroprotection against 6-OHDA-induced neurotoxicity in PD models in vivo and in vitro. Taken together, our findings suggest that activation of Nrf2/ARE/HO-1 signaling cascades contributes to PME-induced anti-oxidative and neuroprotective actions, which are at least partially mediated by AKT and ERK pathways.


Assuntos
Flavanonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/biossíntese , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas de Peixe-Zebra/biossíntese , Animais , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Relação Dose-Resposta a Droga , Flavanonas/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Peixe-Zebra
12.
J Nanobiotechnology ; 18(1): 146, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33076924

RESUMO

BACKGROUNDS: Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors. METHODS: In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer. RESULTS: The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone-vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs. CONCLUSIONS: Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Verde de Indocianina/farmacologia , Fotoquimioterapia/métodos , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Tratamento Farmacológico , Feminino , Humanos , Verde de Indocianina/análogos & derivados , Camundongos Endogâmicos BALB C , Fármacos Fotossensibilizantes/administração & dosagem , Povidona/análogos & derivados
13.
J Nanobiotechnology ; 18(1): 110, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32762751

RESUMO

BACKGROUNDS: Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming. METHODS: In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. RESULTS: The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. CONCLUSIONS: This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.


Assuntos
Bismuto , Meios de Contraste , Tomografia Computadorizada por Raios X/métodos , Animais , Bismuto/química , Bismuto/farmacocinética , Bismuto/toxicidade , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/toxicidade , Iohexol/química , Iohexol/farmacocinética , Rim/diagnóstico por imagem , Rim/metabolismo , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Camundongos , Ácido Pentético/química , Ácido Pentético/farmacocinética , Distribuição Tecidual , Imagem Corporal Total
14.
Int Immunopharmacol ; 84: 106559, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32402951

RESUMO

Accumulating clinical and epidemiological evidence indicates a close relationship between diabetes mellitus and dysfunction in memory and cognition. Neferine (NE) is a unique bis-benzylisoquinoline alkaloid derived from the seed embryo of Nelumbo nucifera (Lotus), an herbal medicine with a long history of use in used in China. NE has been reported to ameliorate diabetes mellitus and exert considerable protective effects on the central nervous system. Thus, this study aimed to investigate the effects of NE on memory and cognitive dysfunction in db/db mouse model of diabetes. First, we found that NE treatments significantly ameliorated behavioral impairment and cognitive dysfunction in the Morris water maze, Y-maze, and fear conditioning test in db/db mice. Additionally, in these diabetic mice, NE decreased fasting glucose and insulin resistance while promoting lipid metabolism. Furthermore, NE treatments alleviated oxidative stress and inhibited inflammatory responses in the hippocampus. Further investigations showed that NE suppressed the NOD-like receptor protein 3 (NLRP3) inflammasome pathway via down-regulating the levels of thioredoxin-interacting protein (TXNIP), NLRP3 inflammasomes, apoptosis-associated speck-like protein containing a CARD (ASC), and mature interleukin-1ß (IL-1ß) in the hippocampus. Moreover, NE alleviated endoplasmic-reticulum (ER) stress via down-regulating the levels of immunoglobulin heavy-chain-binding protein (GRP78), C/EBP homologous protein (CHOP), proteins kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) in the hippocampus. In conclusion, these results suggest that NE ameliorated memory and cognitive dysfunction, possibly through modulating the NLRP3 inflammasome pathways and alleviating ER stress.


Assuntos
Benzilisoquinolinas/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Benzilisoquinolinas/farmacologia , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamassomos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Aprendizagem Espacial/efeitos dos fármacos
15.
Food Funct ; 11(5): 4416-4427, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32374299

RESUMO

Accumulating clinical and epidemiological evidence indicates a close relationship between diabetes mellitus and dementia. The ginsenoside compound K (CK) has been reported to ameliorate diabetes mellitus and confer protection to the central nervous system. In this study, we investigated whether CK could improve memory impairment and cognitive dysfunction in diabetic db/db mice. Firstly, we found that CK treatments significantly improved behavioral impairment and cognitive dysfunction based on Morris water maze, Y-maze, and fear conditioning tests. Besides, CK decreased the fasting glucose level, increased lipid metabolism, and ameliorated glucose tolerance, insulin sensitivity, and dyslipidemia in diabetic db/db mice. In addition, CK treatments alleviated oxidative stress and inhibited the inflammatory response in hippocampal tissue. Further investigations showed that CK treatments inhibited the NLRP3 inflammasome pathway, as evidenced by the declined expression of TXNIP, NLRP3 inflammasomes, ASC, cleaved caspase-1, and mature IL-1ß in hippocampal tissues. Moreover, CK treatments alleviated ER stress via down-regulating the level of BiP, CHOP, p-PERK, p-IRE1α and ATF6 in the hippocampus of db/db mice. These results suggest that CK improves memory and cognitive dysfunction, possibly by ameliorating glucose tolerance, insulin sensitivity, and dyslipidemia, suppressing oxidative stress and inflammatory response and modulating the NLRP3 inflammasome pathway and ER stress.


Assuntos
Demência , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ginsenosídeos/farmacologia , Memória/efeitos dos fármacos , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Diabetes Mellitus Experimental , Feminino , Ginsenosídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos
16.
Cell Death Discov ; 3: 17051, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28845297

RESUMO

Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and no therapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for hemorrhagic stroke. ROCKs, which belong to the serine/threonine protein kinase family and participate in the organization of actin cytoskeleton, have become attractive targets for the treatment of strokes. In this study, in vitro enzyme-based assays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibit ROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1, and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions. Furthermore, FPND significantly prevented statin-induced cerebral hemorrhage in a zebrafish model. In addition, in vitro studies using the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented statin-induced cerebral hemorrhage by enhancing endothelial cell-cell junctions through inhibiting the ROCK-mediated VE-cadherin signaling pathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrity loss-related diseases, such as hemorrhagic stroke.

17.
Sci Rep ; 5: 16815, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26568398

RESUMO

Formononetin is an isoflavone that has been shown to display estrogenic properties and induce angiogenesis activities. However, the interrelationship between the estrogenic properties and angiogenesis activities of formononetin are not well defined. In the present study, docking and enzymatic assay demonstrated that formononetin displayed direct binding to the ligand-binding domain (LBD) of estrogen receptor alpha (ERα) with an agonistic property. Results from Human Umbilical Vein Endothelial Cells (HUVEC) by using real-time migration xCELLigence system, immunofluorescence and western blotting provided strong evidences of formononetin induced endothelial cell migration and dramatic actin cytoskeleton spatial modification through ERα-enhanced-ROCK-II/MMP2/9 signaling pathways. In addition, results from co-immunoprecipitation suggested formononetin induced cell migration via recruiting of ERα/ROCK-II activated complex formation. More interestingly, in zebrafish embryo we observed that formononetin significantly promoted angiogenic sproutings in the subintestinal vessels (SIVs) that could be completely abolished by ROCK inhibitor. In this study, we elucidated the underlying mechanisms that formononetin produced proangiogenesis effects through an ERα-enhanced ROCK-II signaling pathways. Results from the present study also expand our knowledge about the enigmatic underlying mechanisms of phytoestrogenic compounds in the promotion of angiogenesis in relation to ERα and ROCK interaction in endothelial cells and their relationship with actin assembly and cell migration.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Isoflavonas/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Animais , Sítios de Ligação , Movimento Celular/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Estradiol/análogos & derivados , Estradiol/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Fulvestranto , Células Endoteliais da Veia Umbilical Humana , Humanos , Isoflavonas/química , Isoflavonas/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Interferência de RNA , Fator A de Crescimento do Endotélio Vascular/farmacologia , Peixe-Zebra , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/genética
18.
PLoS One ; 9(11): e110656, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25365514

RESUMO

Datura stramonium is a widely used poisonous plant with great medicinal and economic value. Its chloroplast (cp) genome is 155,871 bp in length with a typical quadripartite structure of the large (LSC, 86,302 bp) and small (SSC, 18,367 bp) single-copy regions, separated by a pair of inverted repeats (IRs, 25,601 bp). The genome contains 113 unique genes, including 80 protein-coding genes, 29 tRNAs and four rRNAs. A total of 11 forward, 9 palindromic and 13 tandem repeats were detected in the D. stramonium cp genome. Most simple sequence repeats (SSR) are AT-rich and are less abundant in coding regions than in non-coding regions. Both SSRs and GC content were unevenly distributed in the entire cp genome. All preferred synonymous codons were found to use A/T ending codons. The difference in GC contents of entire genomes and of the three-codon positions suggests that the D. stramonium cp genome might possess different genomic organization, in part due to different mutational pressures. The five most divergent coding regions and four non-coding regions (trnH-psbA, rps4-trnS, ndhD-ccsA, and ndhI-ndhG) were identified using whole plastome alignment, which can be used to develop molecular markers for phylogenetics and barcoding studies within the Solanaceae. Phylogenetic analysis based on 68 protein-coding genes supported Datura as a sister to Solanum. This study provides valuable information for phylogenetic and cp genetic engineering studies of this poisonous and medicinal plant.


Assuntos
Datura stramonium/genética , Genoma de Cloroplastos , Plantas Medicinais/genética , Plantas Tóxicas/genética , Composição de Bases , Códon , Biologia Computacional , Datura stramonium/classificação , Engenharia Genética , Genômica , Repetições de Microssatélites , Anotação de Sequência Molecular , Filogenia , Plantas Medicinais/classificação , Plantas Tóxicas/classificação , Sequências Repetitivas de Ácido Nucleico , Análise de Sequência de DNA
19.
Am J Chin Med ; 42(1): 243-55, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24467547

RESUMO

Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Herein, we systematically investigated the effects of FUR on the significant processes of tumor progression with the relatively low concentrations in 95-D lung cancer cells. FUR concentration-dependently inhibited cell proliferation and blocked the cell cycle progressions in G1 phase by down-regulating the protein levels of cyclin D1 and CDK6, and up-regulating those of p21 and p27 in 95-D cells. FUR also affected the signaling molecules that regulate apoptosis in 95-D cells revealed by the down-regulation of the protein levels of full PARP, pro-caspase-7, survivin, and Bcl-2, and the up-regulation of cleaved PARP. Further studies showed that FUR enhanced the expression of light chain 3-II (LC3-II) in the protein level, indicating that autophagy is involved in this process. Besides, the adhesion ability of 95-D cells to matrigel and fibronectin was slightly inhibited after FUR treatment for 1 h in our experimental condition. FUR also slightly suppressed cell migration and invasion in 95-D cells according to the data from wound healing and Transwell assays, respectively. Taken together, FUR activated the signal molecules regulating G1 cell cycle arrest, apoptosis and autophagy, while slightly affecting the key steps of cell metastasis in 95-D lung cancer cells in the relatively low concentrations.


Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Curcuma/química , Furanos/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Neoplasias Pulmonares/patologia , Apoptose/genética , Autofagia/genética , Caspase 7/metabolismo , Relação Dose-Resposta a Droga , Furanos/isolamento & purificação , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Compostos Heterocíclicos com 2 Anéis/isolamento & purificação , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Metástase Neoplásica , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Rizoma , Survivina , Células Tumorais Cultivadas
20.
Phytother Res ; 28(2): 296-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23554049

RESUMO

Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Recently, we found that the combined treatment of FUR with paclitaxel (TAX) showed synergetic anti-proliferative activities in 95-D lung cancer cells. Herein, we showed that FUR reduced the cell numbers distributed in mitosis phase induced by TAX while increased those in G1 phase. The protein levels of cyclin D1, cyclin B1, CDK6 and c-Myc were all down-regulated in the group of combined treatment. The dramatically down-regulated expression of integrin ß4, focal adhesion kinase and paxillin might partially contribute to the synergic effect. Though FUR alone obviously induced endoplasmic reticulum stress, this signaling pathway may not contribute to the synergetic anti-proliferative effect as the protein expression of CHOP and BIP was similar in FUR alone and combined treatment group.


Assuntos
Ciclo Celular/efeitos dos fármacos , Furanos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Integrina beta4/metabolismo , Neoplasias Pulmonares/metabolismo , Paclitaxel/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Curcuma/química , Ciclina B1/metabolismo , Ciclina D1/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Estresse do Retículo Endoplasmático , Quinase 1 de Adesão Focal/metabolismo , Humanos , Paxilina/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
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