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1.
Cell ; 174(6): 1522-1536.e22, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30146161

RESUMO

How transcription affects genome 3D organization is not well understood. We found that during influenza A (IAV) infection, rampant transcription rapidly reorganizes host cell chromatin interactions. These changes occur at the ends of highly transcribed genes, where global inhibition of transcription termination by IAV NS1 protein causes readthrough transcription for hundreds of kilobases. In these readthrough regions, elongating RNA polymerase II disrupts chromatin interactions by inducing cohesin displacement from CTCF sites, leading to locus decompaction. Readthrough transcription into heterochromatin regions switches them from the inert (B) to the permissive (A) chromatin compartment and enables transcription factor binding. Data from non-viral transcription stimuli show that transcription similarly affects cohesin-mediated chromatin contacts within gene bodies. Conversely, inhibition of transcription elongation allows cohesin to accumulate at previously transcribed intragenic CTCF sites and to mediate chromatin looping and compaction. Our data indicate that transcription elongation by RNA polymerase II remodels genome 3D architecture.


Assuntos
Cromatina/metabolismo , Genoma Humano , Virus da Influenza A Subtipo H5N1/metabolismo , Sítios de Ligação , Fator de Ligação a CCCTC/química , Fator de Ligação a CCCTC/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Cromatina/química , Proteínas Cromossômicas não Histona/metabolismo , Flavonoides/farmacologia , Humanos , Interferon beta/farmacologia , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Piperidinas/farmacologia , Ligação Proteica , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , RNA Interferente Pequeno/metabolismo , Transcrição Gênica/efeitos dos fármacos , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Coesinas
2.
PLoS Genet ; 20(6): e1011308, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38829886

RESUMO

Acute myeloid leukemia (AML) accounts for greater than twenty thousand new cases of leukemia annually in the United States. The average five-year survival rate is approximately 30%, pointing to the need for developing novel model systems for drug discovery. In particular, patients with chromosomal rearrangements in the mixed lineage leukemia (MLL) gene have higher relapse rates with poor outcomes. In this study we investigated the expression of human MLL-ENL and MLL-AF9 in the myeloid lineage of zebrafish embryos. We observed an expansion of MLL positive cells and determined these cells colocalized with the myeloid markers spi1b, mpx, and mpeg. In addition, expression of MLL-ENL and MLL-AF9 induced the expression of endogenous bcl2 and cdk9, genes that are often dysregulated in MLL-r-AML. Co-treatment of lyz: MLL-ENL or lyz:MLL-AF9 expressing embryos with the BCL2 inhibitor, Venetoclax, and the CDK9 inhibitor, Flavopiridol, significantly reduced the number of MLL positive cells compared to embryos treated with vehicle or either drug alone. In addition, cotreatment with Venetoclax and Flavopiridol significantly reduced the expression of endogenous mcl1a compared to vehicle, consistent with AML. This new model of MLL-r-AML provides a novel tool to understand the molecular mechanisms underlying disease progression and a platform for drug discovery.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Quinase 9 Dependente de Ciclina , Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas c-bcl-2 , Peixe-Zebra , Peixe-Zebra/genética , Peixe-Zebra/embriologia , Animais , Quinase 9 Dependente de Ciclina/genética , Quinase 9 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Humanos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sulfonamidas/farmacologia , Piperidinas/farmacologia , Embrião não Mamífero , Flavonoides/farmacologia , Células Mieloides/metabolismo , Células Mieloides/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
3.
Proc Natl Acad Sci U S A ; 120(23): e2305007120, 2023 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-37256931

RESUMO

Plants produce chemical defenses that poison insect herbivores or deter their feeding, but herbivores are also accompanied by microbial endosymbionts crucial for their nutrition, reproduction, and fitness. Hence, plant defenses could target a herbivore's beneficial endosymbionts, but this has not yet been demonstrated. Here, we studied flavonoids that are induced when rice is attacked by a phloem-feeding pest, the brown planthopper (BPH), which harbors beneficial yeast-like symbionts (YLS) essential for insect nutrition, such as by remedying deficiencies in sterols. BPH attack dramatically increased sakuranetin accumulations in leaf sheaths and phloem exudates. Sakuranetin is an antifungal phytoalexin derived from the antibacterial precursor, naringenin, via catalysis of naringenin-O-methyltransferase (NOMT). When added to artificial diets, sakuranetin decreased BPH survivorship, suggesting that it functions as an induced defense. Mutation of NOMT abolished sakuranetin accumulation and increased BPH oviposition and hatching rates. High-throughput amplicon sequencing revealed that BPH fed on sakuranetin-deficient nomt lines were enriched in YLS with only minor changes in the bacterial endosymbionts, compared to those feeding on sakuranetin-rich wild-type (WT) plants. In-vitro feeding of sakuranetin suggested that this flavonoid directly inhibited the growth of YLS. BPH feeding on nomt lines accumulated higher cholesterol levels, which might be attributed to increases in the supply of sterol precursors from the YLS, while nomt lines suffered more damage than WT plants did from BPH herbivory. BPH-elicited accumulation of sakuranetin requires intact jasmonate (JA) signaling. This study reveals that rice uses a JA-induced antifungal flavonoid phytoalexin in defense against BPH by inhibiting its beneficial endosymbionts.


Assuntos
Hemípteros , Oryza , Animais , Feminino , Antifúngicos , Flavonoides/farmacologia , Regulação da Expressão Gênica de Plantas , Oryza/genética
4.
Cancer Metastasis Rev ; 43(1): 87-113, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37789138

RESUMO

Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer.


Assuntos
Neoplasias da Mama , NF-kappa B , Humanos , Feminino , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Plasticidade Celular , Transdução de Sinais , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Microambiente Tumoral
5.
Development ; 149(8)2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523672

RESUMO

Sustained neutrophilic inflammation is detrimental for cardiac repair and associated with adverse outcomes following myocardial infarction (MI). An attractive therapeutic strategy to treat MI is to reduce or remove infiltrating neutrophils to promote downstream reparative mechanisms. CDK9 inhibitor compounds enhance the resolution of neutrophilic inflammation; however, their effects on cardiac repair/regeneration are unknown. We have devised a cardiac injury model to investigate inflammatory and regenerative responses in larval zebrafish using heartbeat-synchronised light-sheet fluorescence microscopy. We used this model to test two clinically approved CDK9 inhibitors, AT7519 and flavopiridol, examining their effects on neutrophils, macrophages and cardiomyocyte regeneration. We found that AT7519 and flavopiridol resolve neutrophil infiltration by inducing reverse migration from the cardiac lesion. Although continuous exposure to AT7519 or flavopiridol caused adverse phenotypes, transient treatment accelerated neutrophil resolution while avoiding these effects. Transient treatment with AT7519, but not flavopiridol, augmented wound-associated macrophage polarisation, which enhanced macrophage-dependent cardiomyocyte number expansion and the rate of myocardial wound closure. Using cdk9-/- knockout mutants, we showed that AT7519 is a selective CDK9 inhibitor, revealing the potential of such treatments to promote cardiac repair/regeneration.


Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Flavonoides/farmacologia , Miocárdio/enzimologia , Neutrófilos/enzimologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Regeneração/efeitos dos fármacos , Proteínas de Peixe-Zebra/antagonistas & inibidores , Animais , Quinase 9 Dependente de Ciclina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
6.
Mol Psychiatry ; 29(8): 2487-2495, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38503930

RESUMO

Baicalin is a flavone glycoside derived from flowering plants belonging to the Scutellaria genus. Previous studies have reported baicalin's anti-inflammatory and neuroprotective properties in rodent models, indicating the potential of baicalin in neuropsychiatric disorders where alterations in numerous processes are observed. However, the extent of baicalin's therapeutic effects remains undetermined in a human cell model, more specifically, neuronal cells to mimic the brain environment in vitro. As a proof of concept, we treated C8-B4 cells (murine cell model) with three different doses of baicalin (0.1, 1 and 5 µM) and vehicle control (DMSO) for 24 h after liposaccharide-induced inflammation and measured the levels of TNF-α in the medium by ELISA. NT2-N cells (human neuronal-like cell model) underwent identical baicalin treatment, followed by RNA extraction, genome-wide mRNA expression profiles and gene set enrichment analysis (GSEA). We also performed neurite outgrowth assays and mitochondrial flux bioanalysis (Seahorse) in NT2-N cells. We found that in C8-B4 cells, baicalin at ≥ 1 µM exhibited anti-inflammatory effects, lowering TNF-α levels in the cell culture media. In NT2-N cells, baicalin positively affected neurite outgrowth and transcriptionally up-regulated genes in the tricarboxylic acid cycle and the glycolysis pathway. Similarly, Seahorse analysis showed increased oxygen consumption rate in baicalin-treated NT2-N cells, an indicator of enhanced mitochondrial function. Together, our findings have confirmed the neuroprotective and mitochondria enhancing effects of baicalin in human-neuronal like cells. Given the increased prominence of mitochondrial mechanisms in diverse neuropsychiatric disorders and the paucity of mitochondrial therapeutics, this suggests the potential therapeutic application of baicalin in human neuropsychiatric disorders where these processes are altered.


Assuntos
Flavonoides , Mitocôndrias , Neurônios , Fármacos Neuroprotetores , Fator de Necrose Tumoral alfa , Flavonoides/farmacologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Fator de Necrose Tumoral alfa/metabolismo , Neuroproteção/efeitos dos fármacos , Camundongos , Linhagem Celular , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Crescimento Neuronal/efeitos dos fármacos
7.
Exp Cell Res ; 440(2): 114138, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38906316

RESUMO

Prolyl 4-hydroxylase beta subunit (P4HB) plays a vital role in bone formation. This study intends to clarify the role of P4HB in the therapeutic effect of Icariin (ICA) on osteoporosis. Herein, in vivo and in vitro models were constructed by performing ovariectomy (OVX) in rats and inducing osteogenic differentiation in bone marrow stem cells (BMSCs), respectively. Hematoxylin and eosin staining and micro-computed tomography analysis were performed to evaluate osteoporosis in OVX rats. Alizarin Red staining, alkaline phosphatase staining, and the ALP activity test were employed to assess osteogenesis. m6A dot blotting and methylated RNA immunoprecipitation were used to determine m6A modification. We found that P4HB was downregulated in bone tissues of patients with osteoporosis and OVX rats. P4HB facilitated osteogenic differentiation of BMSCs. What's more, ICA upregulated P4HB expression, promoted osteogenic differentiation of BMSCs, and alleviated osteoporosis in OVX rats, which were reversed by knocking down P4HB. ICA enhanced the stability and m6A modification of P4HB. METTL14 mediated m6A modification of P4HB mRNA. In addition, METTL14 knockdown overturned the promotive effects of ICA on P4HB m6A level and BMSC osteogenic differentiation. To sum up, ICA elevated the METTL14-mediated m6A modification of P4HB to facilitate BMSC osteogenic differentiation.


Assuntos
Diferenciação Celular , Flavonoides , Metiltransferases , Osteogênese , Ratos Sprague-Dawley , Animais , Osteogênese/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ratos , Feminino , Flavonoides/farmacologia , Metiltransferases/metabolismo , Metiltransferases/genética , Humanos , Osteoporose/patologia , Osteoporose/metabolismo , Osteoporose/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Ovariectomia , Regulação para Cima/efeitos dos fármacos , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Pró-Colágeno-Prolina Dioxigenase/genética , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Adenosina/análogos & derivados , Adenosina/metabolismo
8.
Proc Natl Acad Sci U S A ; 119(48): e2202934119, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36417437

RESUMO

The molecular mechanisms by which dietary fruits and vegetables confer cardiometabolic benefits remain poorly understood. Historically, these beneficial properties have been attributed to the antioxidant activity of flavonoids. Here, we reveal that the host metabolic benefits associated with flavonoid consumption hinge, in part, on gut microbial metabolism. Specifically, we show that a single gut microbial flavonoid catabolite, 4-hydroxyphenylacetic acid (4-HPAA), is sufficient to reduce diet-induced cardiometabolic disease (CMD) burden in mice. The addition of flavonoids to a high fat diet heightened the levels of 4-HPAA within the portal plasma and attenuated obesity, and continuous delivery of 4-HPAA was sufficient to reverse hepatic steatosis. The antisteatotic effect was shown to be associated with the activation of AMP-activated protein kinase α (AMPKα). In a large survey of healthy human gut metagenomes, just over one percent contained homologs of all four characterized bacterial genes required to catabolize flavonols into 4-HPAA. Our results demonstrate the gut microbial contribution to the metabolic benefits associated with flavonoid consumption and underscore the rarity of this process in human gut microbial communities.


Assuntos
Fígado Gorduroso , Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Polifenóis/farmacologia , Microbioma Gastrointestinal/fisiologia , Fígado Gorduroso/prevenção & controle , Obesidade/metabolismo , Dieta Hiperlipídica/efeitos adversos , Flavonoides/farmacologia
9.
Med Res Rev ; 44(2): 497-538, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37602483

RESUMO

Rheumatoid arthritis (RA) is a progressive, chronic, autoimmune, inflammatory, and systemic condition that primarily affects the synovial joints and adjacent tissues, including bone, muscle, and tendons. The World Health Organization recognizes RA as one of the most prevalent chronic inflammatory diseases. In the last decade, there was an expansion on the available RA therapeutic options which aimed to improve patient's quality of life. Despite the extensive research and the emergence of new therapeutic approaches and drugs, there are still significant unwanted side effects associated to these drugs and still a vast number of patients that do not respond positively to the existing therapeutic strategies. Over the years, several references to the use of flavonoids in the quest for new treatments for RA have emerged. This review aimed to summarize the existing literature about the flavonoids' effects on the major pathogenic/molecular targets of RA and their potential use as lead compounds for the development of new effective molecules for RA treatment. It is demonstrated that flavonoids can modulate various players in synovial inflammation, regulate immune cell function, decrease synoviocytes proliferation and balance the apoptotic process, decrease angiogenesis, and stop/prevent bone and cartilage degradation, which are all dominant features of RA. Although further investigation is necessary to determine the effectiveness of flavonoids in humans, the available data from in vitro and in vivo models suggest their potential as new disease-modifying anti-rheumatic drugs. This review highlights the use of flavonoids as a promising avenue for future research in the treatment of RA.


Assuntos
Artrite Reumatoide , Flavonoides , Humanos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Qualidade de Vida , Artrite Reumatoide/tratamento farmacológico , Inflamação
10.
J Lipid Res ; 65(5): 100539, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38556050

RESUMO

Flavonoids, polyphenolic compounds found in plant-based diets, are associated with reduced risk of cardiovascular disease and longevity. These components are reported to reduce plasma levels of low-density lipoprotein (LDL) through an upregulation of the LDL receptor (LDLR), but the mechanism is still largely unknown. In this study, we have systematically screened the effect of 12 flavonoids from six different flavonoid subclasses on the effect on LDLR. This paper provides an in-depth analysis on how these flavonoids affect LDLR regulation and functionality. We found that most but not all of the tested flavonoids increased LDLR mRNA levels. Surprisingly, this increase was attributed to different regulatory mechanisms, such as enhanced LDLR promoter activity, LDLR mRNA stabilization, or LDLR protein stabilization, of which specific effectual parts of the flavonoid molecular structure could be assigned. These types of comparative analysis of various flavonoids enhance clarity and deepen the understanding of how the different structures of flavonoids affect LDLR regulation. Our data offer useful insights that may guide future research in developing therapeutic approaches for cardiovascular health.


Assuntos
Flavonoides , Receptores de LDL , Flavonoides/farmacologia , Flavonoides/química , Receptores de LDL/metabolismo , Receptores de LDL/genética , Humanos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Regiões Promotoras Genéticas
11.
J Cell Mol Med ; 28(8): e18196, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38534093

RESUMO

Liver cirrhosis is a silent disease in humans and is experimentally induced by many drugs and toxins as thioacetamide (TAA) in particular, which is the typical model for experimental induction of hepatic fibrosis. Thus, the objective of the present study was to elucidate the possible protective effects of lactéol® forte (LF) and quercetin dihydrate (QD) against TAA-induced hepatic damage in male albino rats. Induction of hepatotoxicity was performed by TAA injection (200 mg/kg I/P, twice/ week) in rats. LF (1 × 109 CFU/rat 5 times/week) and QD (50 mg/kg 5 times/week) treated groups were administered concurrently with TAA injection (200 mg/kg I/P, twice/ week). The experimental treatments were conducted for 12 weeks. Hepatotoxicity was evaluated biochemically by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) in the serum and histopathologically with the scoring of histopathological changes besides histochemical assessment of collagen by Masson's trichrome and immunohistochemical analysis for α-smooth muscle actin (α-SMA), Ki67 and caspase-3 expression in liver sections. Our results indicated that LF and QD attenuated some biochemical changes and histochemical markers in TAA-mediated hepatotoxicity in rats by amelioration of biochemical markers and collagen, α-SMA, Ki67 and caspase3 Immunoexpression. Additionally, LF and QD supplementation downregulated the proliferative, necrotic, fibroblastic changes, eosinophilic intranuclear inclusions, hyaline globules and Mallory-like bodies that were detected histopathologically in the TAA group. In conclusion, LF showed better hepatic protection than QD against TAA-induced hepatotoxicity in rats by inhibiting inflammatory reactions with the improvement of some serum hepatic transaminases, histopathological picture and immunohistochemical markers.


Assuntos
Carbonato de Cálcio , Doença Hepática Induzida por Substâncias e Drogas , Lactose , Quercetina , Humanos , Ratos , Masculino , Animais , Quercetina/farmacologia , Tioacetamida/toxicidade , Antígeno Ki-67/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Flavonoides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colágeno/metabolismo , Estresse Oxidativo , Combinação de Medicamentos
12.
J Cell Mol Med ; 28(9): e18321, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38712979

RESUMO

As a main extraction compound from Scutellaria baicalensis Georgi, Baicalin exhibits various biological activities. However, the underlying mechanism of Baicalin on hypertension-induced heart injury remains unclear. In vivo, mice were infused with angiotensin II (Ang II; 500 ng/kg/min) or saline using osmotic pumps, followed by intragastrically administrated with Baicalin (5 mg/kg/day) for 4 weeks. In vitro, H9C2 cells were stimulated with Ang II (1 µM) and treated with Baicalin (12.5, 25 and 50 µM). Baicalin treatment significantly attenuated the decrease in left ventricular ejection fraction and left ventricular fractional shortening, increase in left ventricular mass, left ventricular systolic volume and left ventricular diastolic volume of Ang II infused mice. Moreover, Baicalin treatment reversed 314 differentially expressed transcripts in the cardiac tissues of Ang II infused mice, and enriched multiple enriched signalling pathways (including apoptosis, autophagy, AMPK/mTOR signalling pathway). Consistently, Baicalin treatment significantly alleviated Ang II-induced cell apoptosis in vivo and in vitro. Baicalin treatment reversed the up-regulation of Bax, cleaved-caspase 3, cleaved-caspase 9, and the down-regulation of Bcl-2. Meanwhile, Baicalin treatment alleviated Ang II-induced increase of autophagosomes, restored autophagic flux, and down-regulated LC3II, Beclin 1, as well as up-regulated SQSTM1/p62 expression. Furthermore, autophagy inhibitor 3-methyladenine treatment alleviated the increase of autophagosomes and the up-regulation of Beclin 1, LC3II, Bax, cleaved-caspase 3, cleaved-caspase 9, down-regulation of SQSTM1/p62 and Bcl-2 expression after Ang II treated, which similar to co-treatment with Baicalin. Baicalin treatment reduced the ratio of p-AMPK/AMPK, while increased the ratio of p-mTOR/mTOR. Baicalin alleviated Ang II-induced cardiomyocyte apoptosis and autophagy, which might be related to the inhibition of the AMPK/mTOR pathway.


Assuntos
Angiotensina II , Apoptose , Autofagia , Flavonoides , Miócitos Cardíacos , Transdução de Sinais , Animais , Masculino , Camundongos , Ratos , Proteínas Quinases Ativadas por AMP/metabolismo , Angiotensina II/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Flavonoides/farmacologia , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
13.
J Cell Mol Med ; 28(14): e18569, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39072972

RESUMO

Epimedium is thought to enhance the integrity of tendons and bones, ease joint discomfort and rigidity and enhance kidney function. Although glucocorticoids are commonly used in clinical practice, the mechanism by which the active compound Epimedin C (EC) alleviates glucocorticoid-induced osteoporosis (GIOP) is not well understood. The therapeutic potential of EC in treating GIOP was evaluated using alizarin red S staining, calcein immersion and fluorescence imaging, and bone mineralization, bone mass accumulation and bone density in zebrafish larvae were determined. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the key signalling pathways related to bone development were identified. A protein-protein interaction network (PPIN) was constructed to identify osteoclast characteristic genes and the findings were verified using real-time quantitative PCR (RT-qPCR). The bone tissue damage caused by prednisolone was reduced by EC. It also altered physiological processes, improved bone density, boosted mineralization and increased bone mass and activity. Subsequent empirical investigations showed that EC impacted the major signalling pathways involved in bone development, such as osteoclast differentiation, oestrogen, MAPK, insulin resistance, PPAR and AMPK signalling pathways. It also decreased the expression of genes typical of osteoclasts. The results of our study uncover a previously unknown function of EC in controlling bone formation and emphasize the potential of EC as a therapeutic target. The osteoprotective effect of EC indicates its potential as a cost-effective strategy for treating GIOP.


Assuntos
Modelos Animais de Doenças , Flavonoides , Glucocorticoides , Osteoclastos , Osteoporose , Transdução de Sinais , Peixe-Zebra , Animais , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/genética , Osteoporose/patologia , Osteoporose/tratamento farmacológico , Flavonoides/farmacologia , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Osteoclastos/metabolismo , Osteoclastos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Mapas de Interação de Proteínas , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Calcificação Fisiológica/efeitos dos fármacos
14.
Immunology ; 172(2): 295-312, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38453210

RESUMO

Hyperactivation of the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS-STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti-inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow-derived macrophages (BMDMs), THP-1 (Tohoku Hospital Pediatrics-1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS-STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN-ß, CXCL10 and ISG15) and pro-inflammatory cytokines (IL-6 and TNF-α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK-binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS-STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non-alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS-STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS-STING signalling pathway.


Assuntos
Epimedium , Flavonoides , Proteínas de Membrana , Nucleotidiltransferases , Transdução de Sinais , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Animais , Transdução de Sinais/efeitos dos fármacos , Humanos , Camundongos , Flavonoides/farmacologia , Epimedium/química , Fator Regulador 3 de Interferon/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Células THP-1 , Proteínas Serina-Treonina Quinases/metabolismo , Anti-Inflamatórios/farmacologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/efeitos dos fármacos
15.
Immunology ; 173(1): 141-151, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38804253

RESUMO

Retinopathy of prematurity (ROP) is a retinal disease-causing retinal neovascularization that can lead to blindness. Oxygen-induced retinopathy (OIR) is a widely used ROP animal model. Icariin (ICA) has anti-oxidative and anti-inflammation properties; however, whether ICA has a regulatory effect on OIR remains unclear. In this study, ICA alleviated pathological neovascularization, microglial activation and blood-retina barrier (BRB) damage in vivo. Further results indicated that endothelial cell tube formation, migration and proliferation were restored by ICA treatment in vitro. Proteomic microarrays and molecular mimicry revealed that ICA can directly bind to hexokinase 2 (HK2) and decrease HK2 protein expression in vivo and in vitro. In addition, ICA inhibited the AKT/mTOR/HIF1α pathway activation. The effects of ICA on pathological neovascularization, microglial activation and BRB damage disappeared after HK2 overexpression in vivo. Similarly, the endothelial cell function was revised after HK2 overexpression. HK2 overexpression reversed ICA-induced AKT/mTOR/HIF1α pathway inhibition in vivo and in vitro. Therefore, ICA prevented pathological angiogenesis in OIR in an HK2-dependent manner, implicating ICA as a potential therapeutic agent for ROP.


Assuntos
Flavonoides , Hexoquinase , Microglia , Oxigênio , Neovascularização Retiniana , Retinopatia da Prematuridade , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Humanos , Camundongos , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Hexoquinase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Oxigênio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neovascularização Retiniana/tratamento farmacológico , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Retinopatia da Prematuridade/tratamento farmacológico , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
16.
J Cell Biochem ; 125(10): e30564, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38747366

RESUMO

Plants are rich sources of therapeutic compounds that often lack the side effects commonly found in synthetic chemicals. Researchers have effectively synthesized pharmaceuticals from natural sources, taking inspiration from traditional medicine, in their pursuit of modern drugs. This study aims to evaluate the phenolic and flavonoid content of Solanum virginianum seeds using different solvent extracts, enzymatic assays including 2,2-diphenyl-1-picrylhydrazyl activity, reducing power, and superoxide activity. Our phytochemical screening identified active compounds, such as phenols, flavonoids, tannins, and alkaloids. The methanol extract notably possesses higher levels of total phenolic and flavonoid content in comparison to the other extracts. The results highlight the superior antioxidant activity of methanol-extracted leaves, demonstrated by their exceptional IC50 values, which surpass the established standard. In this study, molecular docking techniques were used to assess the binding affinity and to predict the binding conformation of the compounds. Quercetin 3-O beta-d-galactopyranoside displayed a binding energy of -8.35 kcal/mol with several important amino acid residues, PHE222, TRP440, ILE184, LEU192, VAL221, LEU218, SER185, and ALA188. Kaempferol 3-O-beta-l-glucopyranoside exhibited a binding energy of -8.33 kcal/mol, interacting with specific amino acid residues including ALA 441, VAL318, VAL322, MET307, ILI409, GLY442, and PHE439. The results indicate that the methanol extract has a distinct composition of biologically active constituents compared to the other extracts. Overall, seeds exhibit promise as natural antioxidants and potential agents for combating cancer. This study highlights the significance of utilizing the therapeutic capabilities of natural compounds and enhancing our comprehension of their pharmacological characteristics.


Assuntos
Antioxidantes , Simulação de Acoplamento Molecular , Extratos Vegetais , Antioxidantes/química , Antioxidantes/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Humanos , Solanum/química , Simulação de Dinâmica Molecular , Fenóis/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sementes/química
17.
J Neurochem ; 168(7): 1179-1192, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38383146

RESUMO

Arising out of a PhD project more than 50 years ago to synthesise analogues of the neurotransmitter GABA, a series of new chemical entities were found to have selective actions on ionotropic GABA receptors. Several of these neurochemicals are now commercially available. A new subtype of these receptors was discovered that could be a target for the treatment of myopia, the facilitation of learning and memory, and the improvement of post-stroke motor recovery. The development of these new chemical entities over many years demonstrates the importance of neurochemicals with which to investigate selective aspects of GABA receptors and illustrates the significance of collaboration between chemists and biologists in neurochemistry. Vital were the improvements in synthetic organic chemistry and the use of functional human receptors expressed in oocytes. Current interest in ionotropic GABA receptors includes the clinical development of subtype-specific agents and the role of gain-of-function receptor variants in epilepsy. Dietary flavonoids were found to cross the blood-brain barrier to influence brain function. Natural and synthetic flavonoids had a range of effects on GABA receptors, ranging from positive, silent, and negative allosteric modulators, to even second-order modulation of first-order modulators. Flavonoids have been called "a new family of benzodiazepines." Like benzodiazepines, flavonoids reduce stress. Stress produces changes in GABA receptors in the brain that may be because of changes in endogenous modulators, such as neurosteroids and corticosteroids. GABA also occurs naturally in the diet leading to studies of the effects of oral GABA on brain function. This finding has resulted in studies of GABA and related neurochemicals as neuro-nutraceuticals. GABA systems in the gut microbiome are essential to such studies. The actions of oral GABA and of GABA-enriched beverages and foodstuffs are now an area of considerable scientific and commercial interest. GABA is a deceptively simple chemical that can take up many shapes, which may underlie its complex functions. The need for new chemical entities with selective actions for further studies highlights the need for continuing collaboration between chemists and biologists.


Assuntos
Epilepsia , Flavonoides , Receptores de GABA , Ácido gama-Aminobutírico , Humanos , Animais , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Ácido gama-Aminobutírico/metabolismo , Receptores de GABA/metabolismo , Receptores de GABA/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/química , Flavonoides/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Moduladores GABAérgicos/farmacologia
18.
Nat Prod Rep ; 41(9): 1346-1367, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-38717742

RESUMO

Covering 2016 up to the end of 2023Alpinia is the largest genus of flowering plants in the ginger family, Zingiberaceae, and comprises about 500 species. Many Alpinia are commonly cultivated ornamental plants, and some are used as spices or traditional medicine to treat inflammation, hyperlipidemia, and cancers. However, only a few comprehensive reviews have been published on the phytochemistry and pharmacology of this genus, and the latest review was published in 2017. In this review, we provide an extensive coverage of the studies on Alpinia species reported from 2016 through 2023, including newly isolated compounds and potential biological effects. The present review article shows that Alpinia species have a wide spectrum of pharmacological activities, most due to the activities of diarylheptanoids, terpenoids, flavonoids, and phenolics.


Assuntos
Alpinia , Flavonoides , Compostos Fitoquímicos , Alpinia/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Estrutura Molecular , Flavonoides/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Terpenos/farmacologia , Terpenos/química , Terpenos/isolamento & purificação , Humanos , Diarileptanoides/farmacologia , Diarileptanoides/química , Diarileptanoides/isolamento & purificação , Fenóis/farmacologia , Fenóis/química
19.
Mol Med ; 30(1): 77, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840035

RESUMO

BACKGROUND: Ischemic stroke presents a significant threat to human health due to its high disability rate and mortality. Currently, the clinical treatment drug, rt-PA, has a narrow therapeutic window and carries a high risk of bleeding. There is an urgent need to find new effective therapeutic drugs for ischemic stroke. Icariin (ICA), a key ingredient in the traditional Chinese medicine Epimedium, undergoes metabolism in vivo to produce Icaritin (ICT). While ICA has been reported to inhibit neuronal apoptosis after cerebral ischemia-reperfusion (I/R), yet its underlying mechanism remains unclear. METHODS: PC-12 cells were treated with 200 µM H2O2 for 8 h to establish a vitro model of oxidative damage. After administration of ICT, cell viability was detected by Thiazolyl blue tetrazolium Bromide (MTT) assay, reactive oxygen species (ROS) and apoptosis level, mPTP status and mitochondrial membrane potential (MMP) were detected by flow cytometry and immunofluorescence. Apoptosis and mitochondrial permeability transition pore (mPTP) related proteins were assessed by Western blotting. Middle cerebral artery occlusion (MCAO) model was used to establish I/R injury in vivo. After the treatment of ICA, the neurological function was scored by ZeaLonga socres; the infarct volume was observed by 2,3,5-Triphenyltetrazolium chloride (TTC) staining; HE and Nissl staining were used to detect the pathological state of the ischemic cortex; the expression changes of mPTP and apoptosis related proteins were detected by Western blotting. RESULTS: In vitro: ICT effectively improved H2O2-induced oxidative injury through decreasing the ROS level, inhibiting mPTP opening and apoptosis. In addition, the protective effects of ICT were not enhanced when it was co-treated with mPTP inhibitor Cyclosporin A (CsA), but reversed when combined with mPTP activator Lonidamine (LND). In vivo: Rats after MCAO shown cortical infarct volume of 32-40%, severe neurological impairment, while mPTP opening and apoptosis were obviously increased. Those damage caused was improved by the administration of ICA and CsA. CONCLUSIONS: ICA improves cerebral ischemia-reperfusion injury by inhibiting mPTP opening, making it a potential candidate drug for the treatment of ischemic stroke.


Assuntos
Apoptose , Flavonoides , AVC Isquêmico , Potencial da Membrana Mitocondrial , Poro de Transição de Permeabilidade Mitocondrial , Estresse Oxidativo , Espécies Reativas de Oxigênio , Animais , Estresse Oxidativo/efeitos dos fármacos , Ratos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Apoptose/efeitos dos fármacos , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , AVC Isquêmico/etiologia , Células PC12 , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Modelos Animais de Doenças , Peróxido de Hidrogênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Sprague-Dawley
20.
Mol Med ; 30(1): 125, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39152382

RESUMO

BACKGROUND: Epimedin A (EA) has been shown to suppress extensive osteoclastogenesis and bone resorption, but the effects of EA remain incompletely understood. The aim of our study was to investigate the effects of EA on osteoclastogenesis and bone resorption to explore the corresponding signalling pathways. METHODS: Rats were randomly assigned to the sham operation or ovariectomy group, and alendronate was used for the positive control group. The therapeutic effect of EA on osteoporosis was systematically analysed by measuring bone mineral density and bone biomechanical properties. In vitro, RAW264.7 cells were treated with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) to induce osteoclast differentiation. Cell viability assays, tartrate-resistant acid phosphatase (TRAP) staining, and immunofluorescence were used to elucidate the effects of EA on osteoclastogenesis. In addition, the expression of bone differentiation-related proteins or genes was evaluated using Western blot analysis or quantitative polymerase chain reaction (PCR), respectively. RESULTS: After 3 months of oral EA intervention, ovariectomized rats exhibited increased bone density, relative bone volume, trabecular thickness, and trabecular number, as well as reduced trabecular separation. EA dose-dependently normalized bone density and trabecular microarchitecture in the ovariectomized rats. Additionally, EA inhibited the expression of TRAP and NFATc1 in the ovariectomized rats. Moreover, the in vitro results indicated that EA inhibits osteoclast differentiation by suppressing the TRAF6/PI3K/AKT/NF-κB pathway. Further studies revealed that the effect on osteoclast differentiation, which was originally inhibited by EA, was reversed when the TRAF6 gene was overexpressed. CONCLUSIONS: The findings indicated that EA can negatively regulate osteoclastogenesis by inhibiting the TRAF6/PI3K/AKT/NF-κB axis and that ameliorating ovariectomy-induced osteoporosis in rats with EA may be a promising potential therapeutic strategy for the treatment of osteoporosis.


Assuntos
Diferenciação Celular , NF-kappa B , Osteoclastos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Fator 6 Associado a Receptor de TNF , Animais , Fator 6 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Osteoclastos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Feminino , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Camundongos , Células RAW 264.7 , Flavonoides/farmacologia , Osteogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Osteoporose/metabolismo , Osteoporose/etiologia , Ovariectomia/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos
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