RESUMO
PURPOSE: Therapeutic management of colorectal cancer (CRC) does not yet yield promising long-term results. Therefore, there is a need for further investigation of possible therapeutic options. Various experiments have studied the effects of apigenin on CRC and have shown conflicting results. This systematic review and meta-analysis investigates the currently existing evidence on the effect of apigenin on CRC. METHODS: Medline, Embase, Scopus, and Web of Science databases were searched for articles related to apigenin and its effect on CRC in the preclinical setting. Cell viability, growth inhibition, apoptosis, and cell cycle arrest for in-vitro, and body weight, tumor size, and mortality in in-vivo studies were extracted as outcomes. RESULTS: Thirty-nine articles investigating colorectal adenocarcinoma were included in this meta-analysis. Thirty-seven of these studies had data for in vitro experiments, with eight studies having data for in vivo experiments. Six articles had both in vitro and in vivo assessments. Our analysis showed apigenin reduces cell viability and induces growth inhibition, apoptosis, and cell cycle arrest in in vitro studies. The few in vivo studies indicate that apigenin decreases tumor size while showing no effects on the body weight of animal colorectal adenocarcinoma models. CONCLUSION: Our results demonstrated that apigenin, through reducing cell viability, inducing growth inhibition, apoptosis, and cell cycle arrest, and also by decreasing the tumor size, can be considered as a possible adjuvant agent in the management of colorectal adenocarcinoma. However, further in vivo studies are needed before any efforts to translate the current evidence into clinical studies.
Assuntos
Adenocarcinoma , Apigenina , Neoplasias Colorretais , Animais , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Apigenina/farmacologia , Apigenina/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologiaRESUMO
OBJECTIVES: Neurological disorders represent a significant global health challenge, necessitating the exploration of novel therapeutic agents. Apigenin, a natural flavonoid abundantly found in various plants, has garnered attention for its potential neuroprotective properties. In this study, we employed molecular docking simulations to investigate the interaction between apigenin and key molecular targets associated with neurological disorders. METHODS: The molecular docking analysis focused on receptors implicated in neuroinflammation, oxidative stress, and neurotransmission regulation. RESULTS: Our results reveal a high binding affinity of apigenin towards critical targets, including GABA, mACh, nACh, NMDA, 5HTA, AMPA, insulin, and dopamine receptors. The findings suggest that apigenin may exert its neuroprotective effects through multifaceted mechanisms, including anti-inflammatory, antioxidant, and neurotransmission regulatory pathways. Additionally, the absence of adverse binding poses emphasizes the safety profile of apigenin. CONCLUSIONS: This molecular docking study provides valuable insights into the potential therapeutic role of apigenin in mitigating molecular pathways implicated in neurological disorders. Further in vitro and in vivo investigations are warranted to validate and elucidate the neuroprotective mechanisms of apigenin, paving the way for its development as a promising treatment option for various neurological conditions.
Assuntos
Apigenina , Simulação de Acoplamento Molecular , Doenças do Sistema Nervoso , Fármacos Neuroprotetores , Apigenina/farmacologia , Apigenina/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Humanos , AnimaisRESUMO
Neuropathic pain (NP) is associated with astrocytes activation induced by nerve injury. Reactive astrocytes, strongly induced by central nervous system damage, can be classified into A1 and A2 types. Vitexin, a renowned flavonoid compound, is known for its anti-inflammatory and analgesic properties. However, its role in NP remains unexplored. This study aims to investigate the effects of vitexin on astrocyte polarization and its underlying mechanisms. A mouse model of NP was established, and primary astrocytes were stimulated with sphingosine-1-phosphate (S1P) to construct a cellular model. The results demonstrated significant activation of spinal astrocytes on days 14 and 21. Concurrently, reactive astrocytes predominantly differentiated into the A1 type. Western blot analysis revealed an increase in A1 astrocyte-associated protein (C3) and a decrease in A2 astrocyte-associated protein (S100A10). Serum S1P levels increased on days 14 and 21, alongside a significant upregulation of Sphingosine-1-phosphate receptor 1 (S1PR1) mRNA expression and elevated expression of chemokines. In vitro, stimulation with S1P inhibited the Phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) signaling pathway and autophagy flux, promoting polarization of astrocytes towards the A1 phenotype while suppressing the polarization of A2 astrocytes. Our findings suggest that vitexin, acting on astrocytes but not microglia, attenuates S1P-induced downregulation of PI3K/Akt signaling, restores autophagy flux in astrocytes, regulates A1/A2 astrocyte ratio, and reduces chemokine and S1P secretion, thereby alleviating neuropathic pain caused by nerve injury.
Assuntos
Apigenina , Astrócitos , Autofagia , Lisofosfolipídeos , Neuralgia , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato , Esfingosina , Animais , Apigenina/farmacologia , Apigenina/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Polaridade Celular/efeitos dos fármacosRESUMO
INTRODUCTION: Vitexin is a natural flavonoid compound extracted from Vitex leaves or seeds, exhibiting various pharmacological activities including anticancer, antihypertensive, anti-inflammatory, and spasmolytic effects. However, its protective effects on hypertensive nephropathy (HN) and the underlying mechanisms remain unclear. METHODS: Spontaneous hypertension rats were fed a high-sugar and high-fat diet for 8 weeks to induce the disease HN model. From the 5th week, the rats were administered vitexin via gavage. Blood pressure was measured biweekly using the tail-cuff method. Histopathological changes were assessed using HE staining, and biochemical analyses were performed to evaluate the effects of vitexin on HN rats. The underlying mechanisms of vitexin treatment were investigated through western blotting. RESULTS: The data demonstrated that vitexin significantly lowered systolic, diastolic, and mean arterial pressures and ameliorated histopathological changes in HN rats. Biochemical analyses revealed that vitexin reduced the levels of creatinine (Cr), blood urea nitrogen (BUN), total cholesterol (TC), triglycerides (TG), total protein (TP), low-density lipoprotein cholesterol (LDL-C), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), and advanced glycation end products (AGEs), while increasing the levels of albumin (ALB) and superoxide dismutase (SOD). Western blotting results indicated that vitexin treatment decreased the expression of TNF-α, IL-6, and nuclear factor kappa-B (NF-κB), while increasing the expression of SOD. CONCLUSION: The findings of this study suggest that vitexin exerts protective effects against HN, providing pharmacological evidence for its potential use in HN treatment.
Assuntos
Apigenina , Hipertensão Renal , Animais , Apigenina/farmacologia , Apigenina/uso terapêutico , Ratos , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/patologia , Masculino , Ratos Endogâmicos SHR , Nefrite/tratamento farmacológico , Nefrite/prevenção & controle , Nefrite/patologia , Pressão Sanguínea/efeitos dos fármacos , NF-kappa B/metabolismoRESUMO
PANoptosis is manifested with simultaneous activation of biomarkers for both pyroptotic, apoptotic and necroptotic signaling via the molecular platform PANoptosome and it is involved in pathologies of various inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). Scutellarin is a flavonoid isolated from herbal Erigeron breviscapus (Vant.) Hand.-Mazz. and has been shown to possess multiple pharmacological effects, but it is unknown whether scutellarin has any effects on PANoptosis and related inflammatory diseases. In this study, we found that scutellarin inhibited cell death in bone marrow-derived macrophages (BMDMs) and J774A.1 cells treated with TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (OXO) plus lipopolysaccharide (LPS), which has been commonly used to induce PANoptosis. Western blotting showed that scutellarin dose-dependently inhibited the activation biomarkers for pyroptotic (Caspase-1p10 and GSDMD-NT), apoptotic (cleaved Casp3/8/9 and GSDME-NT), and necroptotic (phosphorylated MLKL) signaling. The inhibitory effect of scutellarin was unaffected by NLRP3 or Caspase-1 deletion. Interestingly, scutellarin blocked the assembly of PANoptosome that encompasses ASC, RIPK3, Caspase-8 and ZBP1, suggesting its action on upstream signaling. Consistent with this, scutellarin inhibited mitochondrial damage and mitochondrial reactive oxygen species (mtROS) generation in cells treated with OXO+LPS. Further, mito-TEMPO that can scavenge mtROS significantly inhibited OXO+LPS-induced PANoptotic cell death. In line with the in vitro results, scutellarin markedly alleviated systemic inflammation, multiple organ injury, and activation of PANoptotic biomarkers in mice with HLH. Collectively, our data suggest that scutellarin can inhibit PANoptosis by suppressing mitochondrial damage and mtROS generation and thereby mitigating multiple organ injury in mice with inflammatory disorders.
Assuntos
Apigenina , Glucuronatos , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Mitocôndrias , Espécies Reativas de Oxigênio , Apigenina/farmacologia , Apigenina/uso terapêutico , Glucuronatos/farmacologia , Glucuronatos/uso terapêutico , Animais , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Linhagem Celular , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Necroptose/efeitos dos fármacos , Masculino , MAP Quinase Quinase Quinases/metabolismo , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Zearalenona/administração & dosagem , Lactonas , ResorcinóisRESUMO
Vitexin is a natural flavonoid glycoside compound extracted from the leaves and seeds of Vitex negundo. It is widely distributed in the leaves and stems of numerous plants and exhibites remarkable anti-tumor, anti-inflammatory, and anti-hypertensive properties. However, whether vitexin presents the anti-aging and senescence prevention effect has not been fully elucidated. The purpose of this study is to investigate the effect of vitexin on progeria mice and cellular senescence, as well as its underlying molecular mechanisms. To generate a premature aging/senescence model in vivo and in vitro, we used D-galactose (D-gal), hydrogen peroxide (H2O2), and adriamycin (ADR), respectively. Our findings demonstrated that vitexin potentially delays D-gal-induced progeria mice; similar effects were observed in stress-induced premature senescent fibroblasts in culture. Interestingly, this effect of vitexin is closely correlated with the reduction of the senescence-associated secretory phenotype (SASP) and the inhibition of the SASP-related JAK2/STAT3 pathway. Furthermore, we determined that vitexin meets the pharmacological parameters using the freely available ADMET web tool. Collectively, our findings demonstrate that vitexin possesses anti-senescence and anti-aging properties due to the inhibition of SASP and suppression of JAK2/STAT3 signaling pathway.
Assuntos
Apigenina , Senescência Celular , Galactose , Janus Quinase 2 , Progéria , Fator de Transcrição STAT3 , Animais , Apigenina/farmacologia , Apigenina/uso terapêutico , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Senescência Celular/efeitos dos fármacos , Camundongos , Progéria/tratamento farmacológico , Progéria/patologia , Progéria/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Senilidade Prematura/induzido quimicamente , Senilidade Prematura/tratamento farmacológico , Senilidade Prematura/metabolismo , Senilidade Prematura/patologia , Modelos Animais de Doenças , Fenótipo Secretor Associado à Senescência/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismoRESUMO
Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin receptors -1 and 2 (AdipoR1 and AdipoR2). Systemic depletion of adiponectin causes various metabolic disorders, including MASLD; however adiponectin supplementation is not yet achievable owing to its large size and oligomerization-associated complexities. Small-molecule AdipoR agonists, thus, may provide viable therapeutic options against metabolic disorders. Using a novel luciferase reporter-based assay here, we have identified Apigenin-6-C-glucoside (ACG), but not apigenin, as a specific agonist for the liver-rich AdipoR isoform, AdipoR2 (EC50: 384 pM) with >10000X preference over AdipoR1. Immunoblot analysis in HEK-293 overexpressing AdipoR2 or HepG2 and PLC/PRF/5 liver cell lines revealed rapid AMPK, p38 activation and induction of typical AdipoR targets PGC-1α and PPARα by ACG at a pharmacologically relevant concentration of 100 nM (reported cMax in mouse; 297 nM). ACG-mediated AdipoR2 activation culminated in a favorable modulation of key metabolic events, including decreased inflammation, oxidative stress, mitochondrial dysfunction, de novo lipogenesis, and increased fatty acid ß-oxidation as determined by immunoblotting, QRT-PCR and extracellular flux analysis. AdipoR2 depletion or AMPK/p38 inhibition dampened these effects. The in vitro results were recapitulated in two different murine models of MASLD, where ACG at 10 mg/kg body weight robustly reduced hepatic steatosis, fibrosis, proinflammatory macrophage numbers, and increased hepatic glycogen content. Together, using in vitro experiments and rodent models, we demonstrate a proof-of-concept for AdipoR2 as a therapeutic target for MASLD and provide novel chemicobiological insights for the generation of translation-worthy pharmacological agents.
Assuntos
Apigenina , Glucosídeos , Receptores de Adiponectina , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Animais , Humanos , Camundongos , Apigenina/farmacologia , Apigenina/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Masculino , Células Hep G2 , Células HEK293 , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Proteínas Quinases Ativadas por AMP/metabolismoRESUMO
BACKGROUND: Sepsis is a life-threatening organ dysfunction, which seriously threatens human health. The clinical and experimental results have confirmed that Traditional Chinese medicine (TCM), such as Scutellariae Radix, has anti-inflammatory effects. This provides a new idea for the treatment of sepsis. This study systematically analyzed the mechanism of Scutellariae Radix treatment in sepsis based on network pharmacology, RNA sequencing and molecular docking. METHODS: Gene expression analysis was performed using Bulk RNA sequencing on sepsis patients and healthy volunteers. After quality control of the results, the differentially expressed genes (DEGs) were analyzed. The active ingredients and targets of Scutellariae Radix were identified using The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Ontology (GO) and Protein-Protein Interaction (PPI) analysis were performed for disease-drug intersection targets. With the help of GEO database, Survival analysis and Meta-analysis was performed on the cross-targets to evaluate the prognostic value and screen the core targets. Subsequently, single-cell RNA sequencing was used to determine where the core targets are located within the cell. Finally, in this study, molecular docking experiments were performed to further clarify the interrelationship between the active components of Scutellariae Radix and the corresponding targets. RESULTS: There were 72 active ingredients of Scutellariae Radix, and 50 common targets of drug and disease. GO and PPI analysis showed that the intersection targets were mainly involved in response to chemical stress, response to oxygen levels, response to drug, regulation of immune system process. Survival analysis showed that PRKCD, EGLN1 and CFLAR were positively correlated with sepsis prognosis. Meta-analysis found that the three genes were highly expressed in sepsis survivor, while lowly in non-survivor. PRKCD was mostly found in Macrophages, while EGLN1 and CFLAR were widely expressed in immune cells. The active ingredient Apigenin regulates CFLAR expression, Baicalein regulates EGLN1 expression, and Wogonin regulates PRKCD expression. Molecular docking studies confrmed that the three active components of astragalus have good binding activities with their corresponding targets. CONCLUSIONS: Apigenin, Baicalein and Wogonin, important active components of Scutellaria Radix, produce anti-sepsis effects by regulating the expression of their targets CFLAR, EGLN1 and PRKCD.
Assuntos
Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Scutellaria baicalensis , Sepse , Análise de Sequência de RNA , Humanos , Sepse/tratamento farmacológico , Scutellaria baicalensis/química , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicina Tradicional Chinesa , Flavanonas/uso terapêutico , Flavanonas/farmacologia , Mapas de Interação de Proteínas , Apigenina/uso terapêutico , Apigenina/farmacologia , Perfilação da Expressão Gênica , Ontologia Genética , Farmacologia em RedeRESUMO
Due to its propensity to metastasize, cancer remains one of the leading causes of death worldwide. Thanks in part to their intrinsic low cytotoxicity, the effects of the flavonoid family in the prevention and treatment of various human cancers, both in vitro and in vivo, have received increasing attention in recent years. It is well documented that Apigenin (4',5,7-trihydroxyflavone), among other flavonoids, is able to modulate key signaling molecules involved in the initiation of cancer cell proliferation, invasion, and metastasis, including JAK/STAT, PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and Wnt/ß-catenin pathways, as well as the oncogenic non-coding RNA network. Based on these premises, the aim of this review is to emphasize some of the key events through which Apigenin suppresses cancer proliferation, focusing specifically on its ability to target key molecular pathways involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cells (CSCs), cell cycle arrest, and cancer cell death.
Assuntos
Apigenina , Transição Epitelial-Mesenquimal , Neoplasias , Apigenina/farmacologia , Apigenina/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismoRESUMO
BACKGROUND: Retinal ischemia/reperfusion (RIR) is implicated in various forms of optic neuropathies, yet effective treatments are lacking. RIR leads to the death of retinal ganglion cells (RGCs) and subsequent vision loss, posing detrimental effects on both physical and mental health. Apigenin (API), derived from a wide range of sources, has been reported to exert protective effects against ischemia/reperfusion injuries in various organs, such as the brain, kidney, myocardium, and liver. In this study, we investigated the protective effect of API and its underlying mechanisms on RGC degeneration induced by retinal ischemia/reperfusion (RIR). METHODS: An in vivo model was induced by anterior chamber perfusion following intravitreal injection of API one day prior to the procedure. Meanwhile, an in vitro model was established through 1% oxygen and glucose deprivation. The neuroprotective effects of API were evaluated using H&E staining, spectral-domain optical coherence tomography (SD-OCT), Fluoro-Gold retrograde labeling, and Photopic negative response (PhNR). Furthermore, transmission electron microscopy (TEM) was employed to observe mitochondrial crista morphology and integrity. To elucidate the underlying mechanisms of API, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry assay, western blot, cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, JC-1 kit assay, dichlorofluorescein-diacetate (DCFH-DA) assay, as well as TMRE and Mito-tracker staining were conducted. RESULTS: API treatment protected retinal inner plexiform layer (IPL) and ganglion cell complex (GCC), and improved the function of retinal ganglion cells (RGCs). Additionally, API reduced RGC apoptosis and decreased lactate dehydrogenase (LDH) release by upregulating Bcl-2 and Bcl-xL expression, while downregulating Bax and cleaved caspase-3 expression. Furthermore, API increased mitochondrial membrane potential (MMP) and decreased extracellular reactive oxygen species (ROS) production. These effects were achieved by enhancing mitochondrial function, restoring mitochondrial cristae morphology and integrity, and regulating the expression of OPA1, MFN2, and DRP1, thereby regulating mitochondrial dynamics involving fusion and fission. CONCLUSION: API protects RGCs against RIR injury by modulating mitochondrial dynamics, promoting mitochondrial fusion and fission.
Assuntos
Apigenina , Dinâmica Mitocondrial , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Células Ganglionares da Retina , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Apigenina/farmacologia , Apigenina/uso terapêutico , Animais , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Dinâmica Mitocondrial/efeitos dos fármacos , Masculino , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Modelos Biológicos , Camundongos Endogâmicos C57BLRESUMO
Neuroinflammation, a hallmark of various central nervous system disorders, is often associated with oxidative stress and neuronal or oligodendrocyte cell death. It is therefore very interesting to target neuroinflammation pharmacologically. One therapeutic option is the use of nutraceuticals, particularly apigenin. Apigenin is present in plants: vegetables (parsley, celery, onions), fruits (oranges), herbs (chamomile, thyme, oregano, basil), and some beverages (tea, beer, and wine). This review explores the potential of apigenin as an anti-inflammatory agent across diverse neurological conditions (multiple sclerosis, Parkinson's disease, Alzheimer's disease), cancer, cardiovascular diseases, cognitive and memory disorders, and toxicity related to trace metals and other chemicals. Drawing upon major studies, we summarize apigenin's multifaceted effects and underlying mechanisms in neuroinflammation. Our review underscores apigenin's therapeutic promise and calls for further investigation into its clinical applications.
Assuntos
Anti-Inflamatórios , Apigenina , Doenças Neuroinflamatórias , Apigenina/farmacologia , Apigenina/uso terapêutico , Humanos , Animais , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismoRESUMO
Apigenin (API) is a natural flavonoid compound with antioxidant, anti fibrotic, anti-inflammatory and other effects, but there is limited research on the effect of API on liver fibrosis. This study aims to explore the effect and potential mechanism of API on liver fibrosis induced by CCl4 in mice. The results indicate that API reduces oxidative stress levels, inhibits hepatic stellate cell (HSC) activation, and exerts anti liver fibrosis effects by regulating the PKM2-HIF-1α pathway. We observed that API alleviated liver tissue pathological damage and collagen deposition in CCl4 induced mouse liver fibrosis model, promoting the recovery of liver function in mice with liver fibrosis. In addition, the API inhibits the transition of Pyruvate kinase isozyme type M2 (PKM2) from dimer to tetramer formation by regulating the EGFR-MEK1/2-ERK1/2 pathway, thereby preventing dimer from entering the nucleus and blocking PKM2-HIF-1α access. This change leads to a decrease in malondialdehyde (MDA) and Catalase (CAT) levels and an increase in glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) levels, as well as total antioxidant capacity (T-AOC) in the liver of liver fibrosis mice. At the same time, API downregulated the expression of α-smooth muscle actin (α-SMA), Vimentin and Desmin in the liver tissue of mice with liver fibrosis, inhibited the activation of HSC, and reduced collagen deposition. These results indicate that API can inhibit HSC activation and alleviate CCl4 induced liver fibrosis by inhibiting the PKM2-HIF-1α pathway and reducing oxidative stress, laying an important foundation for the development and clinical application of API as a novel drug for treating liver fibrosis.
Assuntos
Apigenina , Subunidade alfa do Fator 1 Induzível por Hipóxia , Cirrose Hepática , Estresse Oxidativo , Animais , Estresse Oxidativo/efeitos dos fármacos , Apigenina/farmacologia , Apigenina/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Camundongos , Masculino , Piruvato Quinase/metabolismo , Camundongos Endogâmicos C57BL , Tetracloreto de Carbono/toxicidade , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Proteínas de Ligação a Hormônio da Tireoide , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Hormônios Tireóideos/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Receptores ErbBRESUMO
The neuronal and renal deteriorations observed in patients exposed to methotrexate (MTX) therapy highlight the need for medical interventions to counteract these complications. Boswellic acid (BA) and apigenin (APG) are natural phytochemicals with prominent neuronal and renal protective impacts in various ailments. However, their impacts on MTX-provoked renal and hippocampal toxicity have not been reported. Thus, the present work is tailored to clarify the ability of BA and APG to counteract MTX-provoked hippocampal and renal toxicity. BA (250 mg/kg) or APG (20 mg/kg) were administered orally in rats once a day for 10 days, while MTX (20 mg/kg, i.p.) was administered once on the sixth day of the study. At the histopathological level, BA and APG attenuated MTX-provoked renal and hippocampal aberrations. They also inhibited astrocyte activation, as proven by the inhibition of glial fibrillary acidic protein (GFAP). These impacts were partially mediated via the activation of autophagy flux, as proven by the increased expression of beclin1, LC3-II, and the curbing of p62 protein, alongside the regulation of the p-AMPK/mTOR nexus. In addition, BA and APG displayed anti-inflammatory features as verified by the damping of NOD-2 and p-NF-κB p65 to reduce TNF-α, IL-6, and NLRP3/IL-1ß cue. These promising effects were accompanied with a notable reduction in one of the gap junction proteins, connexin-43 (Conx-43). These positive impacts endorse BA and APG as adjuvant modulators to control MTX-driven hippocampal and nephrotoxicity.
Assuntos
Apigenina , Autofagia , Conexina 43 , Hipocampo , Rim , Metotrexato , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Triterpenos , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Metotrexato/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Apigenina/farmacologia , Apigenina/uso terapêutico , Triterpenos/farmacologia , Triterpenos/uso terapêutico , NF-kappa B/metabolismo , Masculino , Ratos , Conexina 43/metabolismo , Autofagia/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
The escalating focus on ageing-associated disease has generated substantial interest in the phenomenon of cognitive impairment linked to diabetes. Hyperglycemia exacerbates oxidative stress, contributes to ß-amyloid accumulation, disrupts mitochondrial function, and impairs cognitive function. Existing therapies have certain limitations, and apigenin (AG), a natural plant flavonoid, has piqued interest due to its antioxidant, anti-inflammatory, and anti-hyperglycemic properties. So, we anticipate that AG might be a preventive medicine for hyperglycemia-associated amnesia. To test our hypothesis, naïve zebrafish were trained to acquire memory and pretreated with AG. Streptozotocin (STZ) was administered to mimic hyperglycemia-induced memory dysfunction. Spatial memory was assessed by T-maze and object recognition through visual stimuli. Acetylcholinesterase (AChE) activity, antioxidant enzyme status, and neuroinflammatory genes were measured, and histopathology was performed in the brain to elucidate the neuroprotective mechanism. AG exhibits a prophylactic effect and improves spatial learning and discriminative memory of STZ-induced amnesia in zebrafish under hyperglycemic conditions. AG also reduces blood glucose levels, brain oxidative stress, and AChE activity, enhancing cholinergic neurotransmission. AG prevented neuronal damage by regulating brain antioxidant response elements (ARE), collectively contributing to neuroprotective properties. AG demonstrates a promising effect in alleviating memory dysfunction and mitigating pathological changes via activation of the Nrf2/ARE mechanism. These findings underscore the therapeutic potential of AG in addressing memory dysfunction and neurodegenerative changes associated with hyperglycemia.
Assuntos
Amnésia , Apigenina , Hiperglicemia , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Estresse Oxidativo , Peixe-Zebra , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Amnésia/tratamento farmacológico , Amnésia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Apigenina/farmacologia , Apigenina/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Acetilcolinesterase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Proteínas de Peixe-Zebra/metabolismo , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Masculino , Estreptozocina , Aprendizagem em Labirinto/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
Apigenin and baicalein are structurally related flavonoids that have been reported to have multiple pharmacological activities. The aim of this study was to investigate the protective effects and potential mechanisms of apigenin and baicalein in D-galactose-induced aging rats. First, apigenin and baicalein showed remarkable antioxidant activity and anti-glycation activity in vitro. Secondly, the protective effects of apigenin and baicalein on aging rats were investigated. We found that apigenin and baicalein supplementation significantly ameliorated aging-related changes such as declines in the spatial learning and memory and histopathological damage of the hippocampus and thoracic aorta. In addition, our data showed that apigenin and baicalein alleviated oxidative stress as illustrated by decreasing MDA level, increasing SOD activity and GSH level. Further data showed that they significantly reduced the accumulation of advanced glycation end products (AGEs), inhibited the expression of RAGE, down-regulated phosphorylated nuclear factor (p-NF-κB (p65)). Our results suggested that the protective effects of apigenin and baicalein on aging rats were at least partially related to the inhibition of AGEs/RAGE/NF-κB pathway and the improvement of oxidative damage. Overall, apigenin and baicalein showed almost equal anti-aging efficacy. Our results provided an experimental basis for the application of apigenin and baicalein to delay the aging process.
Assuntos
Envelhecimento , Aorta Torácica , Apigenina , Flavanonas , Galactose , Produtos Finais de Glicação Avançada , NF-kappa B , Estresse Oxidativo , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Transdução de Sinais , Animais , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Apigenina/farmacologia , Apigenina/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/induzido quimicamente , Antioxidantes/farmacologiaRESUMO
Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.
Assuntos
Catequina , Doenças Neurodegenerativas , Fitoterapia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Catequina/análogos & derivados , Catequina/uso terapêutico , Catequina/farmacologia , Curcumina/uso terapêutico , Curcumina/farmacologia , Quercetina/farmacologia , Quercetina/uso terapêutico , Animais , Canabinoides/uso terapêutico , Canabinoides/farmacologia , Apigenina/farmacologia , Apigenina/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Extratos Vegetais/farmacologiaRESUMO
Isochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1-α-KG-HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.
Assuntos
Carcinoma Hepatocelular , Glucuronatos , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteômica , Apigenina/farmacologia , Apigenina/uso terapêutico , Ácidos Cetoglutáricos/metabolismo , Microambiente Tumoral , Isocitrato DesidrogenaseRESUMO
PURPOSE: Vitexin can cooperate with hyperbaric oxygen to sensitize the radiotherapy of glioma by inhibiting the hypoxia-inducible factor (HIF)-1α. However, whether vitexin has a direct radiosensitization and how it affects the HIF-1α expression remain unclear. This study investigated these issues. METHODS: The SU3 cells-inoculated nude mice were divided into control, radiation, and vitexinâ¯+ radiation groups. The vitexinâ¯+ radiation-treated mice were intraperitoneally injected with 75â¯mg/kg vitexin daily for 21 days. On the 3rd, 10th, and 17th days during the vitexin treatment, the radiation-treated mice were locally irradiated with 10â¯Gy, respectively. In vitro, the microRNA (miR)-17-5p or miR-130b-3p mimics-transfected SU3 cells were used to examine the effects of vitexin plus radiation on expression of miR-17-5p- or miR-130b-3p-induced radioresistance-related pathway proteins. The effects of vitexin on miR-17-5p and miR-130b-3p expression in SU3 cells were also evaluated. RESULTS: Compared with the radiation group, the tumor volume, tumor weight, and expression of HIF-1α, vascular endothelial growth factor, and glucose transporter-1/3 proteins, miR-17-5p, and miR-130b-3p in tumor tissues in the vitexinâ¯+ radiation group decreased, whereas the expression of phosphatase and tensin homolog (PTEN) protein increased. After treatment of miR-17-5p or miR-130b-3p mimics-transfected SU3 cells with vitexin plus radiation, the PTEN protein expression also increased, the HIF-1α protein expression decreased correspondingly. Moreover, vitexin decreased the miR-17-5p and miR-130b-3p expression in SU3 cells. CONCLUSION: Vitexin can enhance the radiosensitivity of glioma, and its mechanism may partly be related to the attenuation of HIF-1α pathway after lowering the inhibitory effect of miR-17-5p and miR-130b-3p on PTEN.
Assuntos
Apigenina , Glioma , Subunidade alfa do Fator 1 Induzível por Hipóxia , Camundongos Nus , MicroRNAs , PTEN Fosfo-Hidrolase , Tolerância a Radiação , Animais , MicroRNAs/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Apigenina/farmacologia , Apigenina/uso terapêutico , PTEN Fosfo-Hidrolase/genética , Camundongos , Glioma/radioterapia , Glioma/patologia , Glioma/genética , Glioma/tratamento farmacológico , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Radiossensibilizantes/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB CRESUMO
Fetuin-A, a hepatokine secreted by hepatocytes, binds to insulin receptors and consequently impairs the activation of the insulin signaling pathway, leading to insulin resistance. Apigenin, a flavonoid isolated from plants, has beneficial effects on insulin resistance; however, its regulatory mechanisms are not fully understood. In the present study, we investigated the molecular mechanisms underlying the protective effects of apigenin on insulin resistance. In Huh7 cells, treatment with apigenin decreased the mRNA expression of fetuin-A by decreasing reactive oxygen species-mediated casein kinase 2α (CK2α)-nuclear factor kappa-light-chain-enhancer of activated B activation; besides, apigenin decreased the levels of CK2α-dependent fetuin-A phosphorylation and thus promoted fetuin-A degradation through the autophagic pathway, resulting in a decrease in the protein levels of fetuin-A. Moreover, apigenin prevented the formation of the fetuin-A-insulin receptor (IR) complex and thereby rescued the PA-induced impairment of the insulin signaling pathway, as evidenced by increased phosphorylation of IR substrate-1 and Akt, and translocation of glucose transporter 2 from the cytosol to the plasma membrane. Similar results were observed in the liver of HFD-fed mice treated with apigenin. Collectively, our findings revealed that apigenin ameliorates obesity-induced insulin resistance in the liver by targeting fetuin-A.
Assuntos
Resistência à Insulina , Camundongos , Animais , alfa-2-Glicoproteína-HS/metabolismo , Apigenina/farmacologia , Apigenina/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Insulina/metabolismo , alfa-Fetoproteínas/metabolismoRESUMO
The present study aimed to explore the potential ameliorative effect of apigenin (APG) against diabetes-associated genitourinary complications in rats. A diabetic rat model was induced by the intraperitoneal injection of streptozotocin (STZ). All experimental animals were treated with vehicle or vehicle plus APG at a dose of 0.78 mg/kg/day for 10 days, either once diabetes was confirmed or at the end of the 3rd week after confirmation of diabetes. Rats were sacrificed at the end of the fifth week. In addition to the histological assessment, an analysis of kidney function tests and serum testosterone was performed to assess diabetic genitourinary complications. Gene expression of the mitochondrial fission protein, dynamin related protein 1 (Drp1), was measured in renal and testicular tissues using qRT PCR. APG can increase body weight, reduce blood glucose levels, and improve renal and testicular functions in diabetic rats. APG decreased Drp1 overexpression in diabetic animals' kidneys and testes. In summary, our current work discloses that APG attenuates diabetic genitourinary lesions in rats via suppressing Drp1 overexpression.