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BACKGROUND: Mitochondrial dysfunction is key to the pathogenesis of vascular dementia (VaD). Sirtuin-3 (SIRT3), an essential member of the sirtuins family, has been proven to be a critical sirtuin in regulating mitochondrial function. The phenolic glucoside gastrodin (GAS), a bioactive ingredient from Gastrodiae Rhizome (known in Chinese as Tian ma) demonstrates significant neuroprotective properties against central nervous system disorders; however, the precise mechanisms through which GAS modulates VaD remain elusive. PURPOSE: This study aims to investigate whether GAS confers a protective role against VaD, and to figure out the underlying molecular mechanisms. METHODS: A bilateral common carotid artery occlusion (BCCAO)-mediated chronic cerebral hypoperfusion (CCH) VaD rat model and a hypoxia model using HT22 cells were employed to investigate pharmacological properties of GAS in mitigating mitochondrial dysfunction. A SIRT3 agonist resveratrol (RES), a SIRT3 inhibitor 3-TYP and SIRT3-knockdown in vitro were used to explore the mechanism of GAS in association with SIRT3. The ability of SIRT3 to bind and deacetylate mitochondrial transcription factor A (TFAM) was detected by immunoprecipitation assay, and TFAM acetylation sites were further validated using mass spectrometry. RESULTS: GAS increased SIRT3 expression and ameliorated mitochondrial structure, mitochondrial respiration, mitochondrial dynamics along with upregulated TFAM, mitigating oxidative stress and senescence. Comparable results were noted with the SIRT3 agonist RES, indicating an impactful neuroprotection played by SIRT3. Specifically, the attenuation of SIRT3 expression through knockdown techniques or exposure to the SIRT3 inhibitor 3-TYP in HT22 cells markedly abrogated GAS-mediated mitochondrial rescuing function. Furthermore, our findings elucidate a novel facet: SIRT3 interacted with and deacetylated TFAM at the K5, K7, and K8 sites. Decreased SIRT3 is accompanied by hyper-acetylated TFAM. CONCLUSION: The present results were the first to demonstrate that the SIRT3/TFAM pathway is a protective target for reversing mitochondrial dysfunction in VaD. The findings suggest that GAS-mediated modulation of the SIRT3/TFAM pathway, a novel mechanism, could ameliorate CCH-induced VaD, offering a potentially beneficial therapeutic strategy for VaD.
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Álcoois Benzílicos , Demência Vascular , Glucosídeos , Mitocôndrias , Fármacos Neuroprotetores , Ratos Sprague-Dawley , Sirtuína 3 , Sirtuínas , Animais , Glucosídeos/farmacologia , Demência Vascular/tratamento farmacológico , Sirtuína 3/metabolismo , Álcoois Benzílicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Masculino , Acetilação , Fármacos Neuroprotetores/farmacologia , Camundongos , Fatores de Transcrição/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ratos , Modelos Animais de Doenças , Linhagem Celular , Resveratrol/farmacologia , Gastrodia/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Honeysuckle, first documented in the Miscellaneous Records of Famous Physicians, is known for its ability to expel toxin and cool blood to stop diarrhea. Modern pharmacological research has shown that honeysuckle has anti-inflammatory, antibacterial, antioxidant, and immune-regulating effects and is widely used in clinical practice. However, the effect of honeysuckle on ulcerative colitis (UC) is still not fully understood, which presents challenges for quality control, research and development. AIM OF THE STUDY: This study aimed to determine the anti-inflammatory properties and mechanism of action of aqueous extracts of honeysuckle in the treatment of ulcerative colitis. MATERIALS AND METHODS: The dextran sodium sulfate (DSS) induced-ulcerative colitis mouse model was established, and the mice were divided into five groups: the control group, the model group, and the low, medium, and high dose honeysuckle treatment groups. RESULTS: All dose groups of honeysuckle were found to significantly reduce IL-6 and TNF-α levels and regulate DSS-induced mRNA levels of CLDN4, COX-2, IL-6, INOS, MUC-2, occludin and NLRP3. The high-dose group displayed the most effective inhibition, and a differentially expressed mRNA detection indicated abnormal mRNA expression. The 16sRNA sequencing revealed that the honeysuckle was able to significantly upregulate the abundance of beneficial bacteria and downregulate the abundance of harmful bacteria. The study of short-chain fatty acids revealed that the levels of acetic, propionic, isobutyric, valeric and isovaleric acids were significantly increased after administering honeysuckle at medium and high doses. CONCLUSION: Honeysuckle reduces the production of pro-inflammatory cytokines, increases the content of short-chain fatty acids and restores the intestinal ecological balance, resulting in better therapeutic effects.
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Colite Ulcerativa , Colite , Lonicera , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo , Interleucina-6/genética , Interleucina-6/metabolismo , Anti-Inflamatórios/efeitos adversos , RNA Mensageiro/metabolismo , Ácidos Graxos Voláteis/metabolismo , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colite/tratamento farmacológicoRESUMO
Alpinia zerumbet is a food flavor additive and a traditional medicine herb around the world. Several studies have reported that A. zerumbet has excellent effects on a variety of cardiovascular diseases, but its potential hypertensive applications, and pharmacokinetic features of main active substances have not been fully investigated. The mechanism of anti-hypertension with ethyl acetate extracts of A. zerumbet fruits (AZEAE) was evaluated by L-NNA-induced hypertensive rats and L-NAME-injured human umbilical vein endothelial cells (HUVECs). Blood pressure, echocardiographic cardiac index and H&E staining were used to preliminary evaluate the antihypertensive effect of AZEAE, the levels of TNF-α, IL-6, and IL-1ß were evaluated by ELISA, and the proteins expression of IL-1ß, IL-18, AGTR1, VCAM, iNOS, EDN1 and eNOS were also evaluated. In addition, isolation, identification, and activity screening of bioactive compounds were carried ou. Next, pharmacokinetics and tissues distribution of dihydro-5,6-dehydrokavain (DDK) in vivo were measured, and preliminary absorption mechanism was conducted with Caco-2 cell monolayers. AZEAE remarkably enhanced the state of hypertensive rats. Twelve compounds were isolated and identified, and five compounds were isolated from this plant for the first time. The isolated compounds also exhibited good resistance against injury of HUVECs. Moreover, pharmacokinetics and Caco-2 cell monolayers demonstrated AZEAE had better absorption capacity than DDK, and DDK exhibited differences in tissues distribution and gender difference. This study was the first to assess the potential hypertensive applications of A. zerumbet in vivo and vitro, and the first direct and concise study of the in vivo behavior of DDK and AZEAE.
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Alpinia , Anti-Hipertensivos , Ratos , Humanos , Animais , Anti-Hipertensivos/farmacologia , Células CACO-2 , Estrutura Molecular , Células Endoteliais da Veia Umbilical Humana , Extratos Vegetais/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Vascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear. AIM OF THE STUDY: To investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes. MATERIALS AND METHODS: A diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cells (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, SA-ß-galactosidase staining, cell cycle, reactive oxygen species (ROS), cell migration, and enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against vascular endothelial cell senescence in diabetes. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats vascular endothelial cell senescence in diabetes. RESULTS: EOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and vascular endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blotting and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ and rosiglitazone treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA. CONCLUSIONS: EOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.
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Diabetes Mellitus Experimental , Óleos Voláteis , Humanos , Camundongos , Animais , Células Endoteliais , PPAR gama/metabolismo , Rosiglitazona/metabolismo , Rosiglitazona/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Óleos Voláteis/farmacologia , Simulação de Acoplamento Molecular , Farmacologia em Rede , Proteômica , RNA Interferente Pequeno , Glucose/metabolismoRESUMO
BACKGROUND: Atherosclerosis (AS) is a progressive chronic disease. Currently, cardiovascular diseases (CVDs) caused by AS is responsible for the global increased mortality. Yanshanjiang as miao herb in Guizhou of China is the dried and ripe fruit of Fructus Alpinia zerumbet. Accumulated evidences have confirmed that Yanshanjiang could ameliorate CVDs, including AS. Nevertheless, its effect and mechanism on AS are still largely unknown. PURPOSE: To investigate the role of essential oil from Fructus Alpinia zerumbet (EOFAZ) on AS, and the potential mechanism. METHODS: A high-fat diet (HFD) ApoE-/- mice model of AS and a oxLDL-induced model of macrophage-derived foam cells (MFCs) were reproduced to investigate the pharmacological properties of EOFAZ on AS in vivo and foam cell formation in vitro, respectively. The underlying mechanisms of EOFAZ were investigated using Network pharmacology and molecular docking. EOFAZ effect on PPARγ protein stability was measured using a cellular thermal shift assay (CETSA). Pharmacological agonists and inhibitors and gene interventions were employed for clarifying EOFAZ's potential mechanism. RESULTS: EOFAZ attenuated AS progression in HFD ApoE-/- mice. This attenuation was manifested by the reduced aortic intima plaque development, increased collagen content in aortic plaques, notable improvement in lipid profiles, and decreased levels of inflammatory factors. Moreover, EOFAZ inhibited the formation of MFCs by enhancing cholesterol efflux through activiting the PPARγ-LXRα-ABCA1/G1 pathway. Interestingly, the pharmacological knockdown of PPARγ impaired the beneficial effects of EOFAZ on MFCs. Additionally, our results indicated that EOFAZ reduced the ubiquitination degradation of PPARγ, and the chemical composition of EOFAZ directly bound to the PPARγ protein, thereby increasing its stability. Finally, PPARγ knockdown mitigated the protective effects of EOFAZ on AS in HFD ApoE-/- mice. CONCLUSION: These findings represent the first confirmation of EOFAZ's in vivo anti-atherosclerotic effects in ApoE-/- mice. Mechanistically, its chemical constituents can directly bind to PPARγ protein, enhancing its stability, while reducing PPARγ ubiquitination degradation, thereby inhibiting foam cell formation via activation of the PPARγ-LXRα-ABCA1/G1 pathway. Simultaneously, EOFAZ could ameliorates blood lipid metabolism and inflammatory microenvironment, thus synergistically exerting its anti-atherosclerotic effects.
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Alpinia , Aterosclerose , Óleos Voláteis , Placa Aterosclerótica , Animais , Camundongos , PPAR gama/metabolismo , Óleos Voláteis/farmacologia , Frutas , Simulação de Acoplamento Molecular , Transdução de Sinais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Placa Aterosclerótica/tratamento farmacológico , Apolipoproteínas E , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Receptores X do Fígado/metabolismoRESUMO
Two new stilbenoids, cajanstilbenoid C (1) and cajanstilbenoid D (2), together with eight other known stilbenoids (3-10) and seventeen known flavonoids (11-27), were isolated from the petroleum ether and ethyl acetate portions of the 95% ethanol extract of leaves of Cajanus cajan (L.) Millsp. The planar structures of the new compounds were elucidated by NMR and high-resolution mass spectrometry, and their absolute configurations were determined by comparison of their experimental and calculated electronic circular dichroism (ECD) values. All the compounds were assayed for their inhibitory activities against yeast α-glucosidase. The results demonstrated that compounds 3, 8-9, 11, 13, 19-21, and 24-26 had strong inhibitory activities against α-glucosidase, with compound 11 (IC50 = 0.87 ± 0.05 µM) exhibiting the strongest activity. The structure-activity relationships were preliminarily summarized. Moreover, enzyme kinetics showed that compound 8 was a noncompetitive inhibitor, compounds 11, 24-26 were anticompetitive, and compounds 9 and 13 were mixed-competitive.
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Cajanus , Estilbenos , Flavonoides/farmacologia , Flavonoides/química , Cajanus/química , alfa-Glucosidases , Estilbenos/farmacologia , Estilbenos/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores de Glicosídeo Hidrolases/farmacologiaRESUMO
Diet dictates nutrient availability in the tumor microenvironment, thus affecting tumor metabolic activity and growth. Intrinsically, tumors develop unique metabolic features and are sensitive to environmental nutrient concentrations. Tumor-driven nutrient dependencies provide opportunities to control tumor growth by nutritional restriction or supplementation. This review summarized the existing data on nutrition and pediatric cancers after systematically searching articles up to 2023 from four databases (PubMed, Web of Science, Scopus, and Ovid MEDLINE). Epidemiological studies linked malnutrition with advanced disease stages and poor clinical outcomes in pediatric cancer patients. Experimental studies identified several nutrient dependencies (i.e., amino acids, lipids, vitamins, etc.) in major pediatric cancer types. Dietary modifications such as calorie restriction, ketogenic diet, and nutrient restriction/supplementation supported pediatric cancer treatment, but studies remain limited. Future research should expand epidemiological studies through data sharing and multi-institutional collaborations and continue to discover critical and novel nutrient dependencies to find optimal nutritional approaches for pediatric cancer patients.
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Alangium chinense has been used as a traditional folk medicine for centuries to treat rheumatism, skin diseases, and diabetes by the people of Southeast Asia. However, the bioactive constituents inhibiting COX-2 and cancer cells (HepG2, Caco-2, HeLa) remain unclear. In this study one new (14) along with twenty-four known compounds (1-13, 15-25) were isolated from the fibrous roots of Alangium chinense by chromatographic methods, and identified by NMR, and Gaussian and CD calculation. Compounds 1, 2, 13, 16, 17, 19, 20, 23, and 24 were isolated from this plant for the first time. Their inhibition effects on COX-2 enzyme and cancer cells were evaluated by MTT assay. Compounds 1-4, 13-14, and 16-18 can be used as good inhibitors against COX-2 enzyme, and compounds 1, 13, 14, and 17 were stronger than the positive control (celecoxib). In addition, molecular docking suggested that compounds 13, 17, and 18 belong to ellagic acids and have good inhibition against COX-2 enzyme. While compounds 1, 5, 13 and 21 showed cytotoxicity against HepG2 cells, compounds 2 and 21 showed cytotoxicity against Caco-2 cells, and compound 20 showed cytotoxicity against HeLa cells.
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Polydopamine (PDA) is capable of wide drug delivery for biomedical applications by virtue of an adjustable polymerization process, including surface coating and conjugation. Inspired by the polymerization of dopamine, we introduce a layer-by-layer hybrid co-assembly strategy for the incorporation of doxorubicin (DOX) and dopamine to form PDA "carrier-drug" hybrid assembly. The "carrier-drug" hybrid assembly relies on the π-π stacking interaction between the drug (DOX) and carrier (PDA), and such the stacked-layer structure enables PDA nanoparticles with a superior drug loading of 58%, which is about 1.7-fold higher than that of the DOX surface coating (â¼35%). To further improve blood circulation stability and enhance tumor penetration, we herein propose the conjugation of native apolipoprotein A-I (apoA-I) with tumor-homing cyclic peptide iRGD for PDA surface modification. The "carrier-drug" hybrid assembly can respond to triple stimuli of the acidic pH, concentrated reactive oxygen species (ROS), and near-infrared (NIR) light irradiation for realizing site-specific and on-demand drug release. In chemo-photothermal synergy therapy, the "carrier-drug" hybrid assembly performs efficient tumor penetration and accumulation, dramatically suppressing tumor growth and metastasis in a 4T1 orthotopic tumor-bearing mice model at a safe level. Collectively, our findings share new insights into the design of "carrier-drug" hybrid assembly for enhanced chemo-photothermal oncotherapy.
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Nanopartículas , Neoplasias , Animais , Apolipoproteína A-I , Linhagem Celular Tumoral , Dopamina , Doxorrubicina/química , Excipientes , Indóis , Camundongos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Peptídeos Cíclicos , Fototerapia , Polímeros , Espécies Reativas de Oxigênio/metabolismoRESUMO
Tumor phototherapies are light-mediated tumor treatment modalities, which usually refer to tumor photothermal therapy (PTT) and photodynamic therapy (PDT). Due to the outstanding spatial-temporal control over treatment through light irradiation, tumor phototherapies display extremely low side effects during treatment and are believed to be a tumor treatment method with a clinical translation potential. However, current tumor phototherapy nanoplatforms face obstacles, including light irradiation-induced skin burning, tumor hypoxia microenvironments, limited light penetration depth, et al. Therefore, one important research direction is developing a tumor phototherapy nanoplatform with multifunctionality and enhanced pharmacological effects to overcome the complexity of tumor treatment. On the other hand, cyclodextrins (CDs) are starch-originated circular oligosaccharides with negligible toxicity and have been used to form supermolecular nanostructures through a host-guest interaction between the inner cavity of CDs and functional biomolecules. In the past few years, numerous studies have focused on CD-based multifunctional tumor phototherapy nanoplatforms with an enhanced photoeffect, responsive morphological transformation, and elevated drug bioavailability. This review focuses on the preparation methods of CD-based tumor phototherapy nanoplatforms and their unique physiochemical properties for improving anti-tumor pharmacological efficacy.
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Pulmonary emphysema is a fatal lung disease caused by the progressive thinning, enlargement and destruction of alveoli that is closely related to inflammation and oxidative stress. Oxymatrine (OMT), as a bioactive constituent of traditional Chinese herbal Sophora flavescens, has great potential to alleviate pulmonary emphysema via its anti-inflammatory and antioxidative activities. Pulmonary administration is the most preferable way for the treatment of lung diseases. To improve the in vivo stability and pulmonary retention of OMT, OMT-loaded liposome with carboxymethyl chitosan (CMCS) modification was developed. The CMCS was modified on the surface of OMT liposomes via electrostatic attraction and covalent conjugation to obtain Lipo/OMT@CMCS and CMCS-Lipo/OMT, respectively. A porcine pancreatic elastase (PPE)-induced emphysema mice model was established to evaluate the alleviation effects of OMT on alveolar expansion and destruction. CMCS-modified liposomal OMT exhibited superior ameliorative effects on emphysema regardless of the preparation methods, and higher sedimentation and longer retention in the lung were observed in the CMCS-Lipo group. The mechanisms of OMT on emphysema were related to the downregulation of inflammatory cytokines and the rebalancing of antioxidant/oxidation via the Nrf2/HO-1 and NF-κB/IκB-α signaling pathways, leading to reduced cell apoptosis. Moreover, the OMT liposomal preparations further enhanced its anti-inflammatory and antioxidative effects. In conclusion, pulmonary administration of OMT is a potential strategy for the treatment of emphysema and the therapeutic effects can be further improved by CMCS-modified liposomes.
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Anti-Inflamatórios/farmacologia , Quitosana , Enfisema , Lipossomos/farmacologia , Enfisema Pulmonar , Alcaloides/química , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Antioxidantes/farmacologia , Lipossomos/química , Camundongos , Quinolizinas , SuínosRESUMO
Squids are globally distributed. Hg-contaminated squids may have high risks on humans. With abundant Se (antagonistic effect on Hg), the risks can be reduced. We collected squids around the world (Northwest Pacific Ocean, Southeast Pacific Ocean and Indian Ocean). Concentrations of Hg and Se were region-based and tissue-based. The higher content of Se were, the lower relative Hg levels were. The correlation between Se:Hg and Se was the strongest in the digestive gland. The values of Se:Hg and THQ all confirm that the health risk was lower in samples with higher concentrations of Se. Despite the risk assessment by Se:Hg, BRV and THQ analysis showed no risk when consumed in moderation, the maximum daily intake is provided based on Monte Carlo simulation. In future, when evaluating the risks cause by Hg exposure and providing the recommended daily amount, it may need to concurrent consideration of Se levels.
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Mercúrio , Selênio , Animais , Decapodiformes , Humanos , Oceano Índico , Mercúrio/análise , Oceano Pacífico , Selênio/análiseRESUMO
BACKGROUND/AIMS: Alpinia zerumbet (Pers.) Burtt. et Smith has been used as a flavor additive in food and a traditional medicine for centuries, especially in Guizhou Province, China, and it prolongs people's lives with multiple beneficial effects. Thus, one of the aims of this review was to expound the chemical constituents of this plant, especially its fruits. Since cardiovascular diseases, including atherosclerosis, pose a health threat to humans, another aim was to expound the possible mechanisms of its potential use as an herbal medication for atherosclerosis. METHODS: In this study, 10 reports are cited to expound the potential bioactive compounds. Moreover, 33 reports explain the antihypertensive and antiatherosclerotic effects of the plant by ameliorating inflammation and endothelial dysfunction, increasing vasodilation, improving hyperlipidemia, downgrading the glucose status, and working as an antioxidant. RESULTS: A. zerumbetis rich in terpenes, essential oils, flavonoids, polyphenolics, and sterols. Pharmacological experiments showed that A. zerumbet has antioxidative and anti-inflammatory effects on the NF-κB signaling pathway and can ameliorate oxidative stress in the NOS-NO signaling pathway. Moreover, A. zerumbet demonstrates antihypertensive effects by accelerating vasorelaxant response and increasing 3T3-L1 intracellular cAMP, which has promising antiobesity properties, as well as hypolipidemic and anti-diabetic complication effects. CONCLUSIONS: A. zerumbet has potential functions and applications in the prevention of atherosclerosis, but further studies are required before clinical trials.
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Alpinia/química , Aterosclerose/tratamento farmacológico , Extratos Vegetais/farmacologia , Preparações de Plantas , Células 3T3-L1 , Animais , Fármacos Antiobesidade/farmacologia , Antioxidantes/farmacologia , Glicemia/química , Humanos , Hiperlipidemias/tratamento farmacológico , Concentração Inibidora 50 , Cinética , Masculino , Medicina Tradicional Chinesa , Mesocricetus , Camundongos , Óxido Nítrico Sintase , Óleos Voláteis/química , Estresse Oxidativo/efeitos dos fármacos , Preparações de Plantas/uso terapêutico , Ratos , Fatores de RiscoRESUMO
Essential oil from Alpinia zerumbet rhizome (EOFAZ), which is termed Yan shanjiang in China, is extensively used as an herbal medicine in the Guizhou area and has been shown to protect against the damaging effects of cardiovascular injury in vitro and in vivo. In the present study, it was hypothesized that the protective effects of EOFAZ on transforming growth factor (TGF)ß1induced endothelialtomesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs) were mediated by inhibition of Krüppellike factor 4 (KLF4). Cell motility was assessed using wound healing and Transwell assays. The expression of endothelial markers and mesenchymal markers were determined by reverse transcriptionquantitative PCR, immunoï¬uorescence staining and western blotting, and additionally, phosphorylated NFκB p65 expression was determined by western blotting. Furthermore, the involvement of KLF4 in EndMT was determined using RNA interference to knockdown the expression of KLF4. TGFß1 treatment significantly promoted EndMT, as evidenced by downregulation of vascular endothelialcadherin and upregulation of αsmooth muscle actin in HUVECs, and by enhancing cell migration. Small interfering RNAmediated knockdown of KLF4 reversed TGFß1induced EndMT. Additionally, treatment with EOFAZ inhibited TGFß1induced EndMT in a dosedependent manner. These results suggest that TGFß1 may induce EndMT through upregulation of KLF4, and this may be reversed by EOFAZ. Therefore, EOFAZ was shown to inhibit TGFß1induced EndMT through regulation of KLF4.
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Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/metabolismo , Óleos Voláteis/farmacologia , Western Blotting , Movimento Celular/efeitos dos fármacos , Imunofluorescência , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoprecipitação , Fator 4 Semelhante a Kruppel , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta1/farmacologia , Cicatrização/efeitos dos fármacosRESUMO
Diabetic cardiomyopathy (DCM) is the principal cause of death in people with diabetes. However, there is currently no effective strategy to prevent the development of DCM. Although cyclovirobuxine D (CVB-D) has been widely used to treat multiple cardiovascular diseases, the possible beneficial effects of CVB-D on DCM remained unknown. The present aim was to explore the potential effects and underlying mechanisms of CVB-D on DCM. We explored the effects of CVB-D in DCM by using high fat high sucrose diet and streptozotocin-induced rat DCM model. Cardiac function and survival in rats with DCM were improved via the amelioration of oxidative damage after CVB-D treatment. Our data also demonstrated that pre-treatment with CVB-D exerted a remarkable cytoprotective effect against high glucose -or H2O2 -induced neonatal rat cardiomyocyte damage via the suppression of reactive oxygen species accumulation and restoration of mitochondrial membrane potential; this effect was associated with promotion of Nrf2 nuclear translocation and its downstream antioxidative stress signals (NQO-1, Prdx1). Overall, the present data has provided the first evidence that CVB-D has potential therapeutic in DCM, mainly by activation of the Nrf2 signalling pathway to suppress oxidative stress. Our findings also have positive implications on the novel promising clinical applications of CVB-D.
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Antioxidantes/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Animais Recém-Nascidos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Glucose/toxicidade , Testes de Função Cardíaca , Peróxido de Hidrogênio/toxicidade , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1- and mTORC2-dependent pathways. BCAAs/branched-chain α-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.
Assuntos
Aminoácidos de Cadeia Ramificada/farmacologia , Dieta Hiperlipídica/efeitos adversos , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Fígado/efeitos dos fármacos , Obesidade/complicações , Proteínas Proto-Oncogênicas c-akt/metabolismo , Aminoácidos de Cadeia Ramificada/administração & dosagem , Animais , Células Cultivadas , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Rim/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Distribuição Aleatória , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Diabetic retinopathy (DR) involves extensive retinal damage and is one of the most common and serious complications of diabetes mellitus. Hyperglycemia is the major pathological trigger for diabetic complications. Müller cell gliosis, a key pathophysiological process in DR, could finally lead to vision loss. Our previous finding revealed that the essential oil of Fructus Alpiniae zerumbet (EOFAZ) protects human umbilical vein endothelial cells (HUVECs) against high glucose (HG)-induced injury via the PPAR-γ signal. However, Whether EOFAZ could prevent HG-induced Müller cell gliosis through the PPAR signaling remains unclear. METHODS: The neuroprotective effects of EOFAZ were evaluated in HG-treated rat retinal Müller cells (RMCs) and DR rat model. RESULT: GFAP and VEGF upregulation is the biomarker of Müller glial reactivity gliosis. Results suggested that EOFAZ could remarkably ameliorate retinal reactive gliosis by suppressing p-CREB and GFAP and VEGF downstream effectors. Its effects on PPAR-γ, a major target for currently available anti-diabetes drugs, were also investigated. EOFAZ treatment remarkably attenuated the reduction of PPAR-γ and high level of p-CaMK II and p-CREB in HG-treated RMCs and diabetic rats. Furthermore, the activation and ectopic expression of PPAR-γ downregulated p-CREB and p-CaMK II in HG-treated RMCs. By contrast, CaMK II inhibitor KN93 and CREB gene silencing did not significantly affect the PPAR-γ expression. CONCLUSIONS: A novel PPAR-γ-p-CREB signaling pathway accounts for the inhibitory effect of EOFAZ on RMCs gliosis. These findings provide scientific evidence for the potential use of EOFAZ as a complementary and alternative medicine for DR prevention and treatment in the future.
RESUMO
Ophiopogon japonicus is one of the commonly used medicines,and it has gradually become a therapeutic food for people's daily health care. O. japonicus in Sichuan province is the famous Dao-di herbs in Sichuan province,and is mainly produced in Santai county,Sichuan province. With the unique geographical advantage,Santai county plans to declare the new food raw materials of O. japonicus based on the geographical indication products( Fu Cheng O. japonicus),so it is necessary to analyze and evaluate the nutritional components of O. japonicus in Santai county. The experimental results showed that the content of the nutrients was characterized by low fat,high polysaccharide,high potassium and high vitamin B2,which can be developed as new food raw materials.
Assuntos
Nutrientes/análise , Valor Nutritivo , Ophiopogon/química , China , Medicamentos de Ervas Chinesas , Raízes de Plantas/química , Polissacarídeos/análise , Potássio/análise , Riboflavina/análiseRESUMO
Triple-negative breast cancer (TNBC) is characterized by elevated metastasis, low survival, and poor response to therapy. Although many specific and effective agents for treating TNBC have been investigated, promising therapeutic options remain elusive. Here, we screened the inhibitory activities of three main components of Lithospermum erythrorhizon Sieb. et Zucc (shikonin, acetylshikonin, and ß,ß-dimethylacrylshikonin) on TNBC cells. The results revealed that shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells. Additionally, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells. Shikonin depressed cell migration and invasion, upregulated E-cadherin levels, downregulated N-cadherin, vimentin, and Snail levels, and reorganized the cytoskeletal proteins F-actin and vimentin. Shikonin reversed EMT by inhibiting activation of ß-catenin signaling through attenuating ß-catenin expression, nuclear accumulation, binding to T-cell factor consensus oligos, and transcription of its targeted EMT-related genes. Moreover, shikonin upregulated glycogen synthase kinase 3ß (GSK-3ß) levels, leading to enhanced phosphorylation and decreased levels of ß-catenin. Furthermore, shikonin administration significantly inhibited lung metastasis of MDA-MB-231 cells in NOD/SCID mice accompanied by low systemic toxicity. Histological analysis confirmed that shikonin elevated levels of E-cadherin, phosphorylated ß-catenin, and GSK-3ß, and decreased levels of vimentin and ß-catenin in pulmonary metastatic foci. These results indicated that shikonin potently inhibits TNBC metastasis by targeting the EMT via GSK-3ß-regulated suppression of ß-catenin signaling, which highlights the importance of shikonin as a potential candidate for novel anticancer therapeutics against TNBC.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Naftoquinonas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , beta Catenina/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Neoplasias de Mama Triplo Negativas/metabolismo , beta Catenina/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Alpinia zerumbet (FAZ), a dry and ripe fruit of Alpinia zerumbet (Pers.) Burtt. et Smith, is widely used as a spice to treat cardiovascular diseases in clinic as a miao folk medicine in Guizhou Province of China. Essential oil extracted from FAZ (EOFAZ) is the key bioactive ingredients. AIM OF THE STUDY: This study aimed to examine the effects and mechanisms of EOFAZ on lipopolysaccharide (LPS)-induced endothelial cell injury, inflammation and apoptosis in vitro and in vivo. MATERIALS AND METHODS: For the in vitro study, LPS-treated human aortic endothelial cells were used to perform PCR, western blot analysis and immunofluorescence. For the in vivo study, male mouse were divided into four groups, vehicle control group and LPS group received 0.5% Tween-80 in saline; and two EOFAZ groups receive different dose of EOFAZ (90â¯mgâ¯kg -1·day-1, 180â¯mgâ¯kg -1·day-1) respectively. Each group was fed for 7 days by intragastrical administration at daily base. Then, except vehicle control group received saline, mice in other three groups were administered with LPS (1â¯mgâ¯kg -1, dissolved in saline) by intraperitoneal injection. 24â¯h later, Aorta tissue was collected and frozen immediately in liquid N2, stored at -80⯰C for western blot analysis. RESULTS: We found that EOFAZ completely prevented LPS-induced HAEC activation and inflammation in vitro and in vivo, as assessed by expression of endothelial adhesion molecules, ICAM-1 and VCAM-1. Similarly, EOFAZ significantly blunted LPS-induced endothelial injury, as tested by MTT assay, LDH release and caspase-3 activation. We further demonstrated that TLR4-dependent NF-κB signaling may be involved in the process. CONCLUSION: EOFAZ protected against LPS-induced endothelial cell injury and inflammation likely via inhibition of TLR4-dependent NF-κB signaling.