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1.
Inorg Chem ; 63(16): 7464-7472, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38598182

RESUMEN

Uranium accumulation in the kidneys and bones following internal contamination results in severe damage, emphasizing the pressing need for the discovery of actinide decorporation agents with efficient removal of uranium and low toxicity. In this work, cinnamic acid (3-phenyl-2-propenoic acid, CD), a natural aromatic carboxylic acid, is investigated as a potential uranium decorporation ligand. CD demonstrates markedly lower cytotoxicity than that of diethylenetriaminepentaacetic acid (DTPA), an actinide decorporation agent approved by the FDA, and effectively removes approximately 44.5% of uranyl from NRK-52E cells. More importantly, the results of the prompt administration of the CD solution remove 48.2 and 27.3% of uranyl from the kidneys and femurs of mice, respectively. Assessments of serum renal function reveal the potential of CD to ameliorate uranyl-induced renal injury. Furthermore, the single crystal of CD and uranyl compound (C9H7O2)2·UO2 (denoted as UO2-CD) reveals the formation of uranyl dimers as secondary building units. Thermodynamic analysis of the solution shows that CD coordinates with uranyl to form a 2:1 molar ratio complex at a physiological pH of 7.4. Density functional theory (DFT) calculations further show that CD exhibits a significant 7-fold heightened affinity for uranyl binding in comparison to DTPA.


Asunto(s)
Cinamatos , Uranio , Cinamatos/química , Cinamatos/farmacología , Animales , Ligandos , Ratones , Uranio/química , Uranio/metabolismo , Uranio/toxicidad , Riñón/efectos de los fármacos , Riñón/metabolismo , Línea Celular , Teoría Funcional de la Densidad , Ratas , Estructura Molecular , Supervivencia Celular/efectos de los fármacos , Quelantes/química , Quelantes/farmacología , Quelantes/síntesis química
2.
Int J Nanomedicine ; 19: 3611-3622, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38660022

RESUMEN

Background: Mangiferin (MA), a bioactive C-glucosyl xanthone with a wide range of interesting therapeutic properties, has recently attracted considerable attention. However, its application in biomedicine is limited by poor solubility and bioavailability. Carbon dots (CDs), novel nanomaterials, have immense promise as carriers for improving the biopharmaceutical properties of active components because of their outstanding characteristics. Methods: In this study, a novel water-soluble carbon dot (MC-CDs) was prepared for the first time from an aqueous extract of Moutan Cortex Carbonisata, and characterized by various spectroscopies, zeta potential and high-resolution transmission electron microscopy (HRTEM). The toxicity effect was investigated using the CCK-8 assay in vitro. In addition, the potential of MC-CDs as carriers for improving the pharmacokinetic parameters was evaluated in vivo. Results: The results indicated that MC-CDs with a uniform spherical particle size of 1-5 nm were successfully prepared, which significantly increased the solubility of MA in water. The MC-CDs exhibited low toxicity in HT-22 cells. Most importantly, the MC-CDs effectively affected the pharmacokinetic parameters of MA in normal rats. UPLC-MS analysis indicated that the area under the maximum blood concentration of MA from mangiferin-MC-CDs (MA-MC-CDs) was 1.6-fold higher than that from the MA suspension liquid (MA control) after oral administration at a dose of 20 mg/kg. Conclusion: Moutan Cortex-derived novel CDs exhibited superior performance in improving the solubility and bioavailability of MA. This study not only opens new possibilities for the future clinical application of MA but also provides evidence for the development of green biological carbon dots as a drug delivery system to improve the biopharmaceutical properties of insoluble drugs.


Asunto(s)
Disponibilidad Biológica , Carbono , Paeonia , Tamaño de la Partícula , Ratas Sprague-Dawley , Solubilidad , Xantonas , Xantonas/farmacocinética , Xantonas/química , Xantonas/administración & dosificación , Animales , Carbono/química , Carbono/farmacocinética , Masculino , Ratas , Paeonia/química , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/administración & dosificación , Puntos Cuánticos/química , Puntos Cuánticos/toxicidad , Línea Celular , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Supervivencia Celular/efectos de los fármacos
3.
J Mater Chem B ; 12(16): 4039-4052, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38591157

RESUMEN

Clear cell renal cell carcinoma (ccRCC) is a disease with high incidence and poor prognosis. The conventional treatment involves radiotherapy and chemotherapy, but chemotherapeutic agents are often associated with side effects, i.e., cytotoxicity to nontumor cells. Therefore, there is an urgent need for the development of novel therapeutic strategies for ccRCC. We synthesized spherical P/TiO2 nanoparticles (P/TiO2 NPs) by vaporization phosphorization (VP). X-ray photoelectron spectroscopy (XPS) and ultraviolet-visible diffuse reflectance spectroscopy (UV-Vis DRS) analyses confirmed that the anatase TiO2 surface was successfully doped with phosphorus and produced a large number of oxygen vacancies (OV). Serving as a photosensitizer, P/TiO2 NPs not only extended the photoresponse range to the near-infrared II region (NIR II) but also introduced a donor energy level lower than the TiO2 conduction band, narrowing the band gap, which could facilitate the migration of photogenerated charges and trigger the synergistic treatment of photodynamic therapy (PDT) and photothermal therapy (PTT). During NIR irradiation in vitro, the P/TiO2 NPs generated local heat and various oxygen radicals, including 1O2, ˙O2-, H2O2, and ˙OH, which damaged the ccRCC cells. In vivo, administration of the P/TiO2 NPs + NIR reduced the tumor volume by 80%, and had the potential to inhibit tumor metastasis by suppressing intratumor neoangiogenesis. The P/TiO2 NPs showed superior safety and efficacy relative to the conventional chemotherapeutic agent used in ccRCC treatment. This study introduced an innovative paradigm for renal cancer treatment, highlighting the potential of P/TiO2 NPs as safe and effective nanomaterials and presenting a compelling new option for clinical applications in anticancer therapy.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Nanocompuestos , Fósforo , Fotoquimioterapia , Terapia Fototérmica , Titanio , Titanio/química , Titanio/farmacología , Fósforo/química , Humanos , Animales , Nanocompuestos/química , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/terapia , Ratones , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales , Tamaño de la Partícula , Línea Celular Tumoral
4.
Int J Pharm ; 656: 124086, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38580074

RESUMEN

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.


Asunto(s)
Portadores de Fármacos , Ivermectina , Lípidos , Nanoestructuras , Humanos , Ivermectina/administración & dosificación , Ivermectina/química , Ivermectina/farmacocinética , Ivermectina/farmacología , Animales , Portadores de Fármacos/química , Lípidos/química , Células K562 , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Sinergismo Farmacológico , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacos , Masculino , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Limoninas/administración & dosificación , Limoninas/farmacología , Limoninas/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Ratas
5.
J Ethnopharmacol ; 330: 118188, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38608797

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The species Jatropha gossypiifolia, popularly known as "pinhão-roxo", is distributed throughout Brazil, is commonly employed for topical or oral administration in treating wounds, inflammations, and snake bites. Given the significant impact of snakebites on public health and the limitations of antivenom, coupled with the diverse molecular composition of this plant species, investigating its healing and antidermonecrotic capacities is relevant. AIM OF THE STUDY: This study aimed to develop a topical nanoemulsion incorporating the hydroethanolic extract of J. gossypiifolia leaves, to evaluate its therapeutic potential, particularly in terms of its efficacy in wound healing and inhibition of dermonecrosis induced by B. erythromelas venom (BeV). MATERIAL AND METHODS: The extract of J. gossypiifolia (JgE) leaves was obtained by maceration and remaceration. The phytochemical analysis was conducted and J. gossypiifolia nanoemulsion (JgNe) was obtained, characterized and assessed for stability. The cytotoxicity was determined in normal cells (erythrocytes and 3T3) using hemolytic assay and cell viability assay using crystal violet staining. The antioxidant activity was evaluated by the reduction of ABTS and DPPH radicals. The evaluation of wound healing was conducted in vivo following treatment with JgNe, wherein the percentage of wound closure and inflammatory mediators. The skin irritation test was assessed in vivo by applying JgNe directly to the animal's skin. In vitro, the antivenom capacity was evaluated through enzymatic inhibition assays (phospholipase A2 and hyaluronidase) of BeV. Additionally, the in vivo antidermonecrotic activity of JgNe was evaluated by measuring the reduction of the dermonecrotic halo. RESULTS: The HPLC-DAD analysis identified flavonoids, specifically vitexin, luteolin derivatives and apigenin derivatives. In addition, 95.08 ± 5.46 mg of gallic acid/g of extract and 137.92 ± 0.99 mg quercetin/g extract, was quantified. JgNe maintained stability over a 4-week period. Moreover, JgE and JgNe demonstrated no cytotoxicity in human erythrocytes and murine fibroblasts at tested concentrations (32.25-250 µg/mL). Additionally, exhibited significant antioxidant activity by reducing ABTS and DPPH radicals. The treatment with JgNe did not induce skin irritation and accelerated wound healing, with significant wound closure observed from 5th day and reduction in nitrite levels, myeloperoxidase activity, and cytokine. Both JgE and JgNe demonstrated in vitro inhibition of the phospholipase and hyaluronidase enzymes of BeV. Moreover, JgNe exhibited antidermonecrotic activity by reducing the dermonecrotic halo caused by BeV after 24 h. CONCLUSIONS: JgNe and JgE exhibited no cytotoxicity at the tested concentrations. Additionally, our findings demonstrate that JgNe has the ability to accelerate wound closure and reduce dermonecrosis caused by BeV, indicating to be promising formulation for complementary therapy to antivenom treatment.


Asunto(s)
Bothrops , Venenos de Crotálidos , Emulsiones , Necrosis , Extractos Vegetales , Hojas de la Planta , Cicatrización de Heridas , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Cicatrización de Heridas/efectos de los fármacos , Hojas de la Planta/química , Venenos de Crotálidos/toxicidad , Ratones , Masculino , Necrosis/tratamiento farmacológico , Piel/efectos de los fármacos , Piel/patología , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Células 3T3 , Hemólisis/efectos de los fármacos , Ratas Wistar , Nanopartículas/química , Serpientes Venenosas
6.
J Ethnopharmacol ; 330: 118187, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38615699

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Bryonia dioica Jacq., Evernia prunastri (L.) Ach., Telephium imperati L., and Aristolochia longa L. are species widely used in traditional medicine to treat several diseases including cancer. Conjugation of two or more extracts is an approach to improve the effectiveness of their pharmacological activities. AIM OF THE STUDY: To evaluate the synergistic anticancer and anti-angiogenic effects of medicinal plants and edible species combinations. MATERIALS AND METHODS: In this work, B. dioica, E. prunastri, Telephium imperati, and Aristolochia longa extracts were conjugated to form four mixtures. The antiproliferative effect of mixtures on several carcinoma cells was examined by MTT assay, and the antiangiogenic activity was estimated through Hen's egg test in vivo. Moreover, in an Ovo model, 35 fertilized Ross eggs were used to test the embryotoxicity of mixtures. RESULTS: At the highest concentration of 200 µg/mL, both mixtures exerted an important cytotoxic effect against human carcinoma cells. The mixture BETE (Bryonia Evernia Telephium Extract) significantly reduced HT-29, PC-3, and A-549 cell viability. Likewise, this mixture strongly suppressed vascularization in vivo at 200 µg/mL. Interestingly, no signs of toxicity on Perdix embryos were recorded within 21 days of treatment. More importantly, the mixture did not have any cytotoxic effect on non cancerous cells. CONCLUSION: Taken together, our results suggest that the synergy between B. dioica, E. prunastri and T. imperati may be promising for developing new anti-cancer treatments.


Asunto(s)
Inhibidores de la Angiogénesis , Antineoplásicos Fitogénicos , Sinergismo Farmacológico , Extractos Vegetales , Plantas Medicinales , Especias , Inhibidores de la Angiogénesis/farmacología , Animales , Humanos , Plantas Medicinales/química , Extractos Vegetales/farmacología , Línea Celular Tumoral , Embrión de Pollo , Antineoplásicos Fitogénicos/farmacología , Argelia , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Pollos
7.
J Ethnopharmacol ; 330: 118206, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38636572

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Croton argyrophyllus Kunth., commonly known as "marmeleiro" or "cassetinga," is widely distributed in the Brazilian Northeast region. Its leaves and flowers are used in traditional medicine as tranquilizers to treat flu and headaches. AIM OF THE STUDY: This study was conducted to determine the chemical composition and toxicological safety of essential oil from C. argyrophyllus leaves using in vitro and in vivo models. MATERIALS AND METHODS: The chemical composition of the essential oil was determined using a gas chromatograph coupled to a mass spectrometer. Cytotoxicity was tested in the HeLa, HT-29, and MCF-7 cell lines derived from human cells (Homo sapiens) and Vero cell lines derived from monkeys (Cercopithecus aethiops) using the MTT method. Acute toxicity, genotoxicity. Mutagenicity tests were performed in Swiss mice (Mus musculus), which were administered essential oil orally in a single dose of 2000 mg/kg by gavage. RESULTS: The main components of the essential oil were p-mentha-2-en-1-ol, α-terpineol, ß-caryophyllene, and ß-elemene. The essential oil exhibited more than 90% cytotoxicity in all cell lines tested. No deaths or behavioral, hematological, or biochemical changes were observed in mice, revealing no acute toxicity. In genotoxic and mutagenic analyses, there was no increase in micronuclei in polychromatic erythrocytes or in the damage and index in the comet assay. CONCLUSIONS: The essential oil was cytotoxic towards the tested cell lines but did not exert toxic effects or promote DNA damage when administered orally at a single dose of 2000 mg/kg in mice.


Asunto(s)
Croton , Aceites Volátiles , Hojas de la Planta , Animales , Croton/química , Aceites Volátiles/toxicidad , Aceites Volátiles/farmacología , Aceites Volátiles/química , Humanos , Chlorocebus aethiops , Ratones , Células Vero , Pruebas de Mutagenicidad , Administración Oral , Células HeLa , Células HT29 , Células MCF-7 , Masculino , Femenino , Supervivencia Celular/efectos de los fármacos , Pruebas de Toxicidad Aguda , Daño del ADN/efectos de los fármacos
8.
J Ethnopharmacol ; 330: 118197, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38636579

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Alternanthera sessilis (L.) R. Br. ex DC., Eryngium foetidum L., and Stephania japonica (Thunb.) Miers plants are traditionally used to treat various central nervous system disorders like paralysis, epilepsy, seizure, convulsion, chronic pain, headache, sleep disturbances, sprain, and mental disorders. However, their possible neuroprotective effects have not been evaluated experimentally so far. AIM OF THE STUDY: The study aims to examine the neuroprotective potential of the three plants against cytotoxicity induced by rotenone in SH-SY5Y neuroblastoma cells and assess its plausible mechanisms of neuroprotection. MATERIALS AND METHODS: The antioxidant properties of the plant extracts were determined chemically by DPPH and ABTS assay methods. The cytotoxicity of rotenone and the cytoprotective activities of the extracts were evaluated using MTT assays. Microtubule-associated protein 2 (MAP2) expression studies in cells were performed to assess neuronal survival after rotenone and extract treatments. Mitochondrial membrane potential and intracellular levels of reactive oxygen species were evaluated using Rhodamine 123 and DCF-DA dye, respectively. Catalase, glutathione peroxidase, and superoxide dismutase activities were also measured. Apoptotic nuclei were examined using DAPI staining. Liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS) analysis of the plant extracts was also performed. RESULTS: The methanol extracts of A. sessilis, S. japonica, and E. foetidum showed excellent free radical scavenging activities. MAP2 expression studies show that A. sessilis and S. japonica have higher neuroprotective effects against rotenone-induced neurotoxicity in SH-SY5Y cells than E. foetidum. Pre-treating cells with the plant extracts reverses the rotenone-induced increase in intracellular ROS. The plant extracts could also restore the reduced mitochondrial membrane potential induced by rotenone treatment and reinstate rotenone-induced increases in catalase, glutathione peroxidase, and superoxide dismutase activities. All the extracts inhibited rotenone-induced changes in nuclear morphology and DNA condensation, an early event of cellular apoptosis. LC-QTOF-MS analysis of the plant extracts shows the presence of neuroprotective compounds. CONCLUSIONS: The plant extracts showed neuroprotective activities against rotenone-treated SH-SY5Y cells through antioxidant and anti-apoptotic mechanisms. These findings support the ethnopharmacological uses of these plants in treating neurological disorders. They probably are a good source of neuroprotective compounds that could be further explored to develop treatment strategies for neurodegenerative diseases like Parkinson's disease.


Asunto(s)
Neuroblastoma , Fármacos Neuroprotectores , Extractos Vegetales , Plantas Medicinales , Rotenona , Rotenona/toxicidad , Humanos , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/química , Línea Celular Tumoral , Plantas Medicinales/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Medicina Tradicional/métodos , Proteínas Asociadas a Microtúbulos/metabolismo , Estrés Oxidativo/efectos de los fármacos
9.
J Ethnopharmacol ; 329: 118178, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38604511

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is widely used clinically as one of the most famous traditional Chinese herbs. Its herb roasted with honey is called honey-processed licorice (HPL). Modern studies have shown that HPL has a stronger cardioprotective ability compared to raw licorice (RL), however the material basis and mechanism of action of the potential cardioprotection have not been fully elucidated. AIM OF THE STUDY: To screen and validate the material basis of cardioprotection exerted by HPL and to preliminarily predict the potential mechanism of action. MATERIALS AND METHODS: UPLC-QTOF-MS/MS was used to analyze HPL samples with different processing levels, and differential compounds were screened out through principal component analysis. Network pharmacology and molecular docking were applied to explore the association between differential compounds and doxorubicin cardiomyopathy and their mechanisms of action were predicted. An in vitro model was established to verify the cardioprotective effects of differential compounds. RESULTS: Six differential compounds were screened as key components of HPL for potential cardioprotection. Based on network pharmacology, 113 potential important targets for the treatment of Dox-induced cardiotoxicity were screened. KEGG enrichment analysis predicted that the PI3K-Akt pathway was closely related to the mechanism of action of active ingredients. Molecular docking results showed that the six differential compounds all had good binding activity with Nrf2 protein. In addition, in vitro experiments had shown that five of the active ingredients (liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, and licochalcone A) can significantly increase Dox-induced H9c2 cell viability, SOD activity, and mitochondrial membrane potential, significantly reduces MDA levels and inhibits ROS generation. CONCLUSION: Liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin and licochalcone A are key components of HPL with potential cardioprotective capabilities. Five active ingredients can alleviate Dox-induced cardiotoxicity by inhibiting oxidative stress and mitochondrial damage.


Asunto(s)
Doxorrubicina , Miel , Simulación del Acoplamiento Molecular , Miocitos Cardíacos , Farmacología en Red , Doxorrubicina/toxicidad , Animales , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratas , Chalconas/farmacología , Chalconas/aislamiento & purificación , Glycyrrhiza uralensis/química , Cardiotónicos/farmacología , Cardiotónicos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Flavanonas/farmacología , Flavanonas/aislamiento & purificación , Factor 2 Relacionado con NF-E2/metabolismo , Línea Celular , Cardiotoxicidad/prevención & control , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Espectrometría de Masas en Tándem , Transducción de Señal/efectos de los fármacos , Glucósidos
10.
Bioorg Chem ; 147: 107375, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38636437

RESUMEN

The dried fruit of Amomum villosum is an important spice and medicinal plant that has received great attention in recent years due to its high content of bioactive components and its potential for food additives and drug development. However, the stems and leaves of A. villosum are usually disposed of as waste. Based on the study of the fruits of A. villosum, we also systematically studied its stems and leaves. Fourteen aromatic compounds (1-14) were isolated and identified from A. villosum, including five new compounds (1-5) and nine known compounds (6-14). Among them, compounds 2-5, 8-10, 12-13 were obtained from the fruits of A. villosum, and compounds 1, 6-7,11, 14 were isolated from the stems and leaves of A. villosum. Based on chemical evidence and spectral data analysis (UV, ECD, Optical rotation data, 1D and 2D-NMR, and HR-ESI-MS), the structures of new compounds were elucidated. Furthermore, all compounds were tested for their effects on the survival rate of BV-2 cells in the presence of hydrogen peroxide. Among them, compound 5 showed antioxidant effects. Through network pharmacology screening and the cell thermal shift assay (CETSA), the Phosphoglycerate Mutase 5 (PGAM5) protein was identified as the antioxidant target of compound 5. Molecular docking results showed that compound 5 maintains binding to PGAM5 by forming hydrogen bond interactions with Lys93 and Agr214. In summary, A. villosum had potential medicinal and food values due to the diverse bioactive components.


Asunto(s)
Amomum , Antioxidantes , Simulación del Acoplamiento Molecular , Amomum/química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacos , Humanos , Animales , Hojas de la Planta/química
11.
Nanotechnology ; 35(29)2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38593752

RESUMEN

Melanoma is one of the most aggressive and lethal types of cancer owing to its metastatic propensity and chemoresistance property. An alternative therapeutic option is photodynamic and photothermal therapies (PDT/PTT), which employ near-infrared (NIR) light to generate heat and reactive oxygen species (ROS). As per previous reports, Melanin (Mel), and its synthetic analogs (i.e. polydopamine nanoparticles) can induce NIR light-mediated heat energy, thereby selectively targeting and ameliorating cancer cells. Similarly, chlorin e6 (Ce6) also has high ROS generation ability and antitumor activity against various types of cancer. Based on this tenet, In the current study, we have encapsulated Mel-Ce6 in a polydopamine (PDA) nanocarrier (MCP NPs) synthesized by the oxidation polymerization method. The hydrodynamic diameter of the synthesized spherical MCP NPs was 139 ± 10 nm. The MCP NPs, upon irradiation with NIR 690 nm laser for 6 min, showed photothermal efficacy of more than 50 °C. Moreover, the red fluorescence in the MCP NPs due to Ce6 can be leveraged for diagnostic purposes. Further, the MCP NPs exhibited considerable biocompatibility with the L929 cell line and exerted nearly 70% ROS-mediated cytotoxicity on the B16 melanoma cell line after the laser irradiation. Thus, the prepared MCP NPs could be a promising theranostic agent for treating the B16 melanoma cancer.


Asunto(s)
Clorofilidas , Indoles , Melaninas , Melanoma Experimental , Nanopartículas , Polímeros , Porfirinas , Indoles/química , Indoles/farmacología , Polímeros/química , Polímeros/farmacología , Nanopartículas/química , Animales , Ratones , Melanoma Experimental/patología , Melanoma Experimental/terapia , Línea Celular Tumoral , Porfirinas/química , Porfirinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Fototerapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fotoquimioterapia/métodos , Terapia Fototérmica
12.
Phytomedicine ; 128: 155412, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38579666

RESUMEN

BACKGROUND: Psoriasis is a long-lasting, inflammatory, continuous illness caused through T cells and characterized mainly by abnormal growth and division of keratinocytes. Currently, corticosteroids are the preferred option. However, prolonged use of traditional topical medication can lead to adverse reactions and relapse, presenting a significant therapeutic obstacle. Improved alternative treatment options are urgently required. Formononetin (FMN) is a representative component of isoflavones in Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.]. It possesses properties that reduce inflammation, combat oxidation, inhibit tumor growth, and mimic estrogen. Although FMN has been shown to ameliorate skin barrier devastation via regulating keratinocyte apoptosis and proliferation, there are no reports of its effectiveness in treating psoriasis. OBJECTIVE: Through transcriptomics clues and experimental investigation, we aimed to elucidate the fundamental mechanisms underlying FMN's action on psoriasis. MATERIALS AND METHODS: Cell viability was examined using CCK8 assay in this study. The results of analysis of differentially expressed genes (DEGs) between FMN-treated HaCaT cells and normal HaCaT cells using RNA-sequencing (RNA-seq) were presented on volcano plots and heatmap. Enrichment analysis was conducted on DEGs using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), and results were validated through RT-qPCR verification. After 12 days of FMN treatment in psoriasis mouse model, we gauged the PASI score and epidermis thickness. A variety of techniques were used to assess FMN's effectiveness on inhibiting inflammation and proliferation related to psoriasis, including RT-qPCR, HE staining, western blot, and immunohistochemistry (IHC). RESULTS: The findings indicated that FMN could suppress the growth of HaCaT cells using CCK8 assay (with IC50 = 40.64 uM) and 20 uM FMN could reduce the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to the greatest extent. FMN-treated HaCaT cells exhibited 985 up-regulated and 855 down-regulated DEGs compared to normal HaCaT cells. GO analysis revealed that DEGs were linked to interferon (IFN) signaling pathway. Furthermore, FMN improved pathological features, which encompassed decreased erythema, scale, and thickness scores of skin lesions in psoriasis mouse model. In vivo experiments confirmed that FMN down-regulated expression of IFN-α, IFN-ß, IFN-γ, decreased secretion of TNF-α and IL-17 inflammatory factors, inhibited expression of IFN-related chemokines included Cxcl9, Cxcl10, Cxcl11 and Cxcr3 and reduced expression of transcription factors p-STAT1, p-STAT3 and IFN regulatory factor 1 (IRF1) in the imiquimod (IMQ) group. CONCLUSIONS: In summary, these results suggested that FMN played an anti-inflammatory and anti-proliferative role in alleviating psoriasis by inhibiting IFN signaling pathway, and FMN could be used as a potential therapeutic agent.


Asunto(s)
Células HaCaT , Isoflavonas , Psoriasis , Transducción de Señal , Isoflavonas/farmacología , Psoriasis/tratamiento farmacológico , Animales , Transducción de Señal/efectos de los fármacos , Humanos , Ratones , Interferones , Supervivencia Celular/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Inflamación/tratamiento farmacológico , Astragalus propinquus/química , Ratones Endogámicos BALB C , Masculino , Modelos Animales de Enfermedad
13.
Biosci Trends ; 18(2): 153-164, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38599881

RESUMEN

NAD(P)H-quinone oxidoreductase 1 (NQO1) is an essential redox enzyme responsible for redox balance and energy metabolism. Despite of its importance, the brain contains high capacity of polyunsaturated fatty acids and maintains low levels of NQO1 expression. In this study, we examined how levels of NQO1 expression affects cell survival in response to toxic insults causing mitochondrial dysfunction and ferroptosis, and whether NQO1 has a potential as a biomarker in different stressed conditions. Following treatment with rotenone, overexpressed NQO1 in SH-SY5Y cells improved cell survival by reducing mitochondrial reductive stress via increased NAD+ supply without mitochondrial biogenesis. However, NQO1 overexpression boosted lipid peroxidation following treatment with RSL3 and erastin. A lipid droplet staining assay showed increased lipid droplets in cells overexpressing NQO1. In contrast, NQO1 knockdown protected cells against ferroptosis by increasing GPX4, xCT, and the GSH/GSSG system. Also, NQO1 knockdown showed lower iron contents and lipid droplets than non-transfectants and cells overexpressing NQO1, even though it could not attenuate cell death when exposed to rotenone. In summary, our study suggests that different NQO1 levels may have advantages and disadvantages depending on the surrounding environments. Thus, regulating NQO1 expression could be a potential supplementary tool when treating neuronal diseases.


Asunto(s)
Ferroptosis , Mitocondrias , NAD(P)H Deshidrogenasa (Quinona) , Rotenona , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Ferroptosis/efectos de los fármacos , Humanos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Rotenona/toxicidad , Rotenona/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Piperazinas/farmacología , Carbolinas
14.
Int J Biol Macromol ; 268(Pt 2): 131365, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38583829

RESUMEN

Wounds are considered one of the most critical medical conditions that must be managed appropriately due to the psychological and physical stress they cause for patients, as well as creating a substantial financial burden on patients and global healthcare systems. Nowadays, there is a growing interest in developing nanofiber mats loaded with varying plant extracts to meet the urgent need for advanced wound ressings. This study investigated the development and characterization of poly(lactic acid) (PLA)/ poly(ethylene glycol) (PEG) nanofiber membranes incorporated with Ora-pro-nóbis (OPN; 12.5, 25, and 50 % w/w) by the solution-blow-spinning (SBS) technique. The PLA/PEG and PLA/PEG/OPN nanofiber membranes were characterized by scanning electron microscopy (SEM), thermal properties (TGA and DSC), Fourier transform infrared spectroscopy (FTIR), contact angle measurements and water vapor permeability (WVTR). In addition, the mats were analyzed for swelling properties in vitro cell viability, and fibroblast adhesion (L-929) tests. SEM images showed that smooth and continuous PLA/PEG and PLA/PEG/OPN nanofibers were obtained with a diameter distribution ranging from 171 to 1533 nm. The PLA/PEG and PLA/PEG/OPN nanofiber membranes showed moderate hydrophobicity (~109-120°), possibly preventing secondary injuries during dressing removal. Besides that, PLA/PEG/OPN nanofibers exhibited adequate WVTR, meeting wound healing requirements. Notably, the presence of OPN gave the PLA/PEG membranes better mechanical properties, increasing their tensile strength (TS) from 3.4 MPa (PLA/PEG) to 5.3 MPa (PLA/PEG/OPN), as well as excellent antioxidant properties (Antioxidant activity with approximately 45 % oxidation inhibition). Therefore, the nanofiber mats based on PLA/PEG, especially those incorporated with OPN, are promising options for use as antioxidant dressings to aid skin healing.


Asunto(s)
Vendajes , Membranas Artificiales , Nanofibras , Extractos Vegetales , Poliésteres , Polietilenglicoles , Polietilenglicoles/química , Poliésteres/química , Nanofibras/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Ratones , Permeabilidad , Supervivencia Celular/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier , Antioxidantes/química , Antioxidantes/farmacología , Línea Celular , Cicatrización de Heridas/efectos de los fármacos , Fibroblastos/efectos de los fármacos
15.
Phytomedicine ; 129: 155631, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38640858

RESUMEN

BACKGROUND: The utilization of Chinese medicine as an adjunctive therapy for cancer has recently gained significant attention. Ferroptosis, a newly regulated cell death process depending on the ferrous ions, has been proved to be participated in glioma stem cells inactivation. PURPOSE: We aim to study whether ginsenoside Rg5 exerted inhibitory effects on crucial aspects of glioma stem cells, including cell viability, tumor initiation, invasion, self-renewal ability, neurosphere formation, and stemness. METHODS: Through comprehensive sequencing analysis, we identified a compelling association between ginsenoside Rg5 and the ferroptosis pathway, which was further validated through subsequent experiments demonstrating its ability to activate this pathway. RESULTS: To elucidate the precise molecular targets affected by ginsenoside Rg5 in gliomas, we conducted an intersection analysis between differentially expressed genes obtained from sequencing and a database-predicted list of transcription factors and potential targets of ginsenoside Rg5. This rigorous approach led us to unequivocally confirm NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1) as a direct target of ginsenoside Rg5, a finding consistently supported by subsequent experimental investigations. Moreover, we uncovered NR3C1's capacity to transcriptionally regulate ferroptosis -related genes HSPB1 and NCOA4. Strikingly, ginsenoside Rg5 induced notable alterations in the expression levels of both HSPB1 (Heat Shock Protein Family B Member 1) and NCOA4 (Nuclear Receptor Coactivator 4). Finally, our intracranial xenograft assays served to reaffirm the inhibitory effect of ginsenoside Rg5 on the malignant progression of glioblastoma. CONCLUSION: These collective findings strongly suggest that ginsenoside Rg5 hampers glioblastoma progression by activating ferroptosis through NR3C1, which subsequently modulates HSPB1 and NCOA4. Importantly, this novel therapeutic direction holds promise for advancing the treatment of glioblastoma.


Asunto(s)
Ferroptosis , Ginsenósidos , Glioblastoma , Ginsenósidos/farmacología , Ferroptosis/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Animales , Línea Celular Tumoral , Coactivadores de Receptor Nuclear/metabolismo , Ratones , Ratones Desnudos , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico
16.
Med Oncol ; 41(5): 123, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38652404

RESUMEN

Colon cancer is on the rise in both men and women. In addition to traditional treatment methods, herbal treatments from complementary and alternative medicine are actively followed. Naturally derived from plants, thymoquinone (TQ) has drawn a lot of attention in the field of cancer treatment. MK-801, an N-methyl-D-aspartate agonist, is used to improve memory and plasticity, but it has also lately been explored as a potential cancer treatment. This study aimed to determine the roles of N-Methyl-D-Aspartate agonists and Thymoquinone on mitochondria and apoptosis. HT-29 cells were treated with different TQ and MK-801 concentrations. We analyzed cell viability, apoptosis, and alteration of mitochondria. Cell viability significantly decreased depending on doses of TQ and MK-801. Apoptosis and mitochondrial dysfunctions induced by low and high doses of TQ and MK-801. Our study emphasizes the need for further safety evaluation of MK-801 due to the potential toxicity risk of TQ and MK-801. Optimal and toxic doses of TQ and MK-801 were determined for the treatment of colon cancer. It should be considered as a possibility that colon cancer can be treated with TQ and MK-801.


Asunto(s)
Apoptosis , Benzoquinonas , Supervivencia Celular , Neoplasias Colorrectales , Maleato de Dizocilpina , Mitocondrias , Receptores de N-Metil-D-Aspartato , Humanos , Benzoquinonas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Células HT29 , Maleato de Dizocilpina/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Supervivencia Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos
17.
J Integr Med ; 22(3): 295-302, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38599914

RESUMEN

OBJECTIVE: The effects of arsenic trioxide (As2O3) on hepatocellular carcinoma have been documented widely. Autophagy plays dual roles in the survival and death of cancer cells. Therefore, we investigated the exact role of autophagy in As2O3-induced apoptosis in liver cancer cells. METHODS: The viability of hepatoma cells was determined using the MTT assay with or without fetal bovine serum. The rate of apoptosis in liver cancer cells treated with As2O3 was evaluated using flow cytometry, Hoechst 33258 staining, and TUNEL assays. The rate of autophagy among liver cancer cells treated with As2O3 was detected using immunofluorescence, Western blot assay and transmission electron microscopy. RESULTS: Upon treatment with As2O3, the viability of HepG2 and SMMC-7721 cells was decreased in a time- and dose-dependent manner. The apoptosis rates of both liver cancer cell lines increased with the concentration of As2O3, as shown by flow cytometry. Apoptosis in liver cancer cells treated with As2O3 was also shown by the activation of the caspase cascade and the regulation of Bcl-2/Bax expression. Furthermore, As2O3 treatment induced autophagy in liver cancer cells; this finding was supported by Western blot, immunofluorescence of LC3-II and beclin 1, and transmission electron microscopy. In liver cancer cells, As2O3 inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway that plays a vital role in both apoptosis and autophagy. The PI3K activator SC-79 partially reversed As2O3-induced autophagy and apoptosis. Furthermore, inhibiting autophagy with 3-methyladenine partially reversed the negative effects of As2O3 on cell viability. Serum starvation increased autophagy and amplified the effect of As2O3 on cell death. CONCLUSION: As2O3 induces apoptosis and autophagy in liver cancer cells. Autophagy induced by As2O3 may have a proapoptotic effect that helps to reduce the viability of liver cancer cells. This study provides novel insights into the effects of As2O3 against liver cancer. Please cite this article as: Deng ZT, Liang SF, Huang GK, Wang YQ, Tu XY, Zhang YN, Li S, Liu T, Cheng BB. Autophagy plays a pro-apoptotic role in arsenic trioxide-induced cell death of liver cancer. J Integr Med. 2024; 22(3): 295-302.


Asunto(s)
Antineoplásicos , Apoptosis , Trióxido de Arsénico , Arsenicales , Autofagia , Neoplasias Hepáticas , Óxidos , Trióxido de Arsénico/farmacología , Humanos , Autofagia/efectos de los fármacos , Arsenicales/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Apoptosis/efectos de los fármacos , Óxidos/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Células Hep G2 , Supervivencia Celular/efectos de los fármacos
18.
Angew Chem Int Ed Engl ; 63(23): e202400476, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38656762

RESUMEN

The novel hetero-dinuclear complex trans,trans,trans-[PtIV(py)2(N3)2(OH)(µ-OOCCH2CH2CONHCH2-bpyMe)IrIII(ppy)2]Cl (Pt-Ir), exhibits charge transfer between the acceptor photochemotherapeutic Pt(IV) (Pt-OH) and donor photodynamic Ir(III) (Ir-NH2) fragments. It is stable in the dark, but undergoes photodecomposition more rapidly than the Pt(IV) parent complex (Pt-OH) to generate Pt(II) species, an azidyl radical and 1O2. The Ir(III)* excited state, formed after irradiation, can oxidise NADH to NAD⋅ radicals and NAD+. Pt-Ir is highly photocytotoxic towards cancer cells with a high photocytotoxicity index upon irradiation with blue light (465 nm, 4.8 mW/cm2), even with short light-exposure times (10-60 min). In contrast, the mononuclear Pt-OH and Ir-NH2 subunits and their simple mixture are much less potent. Cellular Pt accumulation was higher for Pt-Ir compared to Pt-OH. Irradiation of Pt-Ir in cancer cells damages nuclei and releases chromosomes. Synchrotron-XRF revealed ca. 4× higher levels of intracellular platinum compared to iridium in Pt-Ir treated cells under dark conditions. Luminescent Pt-Ir distributes over the whole cell and generates ROS and 1O2 within 1 h of irradiation. Iridium localises strongly in small compartments, suggestive of complex cleavage and excretion via recycling vesicles (e.g. lysosomes). The combination of PDT and PACT motifs in one molecule, provides Pt-Ir with a novel strategy for multimodal phototherapy.


Asunto(s)
Antineoplásicos , Iridio , Fotoquimioterapia , Fármacos Fotosensibilizantes , Platino (Metal) , Iridio/química , Iridio/farmacología , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Platino (Metal)/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Estructura Molecular , Supervivencia Celular/efectos de los fármacos
19.
Phytomedicine ; 129: 155570, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38579645

RESUMEN

BACKGROUND: Energy deficiency and oxidative stress are interconnected during ischemia/reperfusion (I/R) and serve as potential targets for the treatment of cerebral ischemic stroke. Baicalin is a neuroprotective antioxidant, but the underlying mechanisms are not fully revealed. PURPOSE: This study explored whether and how baicalin rescued neurons against ischemia/reperfusion (I/R) attack by focusing on the regulation of neuronal pyruvate dehydrogenase kinase 2 (PDK2)-pyruvate dehydrogenase (PDH) axis implicated with succinate dehydrogenase (SDH)-mediated oxidative stress. STUDY DESIGN: The effect of the tested drug was explored in vitro and in vivo with the model of oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/reperfusion (MCAO/R), respectively. METHODS: Neuronal damage was evaluated according to cell viability, infarct area, and Nissl staining. Protein levels were measured by western blotting and immunofluorescence. Gene expression was investigated by RT-qPCR. Mitochondrial status was also estimated by fluorescence probe labeling. RESULTS: SDH activation-induced excessive production of reactive oxygen species (ROS) changed the protein expression of Lon protease 1 (LonP1) and hypoxia-inducible factor-1ɑ (HIF-1ɑ) in the early stage of I/R, leading to an upregulation of PDK2 and a decrease in PDH activity in neurons and cerebral cortices. Treatment with baicalin prevented these alterations and ameliorated neuronal ATP production and survival. CONCLUSION: Baicalin improves the function of the neuronal PDK2-PDH axis via suppression of SDH-mediated oxidative stress, revealing a new signaling pathway as a promising target under I/R conditions and the potential role of baicalin in the treatment of acute ischemic stroke.


Asunto(s)
Flavonoides , Neuronas , Fármacos Neuroprotectores , Estrés Oxidativo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Daño por Reperfusión , Flavonoides/farmacología , Animales , Daño por Reperfusión/tratamiento farmacológico , Neuronas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Fármacos Neuroprotectores/farmacología , Succinato Deshidrogenasa/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Ratas Sprague-Dawley , Supervivencia Celular/efectos de los fármacos , Ratas , Antioxidantes/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo
20.
Phytomedicine ; 129: 155596, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38626646

RESUMEN

BACKGROUND: Traditional Chinese medicine (TCM) is useful in disease treatment and prevention. Genipin is an active TCM compound used to treat diabetic retinopathy (DR). In this study, a network pharmacology (NP)-based approach was employed to investigate the therapeutic mechanisms underlying genipin administration in DR. METHODS: The potential targets of DR were identified using the gene expression omnibus (GEO) database. TCM database screening and NP were used to predict the potential active targets and pathways of genipin in DR. Cell viability was tested in vitro to determine the effects of different doses of glucose and genipin on Human Retinal Microvascular Endothelial Cells (hRMECs). CCK-8, CCK-F, colony formation, CellTiter-Lum, Annexin V-FITC, wound healing, Transwell, tube-forming, reactive oxygen species (ROS), and other assay kits were used to detect the effects of genipin on hRMECs during high levels of glucose. In vivo, a streptozotocin (STZ)-mouse intraocular genipin injection (IOI.) model was used to explore the effects of genipin on diabetes-induced retinal dysfunction. Western blotting was performed to identify the cytokines involved in proliferation, apoptosis, angiogenesis, ROS, and inflammation. The protein expression of the AKT/ PI3K/ HIF-1α and AGEs/ RAGE pathways was also examined. RESULTS: Approximately 14 types of TCM, and nearly 300 active ingredients, including genipin, were identified. The NP approach successfully identified the HIF-1α and AGEs-RAGE pathways, with the EGR1 and UCP2 genes, as key targets of genipin in DR. In the in vitro and in vivo models, we discovered that high glucose increased cell proliferation, apoptosis, angiogenesis, ROS, and inflammation. However, genipin application regulated cell proliferation and apoptosis, inhibited angiogenesis, and reduced ROS and inflammation in the HRMECs exposed to high glucose. Furthermore, the retinal thickness in the genipin-treated group was lower than that in the untreated group. AKT/ PI3K/ HIF-1α and AGEs/ RAGE signaling was increased by high glucose levels; however, genipin treatment decreased AKT/ PI3K and AGEs/ RAGE pathway expressions. Genipin also increased HIF-1α phosphorylation, oxidative phosphorylation of ATP synthesis, lipid peroxidation, and the upregulation of oxidoreductase. Genipin was found to protect HG-induced hRMECs and the retina of STZ-mice, based on; 1 the inhibition of UCP2 and Glut1 decreased intracellular glucose, and glycosylation; 2 the increased presence of HIF-1α, which increased oxidative phosphorylation and decreased substrate phosphorylation; 3 the increase in oxidative phosphorylation from ATP synthesis increased lipid peroxidation and oxidoreductase activity, and; 4 the parallel effect of phosphorylation and glycosylation on vascular endothelial growth factor (VEGF), MMP9, and Scg3. CONCLUSION: Based on NP, we demonstrated the potential targets and pathways of genipin in the treatment of DR and confirmed its effective molecular mechanism in vitro and in vivo. Genipin protects cells and tissues from high glucose levels by regulating phosphorylation and glycosylation. The activation of the HIF-1α pathway can also be used to treat DR. Our study provides new insights into the key genes and pathways associated with the prognosis and pathogenesis of DR.


Asunto(s)
Diabetes Mellitus Experimental , Retinopatía Diabética , Células Endoteliales , Productos Finales de Glicación Avanzada , Subunidad alfa del Factor 1 Inducible por Hipoxia , Iridoides , Ratones Endogámicos C57BL , Transducción de Señal , Retinopatía Diabética/tratamiento farmacológico , Animales , Iridoides/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Humanos , Productos Finales de Glicación Avanzada/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Ratones , Células Endoteliales/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Retina/efectos de los fármacos , Apoptosis/efectos de los fármacos , Glucosa/metabolismo
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