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1.
Biochem Biophys Res Commun ; 710: 149910, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38593619

RESUMEN

Ginsenoside Rb1 (Rb1), an active component isolated from traditional Chinese medicine Ginseng, is beneficial to many cardiovascular diseases. However, whether it can protect against doxorubicin induced cardiotoxicity (DIC) is not clear yet. In this study, we aimed to investigate the role of Rb1 in DIC. Mice were injected with a single dose of doxorubicin (20 mg/kg) to induce acute cardiotoxicity. Rb1 was given daily gavage to mice for 7 days. Changes in cardiac function, myocardium histopathology, oxidative stress, cardiomyocyte mitochondrion morphology were studied to evaluate Rb1's function on DIC. Meanwhile, RNA-seq analysis was performed to explore the potential underline molecular mechanism involved in Rb1's function on DIC. We found that Rb1 treatment can improve survival rate and body weight in Dox treated mice group. Rb1 can attenuate Dox induced cardiac dysfunction and myocardium hypertrophy and interstitial fibrosis. The oxidative stress increase and cardiomyocyte mitochondrion injury were improved by Rb1 treatment. Mechanism study found that Rb1's beneficial role in DIC is through suppressing of autophagy and ferroptosis. This study shown that Ginsenoside Rb1 can protect against DIC by regulating autophagy and ferroptosis.


Asunto(s)
Cardiotoxicidad , Ferroptosis , Ginsenósidos , Animales , Ratones , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/metabolismo , Cardiotoxicidad/prevención & control , Doxorrubicina/efectos adversos , Doxorrubicina/toxicidad , Ginsenósidos/farmacología , Miocitos Cardíacos/metabolismo , Estrés Oxidativo
2.
Environ Toxicol ; 39(7): 3872-3882, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38558324

RESUMEN

Platycodi radix is a widely used herbal medicine that contains numerous phytochemicals beneficial to health. The health and biological benefits of P. radix have been found across various diseases. The utilization of umbilical cord stromal stem cells, derived from Wharton's jelly of the human umbilical cord, has emerged as a promising approach for treating degenerative diseases. Nevertheless, growing evidence indicates that the function of stem cells declines with age, thereby limiting their regenerative capacity. The primary objective in this study is to investigate the beneficial effects of P. radix in senescent stem cells. We conducted experiments to showcase that diminished levels of Lamin B1 and Sox-2, along with an elevation in p21, which serve as indicative markers for the senescent stem cells. Our findings revealed the loss of Lamin B1 and Sox-2, coupled with an increase in p21, in umbilical cord stromal stem cells subjected to a low-dose (0.1 µM) doxorubicin (Dox) stimulation. However, P. radix restored the Dox-damage in the umbilical cord stromal stem cells. P. radix reversed the senescent conditions when the umbilical cord stromal stem cells exposed to Dox-induced reactive oxygen species (ROS) and mitochondrial membrane potential are significantly changed. In Dox-challenged aged umbilical cord stromal stem cells, P. radix reduced senescence, increased longevity, prevented mitochondrial dysfunction and ROS and protected against senescence-associated apoptosis. This study suggests that P. radix might be as a therapeutic and rescue agent for the aging effect in stem cells. Inhibition of cell death, mitochondrial dysfunction and aging-associated ROS with P. radix provides additional insights into the underlying molecular mechanisms.


Asunto(s)
Senescencia Celular , Doxorrubicina , Mitocondrias , Extractos Vegetales , Especies Reactivas de Oxígeno , Cordón Umbilical , Humanos , Especies Reactivas de Oxígeno/metabolismo , Senescencia Celular/efectos de los fármacos , Cordón Umbilical/citología , Cordón Umbilical/efectos de los fármacos , Extractos Vegetales/farmacología , Doxorrubicina/toxicidad , Doxorrubicina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Platycodon/química , Células Madre Mesenquimatosas/efectos de los fármacos , Células Cultivadas
3.
J Ethnopharmacol ; 329: 118156, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38583729

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Throughout Chinese history, Hydrangea paniculata Siebold has been utilized as a traditional medicinal herb to treat a variety of ailments associated to inflammation. In a number of immune-mediated kidney disorders, total coumarins extracted from Hydrangea paniculata (HP) have demonstrated a renal protective effect. AIM OF THE STUDY: To investigate renal beneficial effect of HP on experimental Adriamycin nephropathy (AN), and further clarify whether reversing lipid metabolism abnormalities by HP contributes to its renoprotective effect and find out the underlying critical pathways. MATERIALS AND METHODS: After establishment of rat AN model, HP was orally administrated for 6 weeks. Biochemical indicators related to kidney injury were determined. mRNAs sequencing using kidney tissues were performed to clarify the underlying mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, western blot, molecular docking, and drug affinity responsive target stability (DARTS) assay was carried out to further explore and confirm pivotal molecular pathways and possible target by which HP and 7-hydroxylcoumarin (7-HC) played their renal protection effect via modulating lipid metabolism. RESULTS: HP could significantly improve renal function, and restore renal tubular abnormal lipid metabolism and interstitial fibrosis in AN. In vitro study demonstrated that HP and its main metabolite 7-HC could reduce ADR-induced intracellular lipid deposition and fibrosis characteristics in renal tubular cells. Mechanically, HP and 7-HC can activate AMP-activated protein kinase (AMPK) via direct interaction, which contributes to its lipid metabolism modulation effect. Moreover, HP and 7-HC can inhibit fibrosis by inhibiting CCAAT/enhancer binding protein beta (C/EBPß) expression in renal tubular cells. Normalization of lipid metabolism by HP and 7-HC further provided protection of mitochondrial structure integrity and inhibited the nuclear factor kappa-B (NF-κB) pathway. Long-term toxicity using beagle dogs proved the safety of HP after one-month administration. CONCLUSION: Coumarin derivates from HP alleviate adriamycin-induced lipotoxicity and fibrosis in kidney through activating AMPK and inhibiting C/EBPß.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Proteína beta Potenciadora de Unión a CCAAT , Cumarinas , Doxorrubicina , Hydrangea , Animales , Doxorrubicina/toxicidad , Cumarinas/farmacología , Cumarinas/aislamiento & purificación , Masculino , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Ratas , Hydrangea/química , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratas Sprague-Dawley , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Enfermedades Renales/prevención & control , Simulación del Acoplamiento Molecular , Metabolismo de los Lípidos/efectos de los fármacos , Línea Celular , Extractos Vegetales/farmacología , Extractos Vegetales/química , Umbeliferonas
4.
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
5.
J Pharm Pharmacol ; 76(4): 405-415, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38241142

RESUMEN

OBJECTIVE: To investigate the mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) protects against doxorubicin (DOX)-induced myocardial injury. METHODS: In vivo experiment, rats were divided into six groups: normal group, model group (15 mg/kg, DOX), Dex group(150 mg/kg, Dex), LGZGD-L group (2.1 g/kg), LGZGD-M group (4.2 g/kg), and LGZGD-H group (8.4 g/kg). We used HE and Masson staining to observe the histopathological changes, echocardiography to assess the cardiac function, and western blot and RT-qPCR to detect the expressions of Nrf2, GPX4, Fpn1, and Ptgs2. In vitro experiment, we used immunofluorescence to detect ROS production, and RT-qPCR to detect gene expression of GPX4, Fpn1, and Ptgs2. KEY FINDINGS: In vivo, LGZGD improved cardiac systolic function. LGZGD significantly reduced MDA, LDH, and CK levels, increased SOD activity, enhanced the protein expression of Nrf2, GPX4, and Fpn1, and decreased Ptgs2 levels. In vitro, LGZGD-containing serum significantly reduced ROS, increased the gene expression of GPX4 and Fpn1, and decreased the gene expression of Ptgs2. Furthermore, compared with the LGZGD (si-NC) group, the LGZGD (si-Nrf2) group had decreased gene expression of Nrf2, GPX4, and Fpn1 and increased gene expression of Ptgs2. CONCLUSIONS: LGZGD can ameliorate DOX-cardiotoxicity by activating the Nrf2 signaling pathway and inhibiting ferroptosis in cardiomyocytes.


Asunto(s)
Ferroptosis , Extractos Vegetales , Ratas , Animales , Ciclooxigenasa 2 , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Doxorrubicina/toxicidad
6.
J Pharm Pharmacol ; 76(4): 391-404, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38289094

RESUMEN

OBJECTIVES: Doxorubicin (DOX) is a chemotherapy drug for treating malignant tumours. However, its cardiotoxicity has limited its clinical application. The Radix Aconiti Lateralis Preparata, also known as Fuzi, has been used for treating heart failure. Nevertheless, there is still a deficiency of claeity as to whether the Fuzi polysaccharide (FPS) may prevent the side effects of DOX. METHODS: Mice were intraperitoneally administered DOX (15 mg/kg) to establish a mouse model of DOX-induced chronic cardiotoxicity (DICC). The mice were then administered different doses of FPS or enalapril intragastrically. KEY FINDINGS: In the DOX group, the activity of CK-MB and LDH and the content of NT-proBNP in serum of mice were increased. Myocardial infiltration of inflammatory cells and cytoplasmic vacuolation occurred. Levels of NLRP3, ASC, Caspase-1, IL-1ß, IL-18, IL-6, and Bax increased, whereas levels of Bcl-2, STAT3, and p-STAT3 decreased. After administering FPS (100 mg/kg and 200 mg/kg), there were reductions in CK-MB activity and NT-proBNP levels. Cytoplasmic vacuolation, interstitial infiltration of blood, and infiltration of inflammatory cells were alleviated. The changes in protein expression mentioned above were reversed. CONCLUSIONS: FPS can protect heart function and structure in DICC mice by inhibiting NLRP3 inflammasome-mediated pyroptosis and IL-6/STAT3 pathway-induced apoptosis.


Asunto(s)
Aconitum , Cardiotoxicidad , Diterpenos , Medicamentos Herbarios Chinos , Ratones , Animales , Cardiotoxicidad/prevención & control , Proteína con Dominio Pirina 3 de la Familia NLR , Aconitum/química , Interleucina-6 , Doxorrubicina/toxicidad
7.
J Biochem Mol Toxicol ; 38(1): e23522, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37650874

RESUMEN

Doxorubicin (Dox) may induce loss of follicles, resulting in the depletion of ovarian reserve and consequent premature ovarian failure. Selenium (Se) is an oligoelement with fundamental biological features and is among the most common chemical inhibitor compounds. The present study describes the curative effects of dietary supplementation with different Se doses on Dox-induced ovarian damage in rats. In this study, 64 adult female Wistar rats were randomly separated into eight groups: Control group, Dox group (5 mg/kg intraperitoneal [i.p.]), low-dose Se (0.5 mg/kg i.p.), middle dose Se (1 mg/kg i.p.), high dose (Se 2 mg/kg i.p.), Dox + low-dose Se group (0.5 mg/kg i.p.), Dox + middle dose Se (1 mg/kg i.p.), and Dox + high-dose Se group (2 mg/kg i.p.). After the experiment, ovarian follicles were counted, and Antimüllerian hormone, interleukin 1 beta, tumor necrosis factor alpha, and caspase-3 expression were determined. Levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase were biochemically measured in ovarian tissue. Dox caused ovarian injury, as evidenced by significant changes in ovarian markers, histological abnormalities, and the debilitation of antioxidant defense mechanisms. Furthermore, Dox therapy significantly changed the expression of inflammatory and apoptotic markers. Dox + 1 mg Se with various saturations was studied, and this study demonstrated both histopathological and follicular reserve and more protective features. 1 mg Se pretreatment improved Dox-induced ovarian toxicity through alleviating the antioxidant mechanism, decreasing inflammation and apoptosis, and restoring ovarian architecture. As a result, our findings indicate that 1 mg Se is a promising therapeutic agent for the prevention of ovarian damage associated with Dox.


Asunto(s)
Antioxidantes , Selenio , Ratas , Femenino , Animales , Antioxidantes/farmacología , Antioxidantes/metabolismo , Selenio/farmacología , Ratas Wistar , Estrés Oxidativo , Doxorrubicina/toxicidad , Suplementos Dietéticos , Apoptosis
8.
Molecules ; 28(24)2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38138580

RESUMEN

Doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, is widely used to treat various types of cancer; however, prolonged treatment induces cardiomyotoxicity. Although studies have been performed to overcome DOX-induced cardiotoxicity (DICT), no effective method is currently available. This study investigated the effects and potential mechanisms of Poncirus trifoliata aqueous extract (PTA) in DICT. Changes in cell survival were assessed in H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells. The C57BL/6 mice were treated with DOX to induce DICT in vivo, and alterations in electrophysiological characteristics, serum biomarkers, and histological features were examined. The PTA treatment inhibited DOX-induced decrease in H9c2 cell viability but did not affect the MDA-MB-231 cell viability. Additionally, the PTA restored the abnormal heart rate, R-R interval, QT interval, and ST segment and inhibited the decrease in serum cardiac and hepatic toxicity indicators in the DICT model. Moreover, the PTA administration protected against myocardial fibrosis and apoptosis in the heart tissue of mice with DICT. PTA treatment restored DOX-induced decrease in the expression of NAD(P)H dehydrogenase quinone acceptor oxidoreductase 1 in a PTA concentration-dependent manner. In conclusion, the PTA inhibitory effect on DICT is attributable to its antioxidant properties, suggesting the potential of PTA as a phytotherapeutic agent for DICT.


Asunto(s)
Miocitos Cardíacos , Poncirus , Ratas , Ratones , Humanos , Animales , NAD/metabolismo , Poncirus/metabolismo , Regulación hacia Arriba , Estrés Oxidativo , Ratones Endogámicos C57BL , Doxorrubicina/toxicidad , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Oxidorreductasas/metabolismo , Quinonas/farmacología
9.
J Physiol ; 601(21): 4699-4721, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37815420

RESUMEN

Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that doxorubicin-induced muscle atrophy is attributable primarily to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. The aim of this study was to demonstrate that doxorubicin triggers severe muscle atrophy via upregulation of oxidative stress (4-hydroxynonenal and malondialdehyde) and atrogenes (atrogin-1/MAFbx and muscle RING finger-1) in association with decreased expression of the antioxidant enzyme extracellular superoxide dismutase (EcSOD), in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1ß (IL-1ß) mRNA expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1ß treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which was associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a potential therapeutic approach to counteract the muscle atrophy mediated by doxorubicin and oxidative stress. KEY POINTS: Doxorubicin, a commonly prescribed chemotherapeutic agent for patients with cancer, induces severe muscle atrophy owing to increased expression of oxidative stress; however, protective therapeutic targets are poorly understood. Doxorubicin induced muscle atrophy owing to increased expression of oxidative stress and atrogenes in association with decreased protein expression of extracellular superoxide dismutase (EcSOD) in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein increased EcSOD levels on the cellular membrane of cultured myotubes, resulting in inhibition of doxorubicin-induced oxidative stress and myotube atrophy. Doxorubicin treatment decreased interleukin-1ß (IL-1ß) expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment in vivo and in vitro increased EcSOD protein expression and attenuated doxorubicin-induced muscle atrophy. These findings reveal that regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a possible therapeutic approach for muscle atrophy mediated by doxorubicin and oxidative stress.


Asunto(s)
Antioxidantes , Neoplasias , Humanos , Ratones , Animales , Antioxidantes/farmacología , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Interleucina-1beta/uso terapéutico , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/inducido químicamente , Atrofia Muscular/prevención & control , Doxorrubicina/toxicidad , Doxorrubicina/metabolismo , Neoplasias/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico
10.
Int Heart J ; 64(5): 910-917, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37778994

RESUMEN

As a kind of anthracycline, doxorubicin (DOX) is commonly used as an antitumor drug, but its clinical application has been greatly hindered due to its severe cardiotoxicity. Hence, in this study, we investigated the role of catalpol (CTP) and its effect on DOX-induced cardiotoxicity.The cardiac function of mice was evaluated by assessing lactate dehydrogenase, creatine kinase isoenzyme, heart weight to body weight, and heart weight/tibia length levels. Histopathological changes were observed using hematoxylin and eosin staining, and the terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to examine myocardial apoptosis. Superoxide dismutase (SOD) activity, glutathione (GSH), and malondialdehyde (MDA) levels were measured to confirm the changes in oxidative stress. Western blotting showed the levels of autophagy- and pathway-related proteins. Expression of autophagy marker LC3 was examined using immunofluorescence staining.CTP alleviated DOX-induced cardiac damage in mice. We further observed upregulated SOD and GSH levels, and downregulated MDA level after the CTP treatment in DOX-treated mice, indicating the protective role of CTP against oxidative injury. DOX-induced myocardial apoptosis was also inhibited by CTP treatment in mice. In addition, CTP decreased the levels of Beclin1 and LC3II/LC3I, increased the levels of P62, and activated the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in DOX-treated mice.CTP ameliorated DOX-induced cardiotoxicity by inhibiting oxidative stress, myocardial apoptosis, and autophagy via the AKT-mTOR pathway.


Asunto(s)
Cardiotoxicidad , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Cardiotoxicidad/etiología , Doxorrubicina/toxicidad , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/farmacología , Serina-Treonina Quinasas TOR/uso terapéutico , Miocardio/patología , Estrés Oxidativo , Autofagia , Superóxido Dismutasa/metabolismo , Apoptosis/fisiología , Miocitos Cardíacos/metabolismo , Mamíferos/metabolismo
11.
Aging (Albany NY) ; 15(17): 9167-9181, 2023 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-37708248

RESUMEN

Pathological cardiac hypertrophy is a considerable contributor to global disease burden. Chinese herbal medicine (CHM) has been used to treat cardiovascular diseases since antiquity. Enhancing stem cell-mediated recovery through CHM represents a promising approach for protection against doxorubicin (Dox)-induced cardiac hypertrophy. Herein, we investigated whether human adipose-derived stem cells (hADSCs) preconditioned with novel herbal formulation Jing Si (JS) improved protective ability of stem cells against doxorubicin-induced cardiac damage. The effect of JS on hADSC viability and migration capacity was determined via MTT and migration assays, respectively. Co-culture of hADSC or JS-preconditioned hADSCs with H9c2 cells was analyzed with immunoblot, flow cytometry, TUNEL staining, LC3B staining, F-actin staining, and MitoSOX staining. The in vivo study was performed M-mode echocardiography after the treatment of JS and JS-preconditioned hADSCs by using Sprague Dawley (SD) rats. Our results indicated that JS at doses below 100 µg/mL had less cytotoxicity in hADSC and JS-preconditioned hADSCs exhibited better migration. Our results also revealed that DOX enhanced apoptosis, cardiac hypertrophy, and mitochondrial reactive oxygen species in DOX-challenged H9c2 cells, while H9c2 cells co-cultured with JS-preconditioned hADSCs alleviated these effects. It also enhanced the expression of autophagy marker LC3B, mTOR and CHIP in DOX-challenged H9c2 cells after co-culture with JS-preconditioned hADSCs. In Dox-challenged rats, the ejection fraction and fractional shortening improved in DOX-challenged SD rats exposed to JS-preconditioned hADSCs. Taken together, our data indicate that JS-preconditioned stem cells exhibit a cardioprotective capacity both in vitro and in vivo, highlighting the value of this therapeutic approach for regenerative therapy.


Asunto(s)
Corazón , Células Madre , Humanos , Animales , Ratas , Ratas Sprague-Dawley , Doxorrubicina/toxicidad , Cardiomegalia
12.
J Biochem Mol Toxicol ; 37(10): e23403, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37701944

RESUMEN

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+ /H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6 ) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX-induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX-induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl-2-associated X protein/B-cell lymphoma-2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX-induced cardiotoxicity.


Asunto(s)
Cardiotoxicidad , Vitamina B 6 , Humanos , Cardiotoxicidad/prevención & control , Cardiotoxicidad/metabolismo , Vitamina B 6/farmacología , Doxorrubicina/toxicidad , Antioxidantes/farmacología , Antioxidantes/metabolismo , Estrés Oxidativo , Vitaminas/farmacología , Apoptosis
13.
Environ Toxicol ; 38(12): 3026-3042, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37661764

RESUMEN

Ohwia caudata (Thunb.) H. Ohashi (Leguminosae) also called as "Evergreen shrub" and Artemisia argyi H.Lév. and Vaniot (Compositae) also named as "Chinese mugwort" those two-leaf extracts frequently used as herbal medicine, especially in south east Asia and eastern Asia. Anthracyclines such as doxorubicin (DOX) are commonly used as effective chemotherapeutic drugs in anticancer therapy around the world. However, chemotherapy-induced cardiotoxicity, dilated cardiomyopathy, and congestive heart failure are seen in patients who receive DOX therapy, with the mechanisms underlying DOX-induced cardiac toxicity remaining unclear. Mitochondrial dysfunction, oxidative stress, inflammatory response, and cardiomyocytes have been shown to play crucial roles in DOX-induced cardiotoxicity. Isoliquiritigenin (ISL, 10 mg/kg) is a bioactive flavonoid compound with protective effects against inflammation, neurodegeneration, cancer, and diabetes. Here, in this study, our aim is to find out the Artemisia argyi (AA) and Ohwia caudata (OC) leaf extract combination with Isoliquiritigenin in potentiating and complementing effect against chemo drug side effect to ameliorate cardiac damage and improve the cardiac function. In this study, we showed that a combination of low (AA 300 mg/kg; OC 100 mg/kg) and high-dose(AA 600 mg/kg; OC 300 mg/kg) AA and OC water extract with ISL activated the cell survival-related AKT/PI3K signaling pathway in DOX-treated cardiac tissue leading to the upregulation of the antioxidant markers SOD, HO-1, and Keap-1 and regulated mitochondrial dysfunction through the Nrf2 signaling pathway. Moreover, the water extract of AA and OC with ISL inhibited the inflammatory response genes IL-6 and IL-1ß, possibly through the NFκB/AKT/PI3K/p38α/NRLP3 signaling pathways. The water extract of AA and OC with ISL could be a potential herbal drug treatment for cardiac hypertrophy, inflammatory disease, and apoptosis, which can lead to sudden heart failure.


Asunto(s)
Artemisia , Cardiotoxicidad , Extractos Vegetales , Animales , Ratas , Apoptosis , Artemisia/química , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/metabolismo , Doxorrubicina/toxicidad , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Miocitos Cardíacos , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Transducción de Señal , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hemo-Oxigenasa 1/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo
14.
Aging (Albany NY) ; 15(19): 10133-10145, 2023 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-37770231

RESUMEN

Doxorubicin (DOX) is a potent chemotherapeutic drug used for treating various cancers. However, its clinical use is limited due to its severe cardiotoxicity, which often results in high mortality rates. Sheng-Mai-Yin (SMY), a Traditional Chinese medicine (TCM) prescription, has been reported to exert a cardioprotective effect in various cardiovascular diseases, including DOX-induced cardiotoxicity (DIC). This study aimed to provide novel insights into the underlying cardioprotective mechanism of SMY. SMY, composed of Codonopsis pilosula (Franch.), Ophiopogon japonicus (Thunb.), and Schisandra chinensis (Turcz.) at a ratio of 3:2:1, was intragastrically administered to male C57BL/6 mice for five days prior to the intraperitoneal injection of mitoTEMPO. One day later, DOX was intraperitoneally injected. Hematoxylin-eosin staining and Sirius red staining were carried out to estimate the pharmacological effect of SMY on cardiotoxicity. Mitochondrial function and ferroptosis biomarkers were also examined. AAV was utilized to overexpress Hmox1 to confirm whether Hmox1-mediated ferroptosis is associated with the cardioprotective effect of SMY on DOX-induced cardiotoxicity. The findings revealed that SMY therapy reduced the number of damaged cardiomyocytes. SMY therapy also reversed the inductions of cardiac MDA, serum MDA, LDH, and CK-MB contents, which dramatically decreased nonheme iron levels. In the meantime, SMY corrected the changes to ferroptosis indices brought on by DOX stimulation. Additionally, Hmox1 overexpression prevented SMY's ability to reverse cardiotoxicity. Our results showed that SMY effectively restrained lipid oxidation, reduced iron overload, and inhibited DOX-induced ferroptosis and cardiotoxicity, possibly via the mediation of Hmox1.


Asunto(s)
Cardiotoxicidad , Ferroptosis , Masculino , Ratones , Animales , Cardiotoxicidad/prevención & control , Ratones Endogámicos C57BL , Doxorrubicina/toxicidad , Miocitos Cardíacos/metabolismo , Estrés Oxidativo , Proteínas de la Membrana/metabolismo , Hemo-Oxigenasa 1/metabolismo
15.
Biomarkers ; 28(6): 544-554, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37555371

RESUMEN

OBJECTIVE: The aim of the present study was to investigate the effects of Grape seed extract (GSE) and exercise training on Doxorubicin (Doxo)-induced cardio, hepato and myo toxicities in healthy rats. METHODS: Thirty male Wistar rats were randomly divided into five groups and daily treated by intraperitoneal route during two months either with ethanol 10% (Control); Doxo (1.5 mg/kg); Doxo + exercise (1.5 mg/kg + swimming exercise for 30 min twice a week); Doxo + GSE (1.5 mg/kg + GSE 2.5 g/kg); Doxo + GSE + exercise (1.5 mg/kg + GSE 2.5 g/kg + swimming exercise for 30 min twice a week). At the end of the treatment, tissues were collected and processed for the determination of oxidative stress (OS), intracellular mediators, energy fuelling biomarkers, carbohydrate metabolism parameters and muscle histopathology. RESULTS: Doxo provoked OS characterised by an increased lipoperoxidation (LPO) and protein carbonylation and decreased antioxidant enzyme activities. Doxo also affected intracellular mediators, disturbed carbohydrate metabolism and energy fuelling in skeletal muscle as assessed by down-regulated Electron Transport Chain (ETC) complex activities leading in fine to altered skeletal muscle structure and function. CONCLUSION: Almost all Doxo-induced disturbances were partially corrected with GSE and exercise on their own and more efficiently with the combined treatment (GSE + exercise).


Asunto(s)
Extracto de Semillas de Uva , Ratas , Masculino , Animales , Extracto de Semillas de Uva/farmacología , Ratas Wistar , Antioxidantes/farmacología , Estrés Oxidativo , Doxorrubicina/toxicidad
16.
Int J Mol Sci ; 24(8)2023 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-37108737

RESUMEN

This study aimed to evaluate if Simvastatin can reduce, and/or prevent, Doxorubicin (Doxo)-induced cardiotoxicity. H9c2 cells were treated with Simvastatin (10 µM) for 4 h and then Doxo (1 µM) was added, and the effects on oxidative stress, calcium homeostasis, and apoptosis were evaluated after 20 h. Furthermore, we evaluated the effects of Simvastatin and Doxo co-treatment on Connexin 43 (Cx43) expression and localization, since this transmembrane protein forming gap junctions is widely involved in cardioprotection. Cytofluorimetric analysis showed that Simvastatin co-treatment significantly reduced Doxo-induced cytosolic and mitochondrial ROS overproduction, apoptosis, and cytochrome c release. Spectrofluorimetric analysis performed by means of Fura2 showed that Simvastatin co-treatment reduced calcium levels stored in mitochondria and restored cytosolic calcium storage. Western blot, immunofluorescence, and cytofluorimetric analyses showed that Simvastatin co-treatment significantly reduced Doxo-induced mitochondrial Cx43 over-expression and significantly increased the membrane levels of Cx43 phosphorylated on Ser368. We hypothesized that the reduced expression of mitochondrial Cx43 could justify the reduced levels of calcium stored in mitochondria and the consequent induction of apoptosis observed in Simvastatin co-treated cells. Moreover, the increased membrane levels of Cx43 phosphorylated on Ser368, which is responsible for the closed conformational state of the gap junction, let us to hypothesize that Simvastatin leads to cell-to-cell communication interruption to block the propagation of Doxo-induced harmful stimuli. Based on these results, we can conclude that Simvastatin could be a good adjuvant in Doxo anticancer therapy. Indeed, we confirmed its antioxidant and antiapoptotic activity, and, above all, we highlighted that Simvastatin interferes with expression and cellular localization of Cx43 that is widely involved in cardioprotection.


Asunto(s)
Antioxidantes , Conexina 43 , Humanos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Conexina 43/metabolismo , Simvastatina/farmacología , Simvastatina/metabolismo , Miocitos Cardíacos/metabolismo , Calcio/metabolismo , Doxorrubicina/toxicidad , Doxorrubicina/metabolismo , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Apoptosis
17.
Neurochem Res ; 48(8): 2476-2489, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37017891

RESUMEN

Chemotherapy-induced cognitive impairment (CICI) is a common complication associated with the use of chemotherapeutics. Doxorubicin (DOX) is a reactive oxygen species (ROS) producing anticancer agent capable of causing potential neurotoxic effects via cytokine-induced oxidative and nitrosative damage to brain tissues. On the other hand, alpha-lipoic acid (ALA), a nutritional supplement, is reputable for its excellent antioxidant, anti-inflammatory, and anti-apoptotic activities. Consequently, the objective of the current investigation was to examine any potential neuroprotective and memory-improving benefits of ALA against DOX-induced behavioral and neurological anomalies. DOX (2 mg/kg/week, i.p.) was administrated for 4 weeks to Sprague-Dawley rats. ALA (50, 100, and 200 mg/kg) was administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NORT) tests were used to assess memory function. Biochemical assays with UV-visible spectrophotometry were used to analyze oxidative stress markers [malondialdehyde (MDA), protein carbonylation (PCO)], endogenous antioxidants [reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and acetylcholinesterase (AChE) activity in hippocampal tissue. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB)], nuclear factor erythroid 2-related factor-2 (NRF-2) and hemeoxygenase-1 (HO-1) levels were estimated using enzyme-linked immunosorbent assay (ELISA). In addition, reactive oxygen species (ROS) levels were measured in hippocampus tissue using 2-7-dichlorofluorescein-diacetate (DCFH-DA) assay with fluorimetry. ALA treatment significantly protected against DOX-induced memory impairment. Furthermore, ALA restored hippocampal antioxidants, halted DOX-induced oxidative and inflammatory insults via upregulation of NRF-2/HO-1 levels, and alleviated the increase in NF-κB expression. These results indicate that ALA offers neuroprotection against DOX-induced cognitive impairment, which could be attributed to its antioxidant potential via the NRF-2/HO-1 signaling pathway.


Asunto(s)
Disfunción Cognitiva , Ácido Tióctico , Animales , Ratas , Acetilcolinesterasa/metabolismo , Antioxidantes , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Doxorrubicina/toxicidad , Hipocampo/metabolismo , Enfermedades Neuroinflamatorias , FN-kappa B/metabolismo , Estrés Oxidativo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal
18.
Sci Rep ; 13(1): 6167, 2023 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-37061575

RESUMEN

Kidneys are complex organs, and reproducing their function and physiology in a laboratory setting remains difficult. During drug development, potential compounds may exhibit unexpected nephrotoxic effects, which imposes a significant financial burden on pharmaceutical companies. As a result, there is an ongoing need for more accurate model systems. The use of renal organoids to simulate responses to nephrotoxic insults has the potential to bridge the gap between preclinical drug efficacy studies in cell cultures and animal models, and the stages of clinical trials in humans. Here we established an accessible fluorescent whole-mount approach for nuclear and membrane staining to first provide an overview of the organoid histology. Furthermore, we investigated the potential of renal organoids to model responses to drug toxicity. For this purpose, organoids were treated with the chemotherapeutic agent doxorubicin for 48 h. When cell viability was assessed biochemically, the organoids demonstrated a significant, dose-dependent decline in response to the treatment. Confocal microscopy revealed visible tubular disintegration and a loss of cellular boundaries at high drug concentrations. This observation was further reinforced by a dose-dependent decrease of the nuclear area in the analyzed images. In contrast to other approaches, in this study, we provide a straightforward experimental framework for drug toxicity assessment in renal organoids that may be used in early research stages to assist screen for potential adverse effects of compounds.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Organoides , Animales , Humanos , Doxorrubicina/toxicidad , Doxorrubicina/metabolismo , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Riñón , Organoides/metabolismo
19.
Int J Med Mushrooms ; 25(1): 1-12, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36734915

RESUMEN

Doxorubicin (DOX), a broad spectrum chemotherapeutic, has toxic effects on healthy tissues. Mitochondrial processes and oxidative stress act in the DOX-induced toxicity, therefore antioxidant therapies are widely used. The study was aimed to evaluate the therapeutic potential of Pleurotus eryngii extract (PEE), an extract of a fungus with antioxidant properties, against DOX-induced lung damage. Rats were divided into Control, DOX, DOX + PEE, and PEE groups (n = 6). DOX was administered intraperitoneally in a single dose (10 mg/kg BW) and PE (200 mg/kg BW) was administered by oral gavage every other day for 21 days. Histopathological evaluations, immunohistochemical analyses, total oxidant status (TOS)/total antioxidant status (TAS) method, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis were performed. DOX led to severe histopathological disruptions in rat lungs. Also, DOX remarkably increased the expression of dynamin 1 like (DRP1) and decreased the expression of mitofusin 1 (MFN1) and mitofusin 2 (MFN2) genes, which are related to mitochondrial dynamics. Moreover, DOX caused an increase in TOS/ TAS and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. On the other hand, PEE treatment remarkably normalized the histopathological findings, mitochondrial dynamics-related gene expressions, markers of oxidative stress, and DNA damage. The present study signs out that PEE can ameliorate the DOX-mediated lung toxicity and the antioxidant mechanism associated with mitochondrial dynamics can have a role in this potent therapeutic effect.


Asunto(s)
Antioxidantes , Pleurotus , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/química , Pleurotus/química , Estrés Oxidativo , Doxorrubicina/toxicidad , Pulmón , Apoptosis
20.
J Toxicol Environ Health A ; 86(4): 87-102, 2023 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-36756732

RESUMEN

The aim of this study was to determine the oxidative/antioxidative effects, modulatory and selective potential of α-tocopherol (vitamin E) on antineoplastic drug-induced toxicogenetic damage. The toxicity, cytotoxicity and genotoxicity induced by antineoplastic agents cyclophosphamide (CPA) and doxorubicin (DOX) was examined utilizing as models Saccharomyces cerevisiae, Allium cepa, Artemia salina and human peripheral blood mononuclear cells (PBMCs) in the presence of α-tocopherol. For these tests, concentrations of α- tocopherol 100 IU/ml (67mg/ml), CPA 20 µg/ml, DOX 2 µg/ml were used. The selectivity of α-tocopherol was assessed by the MTT test using human mammary gland non-tumor (MCF10A) and tumor (MCF-7) cell lines. Data showed cytoplasmic and mitochondrial oxidative damage induced by CPA or DOX was significantly diminished by α-tocopherol in S. cerevisiae. In addition, the toxic effects on A. salina and cytotoxic and mutagenic effects on A. cepa were significantly reduced by α-tocopherol. In PBMCs, α-tocopherol alone did not markedly affect these cells, and when treated in conjunction with CPA or DOX, α-tocopherol reduced the toxicogenetic effects noted after antineoplastic drug administration as evidenced by decreased chromosomal alterations and lowered cell death rate. In human mammary gland non-tumor and tumor cell lines, α-tocopherol produced selective cytotoxicity with 2-fold higher effect in tumor cells. Evidence indicates that vitamin E (1) produced anti-cytotoxic and anti-mutagenic effects against CPA and DOX (2) increased higher selectivity toward tumor cells, and (3) presented chemoprotective activity in PBMCs.


Asunto(s)
Antineoplásicos , alfa-Tocoferol , Humanos , alfa-Tocoferol/farmacología , Saccharomyces cerevisiae , Leucocitos Mononucleares , Antineoplásicos/toxicidad , Antineoplásicos/uso terapéutico , Doxorrubicina/toxicidad , Ciclofosfamida/toxicidad , Vitamina E
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