RESUMO
Recently, the increasing incidence of malignant melanoma has become a major public health concern owing to its poor prognosis and impact on quality of life. Consuming foods with potent antitumor compounds can help prevent melanoma and maintain skin health. Fucoxanthin (FX), a naturally occurring carotenoid found in brown algae, possesses antitumor properties. However, its bioavailability, safety risks, and in vivo effects and mechanisms against melanoma remain unclear. This research focused on evaluating the safety and prospective antimelanoma impact of simulated gastrointestinal digestion products (FX-ID) on HaCaT and A375 cells.The results indicate that FX-ID exerts negative effects on mitochondria in A375 cells, increases Bax expression, releases Cytochrome C, and activates cleaved caspase-3, ultimately promoting apoptosis. Additionally, FX-ID influences the mitogen-activated protein kinase (MAPK) pathway by enhancing cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) levels, consequently facilitating apoptosis and inflammation without significantly impacting HaCaT cells. These findings provide insight into inhibitory mechanism of FX-ID against melanoma, guiding the development of functional foods for prevention.
Assuntos
Apoptose , Queratinócitos , Melanoma , Xantofilas , Humanos , Melanoma/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Apoptose/efeitos dos fármacos , Xantofilas/farmacologia , Xantofilas/química , Linhagem Celular Tumoral , NF-kappa B/metabolismo , NF-kappa B/genética , Digestão , Modelos Biológicos , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Antineoplásicos/farmacologia , Antineoplásicos/química , Phaeophyceae/química , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 3/genéticaRESUMO
Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H2O2 to oxygen (O2) but also augmented intracellular ROS levels through the production of hydroxyl radicals (â¢OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant tumors.
Assuntos
Clorofilídeos , Indóis , Platina , Polímeros , Porfirinas , Neoplasias da Glândula Tireoide , Microambiente Tumoral , Terapia por Ultrassom , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Indóis/química , Terapia por Ultrassom/métodos , Porfirinas/química , Porfirinas/farmacologia , Polímeros/química , Animais , Platina/química , Platina/uso terapêutico , Platina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Apoptose/efeitos dos fármacos , Nanopartículas/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Quinolinas/farmacologia , Quinolinas/química , Camundongos Nus , Portadores de Fármacos/químicaRESUMO
Telomere length plays a crucial role in cellular aging and the risk of diseases. Unlike normal cells, cancer cells can extend their own survival by maintaining telomere stability through telomere maintenance mechanism. Therefore, regulating the lengths of telomeres have emerged as a promising approach for anti-cancer treatment. In this study, we introduce a nanoscale octopus-like structure designed to induce physical entangling of telomere, thereby efficiently triggering telomere dysfunction. The nanoscale octopus, composed of eight-armed PEG (8-arm-PEG), are functionalized with cell penetrating peptide (TAT) to facilitate nuclear entry and are covalently bound to N-Methyl Mesoporphyrin IX (NMM) to target G-quadruplexes (G4s) present in telomeres. The multi-armed configuration of the nanoscale octopus enables targeted binding to multiple G4s, physically disrupting and entangling numerous telomeres, thereby triggering telomere dysfunction. Both in vitro and in vivo experiments indicate that the nanoscale octopus significantly inhibits cancer cell proliferation, induces apoptosis through telomere entanglement, and ultimately suppresses tumor growth. This research offers a novel perspective for the development of innovative anti-cancer interventions and provides potential therapeutic options for targeting telomeres.
Assuntos
Apoptose , Telômero , Telômero/metabolismo , Apoptose/efeitos dos fármacos , Humanos , Animais , Linhagem Celular Tumoral , Camundongos , Quadruplex G/efeitos dos fármacos , Camundongos Nus , Polietilenoglicóis/química , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Feminino , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Nanoestruturas/químicaRESUMO
Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.
Assuntos
Neoplasias da Mama , Senescência Celular , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas , Humanos , Animais , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Senescência Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Engenharia Genética/métodos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Nanopartículas/química , Anticorpos de Cadeia Única/química , Evasão Tumoral/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Apoptose/efeitos dos fármacos , Biomimética/métodos , Antígenos B7RESUMO
Radiotherapy as a mainstay of in-depth cervical cancer (CC) treatment suffers from its radioresistance. Radiodynamic therapy (RDT) effectively reverses radio-resistance by generating reactive oxygen species (ROS) with deep tissue penetration. However, the photosensitizers stimulated by X-ray have high toxicity and energy attenuation. Therefore, X-ray responsive diselenide-bridged mesoporous silica nanoparticles (DMSNs) are designed, loading X-ray-activated photosensitizer acridine orange (AO) for spot blasting RDT like Trojan-horse against radio-resistance cervical cancer (R-CC). DMSNs can encapsulate a large amount of AO, in the tumor microenvironment (TME), which has a high concentration of hydrogen peroxide, X-ray radiation triggers the cleavage of diselenide bonds, leading to the degradation of DMSNs and the consequent release of AO directly at the tumor site. On the one hand, it solves the problems of rapid drug clearance, adverse distribution, and side effects caused by simple AO treatment. On the other hand, it fully utilizes the advantages of highly penetrating X-ray responsive RDT to enhance radiotherapy sensitivity. This approach results in ROS-induced mitochondria damage, inhibition of DNA damage repair, cell cycle arrest and promotion of cancer cell apoptosis in R-CC. The X-ray responsive DMSNs@AO hold considerable potential in overcoming obstacles for advanced RDT in the treatment of R-CC.
Assuntos
Nanopartículas , Dióxido de Silício , Humanos , Animais , Raios X , Nanopartículas/química , Feminino , Dióxido de Silício/química , Camundongos , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Espécies Reativas de Oxigênio/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Tolerância a Radiação/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Camundongos Nus , Células HeLa , Camundongos Endogâmicos BALB C , Apoptose/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
While numerous methods exist for diagnosing tumors through the detection of miRNA within tumor cells, few can simultaneously achieve both tumor diagnosis and treatment. In this study, a novel graphene oxide (GO)-based DNA nanodevice (DND), initiated by miRNA, was developed for fluorescence signal amplification imaging and photodynamic therapy in tumor cells. After entering the cells, tumor-associated miRNA drives DND to Catalyzed hairpin self-assembly (CHA). The CHA reaction generated a multitude of DNA Y-type structures, resulting in a substantial amplification of Ce6 fluorescence release and the generation of numerous singlet oxygen (1O2) species induced by laser irradiation, consequently inducing cell apoptosis. In solution, DND exhibited high selectivity and sensitivity to miRNA-21, with a detection limit of 11.47 pM. Furthermore, DND discriminated between normal and tumor cells via fluorescence imaging and specifically generated O21 species in tumor cells upon laser irradiation, resulting in tumor cells apoptosis. The DND offer a new approach for the early diagnosis and timely treatment of malignant tumors.
Assuntos
DNA , Grafite , MicroRNAs , Fotoquimioterapia , Nanomedicina Teranóstica , Fotoquimioterapia/métodos , Humanos , MicroRNAs/análise , Grafite/química , Nanomedicina Teranóstica/métodos , DNA/química , Apoptose/efeitos dos fármacos , Imagem Óptica , Linhagem Celular Tumoral , Oxigênio Singlete/metabolismo , Oxigênio Singlete/química , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagemRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Mountain-cultivated Panax ginseng C.A.Mey. (MCG) with high market price and various properties was valuable special local product in Northeast of Asia. MCG has been historically used to mitigate heart failure (HF) for thousand years, HF is a clinical manifestation of deficiency of "heart-qi" in traditional Chinese medicine. However, there was little report focus on the activities of extracted residue of MCG. AIM OF THE STUDY: A novel glycopeptide (APMCG-1) was isolated from step ethanol precipitations of alkaline protease-assisted extract from MCG residue. MATERIALS AND METHODS: The molecular weight and subunit structure of APMCG-1 were determined by FT-IR, HPLC and GPC technologies, as well as the H9c2 cells, Tg (kdrl:EGFP) zebrafish were performed to evaluated the protective effect of APMCG-1. RESULTS: APMCG-1 was identified as a glycopeptide containing seven monosaccharides and seven amino acids via O-lined bonds. Further, in vitro, APMCG-1 significantly decreased reactive oxygen species production and lactate dehydrogenase contents in palmitic acid (PA)-induced H9c2 cells. APMCG-1 also attenuated endoplasmic reticulum stress and mitochondria-mediated apoptosis in H9c2 cells via the PI3K/AKT signaling pathway. More importantly, APMCG-1 reduced the blood glucose, lipid contents, the levels of heart injury, oxidative stress and inflammation of 5 days post fertilization Tg (kdrl:EGFP) zebrafish with type 2 diabetic symptoms in vivo. CONCLUSIONS: APMCG-1 protects PA-induced H9c2 cells while reducing cardiac dysfunction in zebrafish with type 2 diabetic symptoms. The present study provides a new insight into the development of natural glycopeptides as heart-related drug therapies.
Assuntos
Diabetes Mellitus Tipo 2 , Glicopeptídeos , Insuficiência Cardíaca , Panax , Peixe-Zebra , Animais , Panax/química , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ratos , Linhagem Celular , Glicopeptídeos/farmacologia , Glicopeptídeos/química , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Cardiotônicos/farmacologia , Cardiotônicos/química , Cardiotônicos/isolamento & purificação , Cardiotônicos/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.
Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Fármacos Neuroprotetores , Estresse Oxidativo , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ratos , Células PC12 , Masculino , Fármacos Neuroprotetores/farmacologia , Apoptose/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. AIM OF THE STUDY: To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. MATERIALS AND METHODS: The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by Western blot assay. RESULTS: Diosmetin-7-O-ß-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 0.625-2.5 µM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. CONCLUSIONS: DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Macrófagos , SARS-CoV-2 , Replicação Viral , Animais , Camundongos , Células RAW 264.7 , Replicação Viral/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/virologia , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Camundongos Transgênicos , Pogostemon/química , Citocinas/metabolismo , Apoptose/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/virologia , Pulmão/patologia , Glucosídeos/farmacologia , Glucosídeos/isolamento & purificação , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Enzima de Conversão de Angiotensina 2/metabolismo , Anti-Inflamatórios/farmacologia , Masculino , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , HumanosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (G. lucidum) has been widely used as adjuvant of anti-tumor therapy for variety tumors. The bioactive ingredients of G. lucidum mainly include triterpenes, such as Ganoderic acid A, Ganoderic acid B, Ganoderenic acid A, Ganoderenic acid B, Ganoderenic acid D, and Ganoderic acid X. However, the effects and underlying mechanisms of G. lucidum are often challenging in hepatocellular carcinoma (HCC) treatment. AIM OF THE STUDY: To explore the potential role and mechanism of enhancer-associated lncRNAs (en-lncRNAs) in G. lucidum treated HCC through the in vivo and in vitro experiments. MATERIALS AND METHODS: Hepa1-6-bearing C57 BL/6 mice model were established to evaluate the therapeutic efficacy of G. lucidum treated HCC. Ki67 and TUNEL staining were used to detect the tumor cell proliferation and apoptosis in vivo. The Mouse lncRNA 4*180K array was implemented to identify the differentially expressed (DE) lncRNAs and mRNAs of G. lucidum treated tumor mice. The constructed lncRNA-mRNA co-expression network and bioinformatics analysis were used to selected core en-lncRNAs and its neighboring genes. The UPLC-MS method was used to identify the triterpenes of G. lucidum, and the in vitro experiments were used to verify which triterpene monomers regulated en-lncRNAs in tumor cells. Finally, a stable knockdown/overexpression cell lines were used to confirm the relationship between en-lncRNA and neighboring gene. RESULTS: Ki67 and TUNEL staining demonstrated G. lucidum significantly inhibited tumor growth, suppressed cell proliferation and induced apoptosis in vivo. Transcriptomic analysis revealed the existence of 126 DE lncRNAs high correlated with 454 co-expressed mRNAs in G. lucidum treated tumor mice. Based on lncRNA-mRNA network and qRT-PCR validation, 6 core lncRNAs were selected and considered high correlated with G. lucidum treatment. Bioinformatics analysis revealed FR036820 and FR121302 might act as enhancers, and qRT-PCR results suggested FR121302 might enhance Popdc2 mRNA level in HCC. Furthermore, 6 main triterpene monomers of G. lucidum were identified by UPLC-MS method, and in vitro experiments showed FR121302 and Popdc2 were significantly suppressed by Ganoderenic acid A and Ganoderenic acid B, respectively. The knock/overexpression results demonstrated that FR121302 activating and enhancing Popdc2 expression levels, and Ganoderenic acid A and Ganoderenic acid B dramatically suppressed FR121302 and decreased Popdc2 level in Hepa1-6 cells. CONCLUSIONS: Enhancer-associated lncRNA plays a crucial role as an enhancer during hepatocarcinogenesis, and triterpenes of G. lucidum significantly inhibited tumor cell proliferation and induced apoptosis by regulating en-lncRNAs. Our study demonstrated Ganoderenic acid A and Ganoderenic acid B suppressed en-lncRNA FR121302 may be one of the critical strategies of G. lucidum inhibit hepatocellular carcinoma growth.
Assuntos
Apoptose , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Camundongos Endogâmicos C57BL , RNA Longo não Codificante , Reishi , Triterpenos , Animais , Triterpenos/farmacologia , Triterpenos/isolamento & purificação , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Reishi/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificaçãoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese traditional medicine frankincense, which can promote blood circulation, is often used to treat skin lesions, including frostbite. AIM OF THE STUDY: To explore the properties of frankincense oil extract (FOE) and its active ingredients and their effect on frostbite wound recovery as an approach to understand the mechanism associated with microcirculation-improvement therapy. MATERIALS AND METHODS: The microcirculation-improving effects of FOE and its active ingredients were evaluated using liquid nitrogen-induced frostbite animal models. The rewarming capacity of FOE on the skin was determined through infrared detection, and frostbite wound healing was evaluated following haematoxylin and eosin (H&E) staining and fibre analysis. Moreover, related factors were examined to determine the anti-apoptotic, anti-inflammatory, and microcirculatory properties of FOE and its active ingredients on affected tissue in the context of frostbite. RESULTS: FOE and its active ingredients rapidly rewarmed wound tissue after frostbite by increasing the temperature. Moreover, these treatments improved wound healing and restored skin structure through collagen and elastin fibre remodelling. In addition, they exerted anti-apoptotic effects by decreasing the number of apoptotic cells, reducing caspase-3 expression, and eliciting anti-inflammatory effects by decreasing COX-2 and ß-catenin expression. They also improved microcirculatory disorders by decreasing HIF-1α expression and increasing CD31 expression. CONCLUSIONS: FOE and its active components can effectively treat frostbite by enhancing microcirculation, inhibiting the infiltration of inflammatory cells, decreasing cell apoptosis, and exerting antinociceptive effects. These findings highlight FOE as a new treatment option for frostbite, providing patients with an effective therapeutic strategy.
Assuntos
Congelamento das Extremidades , Microcirculação , Cicatrização , Congelamento das Extremidades/tratamento farmacológico , Animais , Microcirculação/efeitos dos fármacos , Masculino , Cicatrização/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/irrigação sanguínea , Pele/patologia , Apoptose/efeitos dos fármacos , Ratos , Modelos Animais de Doenças , Camundongos , Administração Tópica , Ratos Sprague-Dawley , Óleos de Plantas/farmacologia , Óleos de Plantas/uso terapêutico , Extratos Vegetais/farmacologiaRESUMO
Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide because of its high morbidity and the absence of effective therapies. Even though paclitaxel is a powerful anticancer chemotherapy drug, recent studies have indicated its ineffectiveness against GC cells. Long non-coding RNA (lncRNA) PVT1 has a high expression in GC cells and increases the progression of tumors via inducing drug resistance. In the present study, the effects of the siRNA-mediated lncRNA PVT1 gene silencing along with paclitaxel treatment on the rate of apoptosis, growth, and migration of AGS GC cells were investigated. AGS cells were cultured and then transfected with siRNA PVT1 using electroporation. The MTT test was used to examine the effect of treatments on the viability of cultured cells. Furthermore, the flow cytometry method was used to evaluate the impact of treatments on the cell cycle process and apoptosis induction in GC cells. Finally, the mRNA expression of target genes was assessed using the qRT-PCR method. The results showed that lncRNA PVT1 gene suppression, along with paclitaxel treatment, reduces the viability of cancer cells and significantly increases the apoptosis rate of cancer cells and the number of cells arrested in the G2/M phase compared to the control group. Based on the results of qRT-PCR, combined treatment significantly decreased the expression of MMP3, MMP9, MDR1, MRP1, Bcl-2, k-Ras, and c-Myc genes and increased the expression of the Bax gene compared to the control group. The results of our study showed that lncRNA PVT1 gene targeting, together with paclitaxel treatment, induces apoptosis, inhibits growth, alleviates drug resistance, and reduces the migratory capability of GC cells. Therefore, there is a need for further investigations to evaluate the feasibility and effectiveness of this approach in vivo in animal models.
Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Inativação Gênica , Paclitaxel , RNA Longo não Codificante , Neoplasias Gástricas , RNA Longo não Codificante/genética , Paclitaxel/farmacologia , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Apoptose/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , RNA Interferente Pequeno/genéticaRESUMO
BACKGROUND: Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies. METHODS: The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay. RESULTS: E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10-8 M (45.36 µg/ml) to 6.71 × 10-8 M (26.66 µg/ml) and Ifosfamide from 12.52 × 10-5 M (32.7 µg/ml) to 8.206 × 10-5 M (21.43 µg/ml). Flow cytometry analysis demonstrated a significant increase in apoptosis for combination treatments, with apoptosis rates rising from 11.02 % (Oxaliplatin alone) and 16.98 % (Ifosfamide alone) to 24.8 % (Oxaliplatin + E5-siRNA) and 34.9 % (Ifosfamide + E5-siRNA). The sub-G1 cell population increased from 15.7 % (Oxaliplatin alone) and 18 % (Ifosfamide alone) to 21.9 % (Oxaliplatin + E5-siRNA) and 27.1 % (Ifosfamide + E5-siRNA), indicating cell cycle arrest. The colony formation assay revealed a substantial decrease in the number of colonies following combination treatment. qRT-PCR analysis showed decreased expression of stemness-related genes CD44 and Nanog, and migration-related genes MMP2 and CXCL8 in the combination groups. Apoptosis-related genes Casp-3, Casp-9, and pP53 showed increased expression following combination therapy, while BAX expression increased and BCL2 expression decreased relative to the control. CONCLUSION: The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.
Assuntos
Apoptose , Papillomavirus Humano 16 , Ifosfamida , Oxaliplatina , RNA Interferente Pequeno , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Oxaliplatina/farmacologia , Feminino , RNA Interferente Pequeno/genética , Linhagem Celular Tumoral , Ifosfamida/farmacologia , Apoptose/efeitos dos fármacos , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Sobrevivência Celular/efeitos dos fármacos , Proteínas Oncogênicas Virais/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Acute myeloid leukemia (AML) is a deadly form of leukemia with ineffective traditional treatment and frequent chemoresistance-associated relapse. Personalized drug screening holds promise in identifying optimal regimen, nevertheless, primary AML cells undergo spontaneous apoptosis during cultures, invalidating the drug screening results. Here, we reconstitute a 3D osteogenic niche (3DON) mimicking that in bone marrow to support primary AML cell survival and phenotype maintenance in cultures. Specifically, 3DON derived from osteogenically differentiated mesenchymal stem cells (MSC) from healthy and AML donors are co-cultured with primary AML cells. The AML cells under the AML_3DON niche showed enhanced viability, reduced apoptosis and maintained CD33+ CD34-phenotype, associating with elevated secretion of anti-apoptotic cytokines in the AML_3DON niche. Moreover, AML cells under the AML_3DON niche exhibited low sensitivity to two FDA-approved chemotherapeutic drugs, further suggesting the physiological resemblance of the AML_3DON niche. Most interestingly, AML cells co-cultured with the healthy_3DON niche are highly sensitive to the same sample drugs. This study demonstrates the differential responses of AML cells towards leukemic and healthy bone marrow niches, suggesting the impact of native cancer cell niche in drug screening, and the potential of re-engineering healthy bone marrow niche in AML patients as chemotherapeutic adjuvants overcoming chemoresistance, respectively.
Assuntos
Sobrevivência Celular , Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Fenótipo , Microambiente Tumoral , Humanos , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura/métodos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Medula Óssea/patologia , Medula Óssea/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Células da Medula Óssea/citologia , Masculino , Diferenciação Celular/efeitos dos fármacos , FemininoRESUMO
The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.
Assuntos
Doença de Alzheimer , Apoptose , Barreira Hematoencefálica , Azul de Metileno , Nanomedicina , Doenças Neuroinflamatórias , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Apoptose/efeitos dos fármacos , Células PC12 , Doenças Neuroinflamatórias/tratamento farmacológico , Ratos , Camundongos , Nanomedicina/métodos , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Masculino , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.
Assuntos
Antineoplásicos , Compostos de Bifenilo , Resistencia a Medicamentos Antineoplásicos , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ligante Indutor de Apoptose Relacionado a TNF , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Ligante Indutor de Apoptose Relacionado a TNF/farmacologiaRESUMO
BACKGROUND: Nanostructured materials used have unique properties and many uses in nanotechnology. The most striking of these is using herbal compounds for the green synthesis of nanoparticles. Among the nanoparticle types used for green synthesis, gold nanoparticles (AuNPs) are used for cancer therapy due to their stable structure and non-cytotoxic. Lung cancer is the most common and most dangerous cancer worldwide in terms of survival and prognosis. In this study, Nasturtium officinale (L.) extract (NO), which contains biomolecules with antioxidant and anticancer effects, was used to biosynthesize AuNPs, and after their characterization, the effect of the green-synthesized AuNPs against lung cancer was evaluated in vitro. METHODS: Ultravioletâvisible (UVâVis) spectrophotometry, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), multiple analysis platform (MAP), and Fourier transform infrared (FT-IR) spectroscopy analyses were performed to characterize the AuNPs prepared from the N. officinale plant extract. Moreover, the antioxidant activity, total phenolic and flavonoid contents and DNA interactions were examined. Additionally, A549 lung cancer cells were treated with 2-48 µg/mL Nasturtium officinale gold nanoparticles (NOAuNPs) for 24 and 48 h to determine the effects on cell viability. The toxicity of the synthesized NOAuNPs to lung cancer cells was determined by the 3-(4,5-dimethylthiazol-2-il)-2,5-diphenyltetrazolium bromide (MTT) assay, and the anticancer effect of the NOAuNPs was evaluated by apoptosis and cell cycle analyses using flow cytometry. RESULTS: The average size of the NPs was 56.4 nm. The intensities of the Au peaks from EDS analysis indicated that the AuNPs were synthesized successfully. Moreover, the in vitro antioxidant activities of the NO and NOAuNPs were evaluated; these materials gave values of 31.78 ± 1.71% and 31.62 ± 0.46%, respectively, in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay at 200 g/mL and values of 25.89 ± 1.90% and 33.81 ± 0.62%, respectively, in the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay. The NO and NOAuNPs gave values of 0.389 ± 0.027 and 0.308 ± 0.005, respectively, in the ferrous ion reducing antioxidant capacity (FRAP) assay and values of 0.078 ± 0.009 and 0.172 ± 0.027, respectively, in the copper ion reducing antioxidant capacity (CUPRAC) assay. When the DNA cleavage activities of NO and the NOAuNPs were evaluated via hydrolysis, both samples cleaved DNA starting at a concentration of 25 g/mL in the cell culture analysis, while the nanoformulation of the NO components gave greater therapeutic and anticancer effects. We determined that the Au nanoparticles were not toxic to A549 cells. Moreover, after treatment with the half-maximal inhibitory concentration (IC50), determined by the MTT assay with A549 cells, we found that at 24 and 48 h, while the necrosis rates were high in cells treated with NO, the rates of apoptosis were greater in cells treated with NOAuNPs. Notably, for anticancer treatment, activating apoptotic pathways that do not cause inflammation is preferred. We believe that these results will pave the way for the use of NOAuNPs in in vitro studies of other types of cancer. CONCLUSION: In this study, AuNPs were successfully synthesized from N. officinale extract. The biosynthesized AuNPs exhibited toxicity to and apoptotic effects on A549 lung cancer cells. Based on these findings, we suggest that green-synthesized AuNPs are promising new therapeutic agents for lung cancer treatment. However, since this was an in vitro study, further research should be performed in in vivo lung cancer models to support our findings and to explain the mechanism of action at the molecular level.
Assuntos
Ouro , Química Verde , Nanopartículas Metálicas , Nasturtium , Extratos Vegetais , Ouro/química , Ouro/farmacologia , Nanopartículas Metálicas/química , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Células A549 , Nasturtium/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antioxidantes/farmacologia , Antioxidantes/química , Apoptose/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Introduction: The therapeutic efficacy for airway allergies needs to be improved. Th2 polarization is a primary pathological feature of airway allergies. We constructed chimeric antigen-LgDNA (Lactobacillus rhamnosus DNA) nanoparticles (CAP-NPs). The effects of CAP-NPs on reconciling airway Th2 polarization were tested. Methods: In this study, disulfide bond-linked antigen-major histocompatibility complex II (MHC II)-LgDNA nanoparticles (NPs) were constructed and designated CAP-NPs. An airway Th2 polarization mouse model was established to test the effects of CAP-NPs on suppressing the Th2 response. Results: The CAP-NP components of ovalbumin (OVA), major histocompatibility complex II (MHC II), and LgDNA were confirmed in a series of laboratory tests. The CAP-NPs remained stable at pH7.2 for at least 96 h. In in vitro experiments, CAP-NPs bound to the surface of OVA-specific CD4+ T cells, which resulted in apoptosis of the antigen-specific CD4+ T cells. Removal of any of the three components from the NPs abolished the induction of apoptosis of antigen specific CD4+ T cells. CAP-NPs increased the expression of lysine-specific demethylase 5A (KDM5A) in CD4+ T cells. Histone H3K9 and the gene promoter of caspase 8 were demethylated by KDM5A, which led to transcription and expression of the caspase 8 gene. Administration of CAP-NPs significantly alleviated experimental airway Th2 polarization through activating the caspase 8-apoptosis signaling pathway. Discussion: In this paper, we constructed CAP-NPs that could induce antigen-specific CD4+ T cell apoptosis. Administration of CAP-NPs efficiently alleviated experimental airway Th2 polarization.
Assuntos
Apoptose , Nanopartículas , Ovalbumina , Células Th2 , Animais , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Nanopartículas/química , Camundongos , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Caspase 8/metabolismo , Caspase 8/genética , Feminino , DNA/química , DNA/administração & dosagem , Antígenos/administração & dosagem , Antígenos/química , Linfócitos T CD4-Positivos/efeitos dos fármacosRESUMO
PURPOSE: This work aimed to investigate the effects of Tanshinone IIA (Tan IIA) on myocardial cell (MC) apoptosis in a rat model of heart failure (HF). METHODS: Tan IIA was extracted from Salvia miltiorrhiza Bunge (SMB) using an ethanol reflux method. Fifty rats were randomly divided into five groups: sham (no treatment), mod (HF model establishment), low dose (LD: 0.1 mL/kg Tan IIA), medium dose (MD: 0.3 mL/kg Tan IIA), and high dose (HD: 0.5 mL/kg Tan IIA), with 10 rats in each group. The effects of different doses of Tan IIA on cardiac function, MC apoptosis, and the levels of proteins associated with the PI3K/Akt/mTOR signaling pathway were compared. RESULTS: Mod group showed a significant decrease in systolic arterial pressure, mean arterial pressure, heart rate, left ventricular systolic pressure, left ventricular ejection fraction, left ventricular fractional shortening, and the levels of p-PI3K, p-Akt, and p-mTOR proteins versus sham group (p < 0.05). Additionally, the left ventricular end-diastolic diameter (LVIDd), end-systolic diameter, diastolic pressure, and MC apoptosis were significantly increased (p < 0.05). LD, MD, and HD groups exhibited significant improvements across various indicators of cardiac function and MC apoptosis versus mod group (p < 0.05). CONCLUSIONS: Tan IIA may improve cardiac function and inhibit MC apoptosis in rats with HF by modulating the PI3K/Akt/mTOR signaling pathway.
Assuntos
Abietanos , Apoptose , Modelos Animais de Doenças , Insuficiência Cardíaca , Miócitos Cardíacos , Salvia miltiorrhiza , Animais , Apoptose/efeitos dos fármacos , Salvia miltiorrhiza/química , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Masculino , Abietanos/farmacologia , Abietanos/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-Dawley , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Ratos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Reprodutibilidade dos TestesRESUMO
PURPOSE: To examine whether isoflurane preconditioning (IsoP) has a protective effect against renal ischemia/reperfusion injury (I/RI) in diabetic conditions and to further clarify the underlying mechanisms. METHODS: Control and streptozotocin-induced diabetic rats were randomly assigned to five groups, as follows: normal sham, normal I/R, diabetic sham, diabetic I/R, and diabetic I/R + isoflurane. Renal I/RI was induced by clamping renal pedicle for 45 min followed by reperfusion for 24 h. IsoP was achieved by exposing the rats to 2% isoflurane for 30 min before vascular occlusion. Kidneys and blood were collected after reperfusion for further analysis. Renal histology, blood urea nitrogen, serum creatinine, oxidative stress, inflammatory cytokines, and renal cell apoptosis were assessed. Furthermore, the expression of brahma related gene 1 (Brg1), nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and nuclear factor-κB (NF-κB) were determined. RESULTS: Compared with control, diabetic rats undergoing I/R presented more severe renal injury, oxidative stress, inflammatory reaction, and apoptosis with the impairment of Brg1/Nrf2/HO-1 signaling. All these alterations were significantly attenuated by pretreatment with isoflurane. CONCLUSIONS: These findings suggest that isoflurane could alleviate renal I/RI in diabetes, possibly through improving Brg1/Nrf2/HO-1 signaling.