RESUMO
Oxidative stress is a pivotal factor in the pathogenesis of various cardiovascular diseases. Rhodiola, a traditional Chinese medicine, is recognized for its potent antioxidant properties. Salidroside, a phenylpropanoid glycoside derived from Rhodiola rosea, has shown remarkable antioxidant capabilities. This study aimed to elucidate the potential protective mechanisms of Rhodiola and salidroside against H2O2-induced cardiac apoptosis in H9c2 cardiomyoblast cells. H9c2 cells were exposed to H2O2 for 4 h, and subsequently treated with Rhodiola or salidroside for 24 h. Cell viability and apoptotic pathways were assessed. The involvement of insulin-like growth factor 1 receptor (IGF1R) and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) were investigated. H2O2 (100 µM) exposure significantly induced cardiac apoptosis in H9c2 cells. However, treatment with Rhodiola (12.5, 25, and 50 µg/mL) and salidroside (0.1, 1, and 10 nM) effectively attenuated H2O2-induced cytotoxicity and apoptosis. This protective effect was associated with IGF1R-activated phosphorylation of ERK1/2, leading to the inhibition of Fas-dependent proteins, HIF-1α, Bax, and Bak expression in H9c2 cells. The images from hematoxylin and eosin staining and immunofluorescence assays also revealed the protective effects of Rhodiola and salidroside in H9c2 cells against oxidative damage. Our findings suggest that Rhodiola and salidroside possess antioxidative properties that mitigate H2O2-induced apoptosis in H9c2 cells. The protective mechanisms involve the activation of IGF1R and subsequent phosphorylation of ERK1/2. These results propose Rhodiola and salidroside as potential therapeutic agents for cardiomyocyte cytotoxicity and apoptosis induced by oxidative stress in heart diseases. Future studies may explore their clinical applications in cardiac health.
RESUMO
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.
Assuntos
Senescência Celular , Doxorrubicina , Mitocôndrias , Extratos Vegetais , Espécies Reativas de Oxigênio , Cordão Umbilical , Humanos , Espécies Reativas de Oxigênio/metabolismo , Senescência Celular/efeitos dos fármacos , Cordão Umbilical/citologia , Cordão Umbilical/efeitos dos fármacos , Extratos Vegetais/farmacologia , Doxorrubicina/toxicidade , Doxorrubicina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Platycodon/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Células CultivadasRESUMO
Lung cancer is one of the most common cancers in the world. Chemotherapy is a standard clinical treatment. However, tumor cells often develop multidrug resistance after chemotherapy, an inevitable bottleneck in cancer treatment. Therefore, this study used gemcitabine-resistant (GEM-R) CL1-0 lung cancer cells. First, we used flow cytometry and western blot analysis to examine differences in performance between resistant and parental cells. The results showed that compared with parental cells, GEM-R CL1-0 cells significantly enhanced the activation of the AKT pathway, which promoted survival and growth, and decreased the activation of the reactive oxygen species-extracellular signal-regulated kinase (ROS)-ERK pathway. Next, the AKT and ERK pathways' role in tumor growth was further explored in vivo using a xenograft model. The results showed that enhancing AKT and inhibiting ERK activation reduced GEM-induced inhibition of tumor growth. Finally, combining the above results, we found that GEM-R CL1-0 cells showed reduced sensitivity to GEM by activating the phosphatidylinositol 3-kinase/AKT/NF-kB pathway and inhibiting the ROS-ERK pathway leading to resistance against GEM. Therefore, the AKT and ERK pathways are potential targets for improving the sensitivity of cancer cells to anticancer drugs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Gencitabina , NF-kappa B/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Linhagem Celular Tumoral , ApoptoseRESUMO
Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX-induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX-induced cell death in a dose-dependent manner. Moreover, western blotting and TUNEL-DAPI staining showed that fisetin significantly attenuated DOX-induced cardiotoxicity in vitro and in vivo by inhibiting the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway through estrogen receptor (ER)-α/-ß activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX-induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX-induced cardiotoxicity.
Assuntos
Cardiotoxicidade , Fator de Crescimento Insulin-Like II , Ratos , Animais , Cardiotoxicidade/tratamento farmacológico , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like II/farmacologia , Fator de Crescimento Insulin-Like II/uso terapêutico , Receptores de Estrogênio/metabolismo , Doxorrubicina/efeitos adversos , Estresse Oxidativo , Miócitos Cardíacos , ApoptoseRESUMO
The most common cancer-related death in the world is non-small cell lung cancer (NSCLC). Gemcitabine (GEM) is a common and effective first-line chemotherapeutic drug for the treatment of NSCLC. However, the long-term use of chemotherapeutic drugs in patients usually induces cancer cell drug resistance, leading to poor survival, and prognosis. In this study, to observe and explore the key targets and potential mechanisms of NSCLC resistance to GEM, we first cultured lung cancer CL1-0 cells in a GEM-containing medium to induce CL1-0 cells to develop GEM resistance. Next, we compared protein expression between the parental and GEM-R CL1-0 cell groups. We observed significantly lower expression of autophagy-related proteins in GEM-R CL1-0 cells than in parental CL1-0 cells, indicating that autophagy is associated with GEM resistance in CL1-0 cells. Furthermore, a series of autophagy experiments revealed that GEM-R CL1-0 cells had significantly reduced GEM-induced c-Jun N-terminal kinase phosphorylation, which further affected the phosphorylation of Bcl-2, thereby reducing the dissociation of Bcl-2 and Beclin-1 and ultimately reducing the generation of GEM-induced autophagy-dependent cell death. Our findings suggest that altering the expression of autophagy is a promising therapeutic option for drug-resistant lung cancer.
Assuntos
Morte Celular Autofágica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Gencitabina , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fosforilação , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Autofagia , ApoptoseRESUMO
Mitochondrial dysfunction has been linked to many diseases, including organ degeneration and cancer. Wharton's jelly-derived mesenchymal stem cells provide a valuable source for stem cell-based therapy and represent an emerging therapeutic approach for tissue regeneration. This study focused on screening the senomorphic properties of Ohwia caudata aqueous extract as an emerging strategy for preventing or treating mitochondrial dysfunction in stem cells. Wharton's jelly-derived mesenchymal stem cells were incubated with 0.1 µM doxorubicin, for 24 h to induce mitochondrial dysfunction. Next, the cells were treated with a series concentration of Ohwia caudata aqueous extract (25, 50, 100, and 200 µg/mL) for another 24 h. In addition, an untreated control group and a doxorubicin-induced mitochondrial dysfunction positive control group were maintained under the same conditions. Our data showed that Ohwia caudata aqueous extract markedly suppressed doxorubicin-induced mitochondrial dysfunction by increasing Tid1 and Tom20 expression, decreased reactive oxygen species production, and maintained mitochondrial membrane potential to promote mitochondrial stability. Ohwia caudata aqueous extract retained the stemness of Wharton's jelly-derived mesenchymal stem cells and reduced the apoptotic rate. These results indicate that Ohwia caudata aqueous extract protects Wharton's jelly-derived mesenchymal stem cells against doxorubicin-induced mitochondrial dysfunction and can potentially prevent mitochondrial dysfunction in other cells. This study provides new directions for the medical application of Ohwia caudata.
Assuntos
Células-Tronco Mesenquimais , Geleia de Wharton , Animais , Geleia de Wharton/metabolismo , Células-Tronco Mesenquimais/metabolismo , Doxorrubicina/toxicidade , Células Cultivadas , Mitocôndrias/metabolismo , Urodelos , Diferenciação CelularRESUMO
Hypertension is a common chronic cardiovascular disease reported among both men and women. Hypertension in males affects the testis and reproduction function; however, the pathogenesis is poorly understood. Rapamycin has been reported to have a variety of beneficial pharmacological effects; however, high-doses rapamycin does have side effects such as immunosuppression. The present study investigates whether low-dose rapamycin can reduce the damage caused by hypertension to the testis of spontaneously hypertensive rats (SHRs) and further examines molecular mechanism of low-dose rapamycin in preventing testicular toxicity induced by angiotensin II (Ang II). Low rapamycin dose restores the testicle size, histological alterations, 3ß-hydroxysteroid dehydrogenase (3ß-HSD) expression, and prevents apoptosis in SHR rats. Ang II downregulates angiotensin-converting enzyme-2 (ACE2) expression through AT1R, p-ERK, and MAS receptor in LC-540 Leydig cells in a dose-dependent manner. Low doses of rapamycin effectively upregulate steroidogenic enzymes, steroidogenic acute regulatory protein and 3ß-HSD expression in Leydig cells. Rapamycin upregulates ACE2 expression through p-PKAc and p-PI3k in Ang II-treated cells. Further, rapamycin curbs mitochondrial superoxide generation and depleted mitochondrial membrane potential induced by Ang II through activation of Nrf2-mediated Gpx4 and superoxide dismutase 2 expression. Our results revealed the involvement of ACE2, AT1R, AT2R, PKAc, and oxidative stress in Ang-II-induced testicular toxicity, suggesting low-dose rapamycin could be a potential therapeutic candidate to attenuate testicular toxicity.
Assuntos
Angiotensina II , Hipertensão , Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2 , Animais , Feminino , Humanos , Hidroxiesteroide Desidrogenases , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Células Intersticiais do Testículo/metabolismo , Masculino , Fator 2 Relacionado a NF-E2 , Fosfatidilinositol 3-Quinases , Ratos , Ratos Endogâmicos SHR , Sirolimo/farmacologia , Sirolimo/uso terapêutico , SuperóxidosRESUMO
Oral squamous cell carcinoma (OSCC) is particularly prevalent in Taiwan. The goal of this study was to determine the clinicopathological role of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) proteins as an indicator of clinical outcomes in OSCC patients. In this study, immunohistochemical (IHC) analysis was used to examine IGF2BP2 protein expression in 244 OSCC patients. We investigated the relationships among IGF2BP2 expression, clinicopathological variables, and patient survival. Our results showed that IGF2BP2 cytoplasmic protein expression was significantly correlated with lymph node metastasis, cancer stage, and patient survival. Kaplan-Meier survival curves revealed that elevated cytoplasmic IGF2BP2 expression levels in OSCC patients were associated with poor overall survival. Moreover, multivariate cox proportional hazard models revealed that cytoplasmic IGF2BP2 expression, T status, and lymph node metastasis were independent prognostic factors for survival. In conclusion, IGF2BP2 protein was found to be a helpful predictive marker for OSCC patients, as well as a possible therapeutic target for OSCC treatment.
Assuntos
Neoplasias de Cabeça e Pescoço , Proteínas de Ligação a RNA/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Biomarcadores Tumorais/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/fisiopatologiaRESUMO
Background and Objectives: Kruppel-like factor 10 (KLF10) participates in the tumorigenesis of several human cancers by binding to the GC-rich region within the promoter regions of specific genes. KLF10 is downregulated in human cancers. However, the role of KLF10 in gastric cancer formation remains unclear. Materials and Methods: In this study, we performed immunohistochemical staining for KLF10 expression in 121 gastric cancer sections. Results: The loss of KLF10 expression was correlated with advanced stages and T status. Kaplan-Meier analysis revealed that patients with higher KLF10 levels had longer overall survival than those with lower KLF10 levels. Univariate analysis revealed that in patients with gastric cancer, advanced stages and low KLF10 levels were associated with survival. Multivariate analysis indicated that age, gender, advanced stages, and KLF10 expression were independent prognostic factors of the survival of patients with gastric cancer. After adjusting for age, gender, and stage, KLF10 expression was also found to be an independent prognostic factor in the survival of patients with gastric cancer. Conclusion: Our results collectively suggested that KLF10 may play a critical role in gastric cancer formation and is an independent prognosis factor of gastric cancer.
Assuntos
Fatores de Transcrição de Resposta de Crescimento Precoce , Neoplasias Gástricas , Transformação Celular Neoplásica , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Prognóstico , Neoplasias Gástricas/genéticaRESUMO
OBJECTIVES: Distinguishing Kikuchi disease (KD) from lupus lymphadenitis (LL) histologically is nearly impossible. We applied C4d immunohistochemical (IHC) stain to develop diagnostic tools. METHODS: We retrospectively investigated clinicopathological features and C4d IHC staining in an LL-enriched development cohort (19 LL and 81 KD specimens), proposed risk stratification criteria and trained machine learning models, and validated them in an external cohort (2 LL and 55 KD specimens). RESULTS: Clinically, we observed that LL was associated with an older average age (33 vs 25 years; P=0.005), higher proportion of biopsy sites other than the neck [4/19 (21%) vs 1/81 (1%); P=0.004], and higher proportion of generalized lymphadenopathy compared with KD [9/16 (56%) vs 7/31 (23%); P=0.028]. Histologically, LL involved a larger tissue area than KD did (P=0.006). LL specimens exhibited more frequent interfollicular pattern [5/19 (26%) vs 3/81 (4%); P=0.001] and plasma cell infiltrates (P=0.002), and less frequent histiocytic infiltrates in the necrotic area (P=0.030). Xanthomatous infiltrates were noted in 6/19 (32%) LL specimens. Immunohistochemically, C4d endothelial staining in the necrotic area [11/17 (65%) vs 2/62 (3%); P<10-7], and capillaries/venules [5/19 (26%) vs 7/81 (9%); P=0.048] and trabecular/hilar vessels [11/18 (61%) vs 8/81 (10%); P<10-4] in the viable area was more common in LL. During validation, both the risk stratification criteria and machine learning models were superior to conventional histological criteria. CONCLUSIONS: Integrating clinicopathological and C4d findings could distinguish LL from KD.
Assuntos
Complemento C4b/metabolismo , Linfadenite Histiocítica Necrosante/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Linfadenite/diagnóstico , Fragmentos de Peptídeos/metabolismo , Diagnóstico Diferencial , Feminino , Linfadenite Histiocítica Necrosante/patologia , Humanos , Lúpus Eritematoso Sistêmico/patologia , Linfonodos/patologia , Linfadenite/patologia , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The aim of this study was to investigate the effects of longan flower (LF) water extract on cardiac apoptotic and survival pathways in rat models of fructose-induced metabolic syndrome. The study findings revealed that the levels of glucose, insulin, triglyceride, and cholesterol and TUNEL-positive apoptotic cells were significantly increased in the HF group compared with the control group; whereas, the levels were decreased in the HFLF group. The expressions of Fas, FADD, and activated caspases 8 and 3, as well as the expressions of Bax, Bak, Bax/Bcl-2, Bak/Bcl-xL, cytosolic cytochrome c, and activated caspases 9 and 3 were increased in the HF group were significantly reversed in HFLF administrated group. Furthermore, LF extract increased IGF-1R, p-PI3K, p-Akt, Bcl-2, and Bcl-xL expression compared to HF group. Taken together, the present findings help identify LF as a potential cardioprotective agent that can be effectively used in treating fructose-induced metabolic syndrome.
Assuntos
Síndrome Metabólica , Animais , Apoptose , Flores , Frutose/toxicidade , Síndrome Metabólica/induzido quimicamente , Miocárdio , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Sapindaceae , Proteína X Associada a bcl-2 , Receptor fasRESUMO
Background and Objectives: Oral squamous cell carcinoma (OSCC) is a malignant disease with a particularly high incidence in Taiwan. Our objective in this study was to elucidate the involvement of sphingolipid transporter 2 (SPNS2) expression and SPNS2 protein expression in the clinicopathological indexes and the clinical outcomes of OSCC patients. Materials and Methods: Immunohistochemistry analysis was performed for SPNS2 protein expression in samples from 264 cases of OSCC. Correlations of SPNS2 expression with clinicopathological variables and patient survival were analyzed. Results: Our results revealed that the cytoplasmic protein expression of SPNS2 in OSCC tissue specimens was lower than in normal tissue specimens. Negative cytoplasmic protein expression of SPNS2 was significantly correlated with T status and stage. Kaplan-Meier survival curve analysis revealed that negative cytoplasmic SPNS2 expression was predictive of poorer overall survival of OSCC patients in stage III/IV. We also determined that low SPNS2 expression was an independent prognostic factor related to overall survival among OSCC patients in stage III/IV from univariate Cox proportional hazard models. Multivariate Cox proportional hazard models revealed that cytoplasmic SPNS2 expression, T status, lymph node metastasis, and histological grade were independent prognostic factors for survival. Conclusions: Overall, this study determined that SPNS2 protein may be a useful prognostic marker for OSCC patients and potential therapeutic target for OSCC treatment.
Assuntos
Proteínas de Transporte de Ânions , Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Biomarcadores Tumorais , Humanos , Prognóstico , TaiwanRESUMO
BACKGROUND AND OBJECTIVES: Krüppel-like transcription factor 10 (KLF10) plays a vital role in regulating cell proliferation, including the anti-proliferative process, activation of apoptosis, and differentiation control. KLF10 may also act as a protective factor against oral cancer. We studied the impact of KLF10 expression on the clinical outcomes of oral cancer patients to identify its role as a prognostic factor in oral cancer. MATERIALS AND METHODS: KLF10 immunoreactivity was analyzed by immunohistochemical (IHC) stain analysis in 286 cancer specimens from primary oral cancer patients. The prognostic value of KLF10 on overall survival was determined by Kaplan-Meier analysis and the Cox proportional hazard model. RESULTS: High KLF10 expression was significantly associated with male gender and betel quid chewing. The 5-year survival rate was greater for patients with high KLF10 expression than for those with low KLF10 expression (62.5% vs. 51.3%, respectively; p = 0.005), and multivariate analyses showed that high KLF10 expression was the only independent factor correlated with greater overall patient survival. The significant correlation between high KLF10 expression and a higher 5-year survival rate was observed in certain subgroups of clinical parameters, including female gender, non-smokers, cancer stage T1, and cancer stage N0. CONCLUSIONS: KLF10 expression, detected by IHC staining, could be an independent prognostic marker for oral cancer patients.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Fatores de Transcrição de Resposta de Crescimento Precoce , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Neoplasias Bucais/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Cancer stem cells (CSCs) exist in colon cancer and exhibit characteristics of stem cells which are due to lineages of tissues where they arise. Epithelial to mesenchymal transition (EMT)-undergoing cancer cells display CSC properties and therapeutic resistance. Cancer and stromal cells comprise of a tumor microenvironment. One way the two populations communicate with each other is to secret CXC ligands (CXCLs). CXCLs are capable of causing chemotaxis of specific types of stromal cells and control angiogenesis. Double immunofluorescence, western blot analysis, and colony-formation assay were carried out to compare parental and CPT-11-resistant LoVo cells. CPT-11-R LoVo colon cancer cells showed increased expression of CXCL1, CXCL2, CXCL3, and CXCL8. They displayed significantly increased intracellular protein levels of CXCL2 and CXCR2. CPT-11-R LoVo cells showed significantly elevated expression in aldehyde dehydrogenase 1 (ALDH1), cluster of differentiation 24 (CD24), cluster of differentiation 44 (CD44), and epithelial cell adhesion molecule (EpCAM). CXCL2 knockdown by short hairpin RNA resulted in reduced expression of CSC proteins, cyclins, EMT markers, G proteins, and matrix metalloproteinases (MMPs). Finally, Gαi-2 was found to promote expression of CSC genes and tumorigenesis which were more apparent in the resistant cells. In addition, Gαq/11 showed a similar pattern with exceptions of EpCAM and MMP9. Therefore, CXCL2-CXCR2 axis mediates through Gαi-2 and Gαq/11 to promote tumorigenesis and contributes to CSC properties of CPT-11-R LoVo cells.
Assuntos
Quimiocina CXCL2/metabolismo , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Irinotecano/farmacologia , Células-Tronco Neoplásicas/patologia , Receptores de Interleucina-8B/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Pancreatic damage results in insufficient insulin secretion, leading to type 1 diabetes. Stem cell-based therapy has recently shown potential in the treatment of type 1 diabetes. Resveratrol supplementation has demonstrated a beneficial effect in treating diabetes. This study investigates if adipose-derived stem cells (ADSC), preconditioned with resveratrol, show better effects on experimental diabetic animals. Wistar rats were randomly divided into four groups including sham (normal rats), DM (diabetic rats induced by SZT injection), DM+ADSC (DM rats with receiving autologous ADSC transplantation) and DM+R-ADSC (DM rats receiving resveratrol preconditioned ADSC). The experimental results show that SZT induced pancreatic damage (DM group), including reduction of islet size, fibrosis pathway activation, survival signaling suppression, and apoptotic pathway expression, lead to serum glucose elevation. Autologous ADSC (DM+ADSC group) transplantation shows improvement in the above observations in DM rats. Furthermore, ADSC precondition with resveratrol (DM+R-ADSC group) reveals significant improvement in the above pathological observations over both DM and DM+ADSC groups. We found that ADSC precondition with resveratrol increases the survival marker p-Akt expression, leading to enhanced ADSC viability. This study suggests that ADSC precondition with resveratrol shows potential in the treatment of patients with type 1 DM.
Assuntos
Células-Tronco Mesenquimais/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Resveratrol/farmacologia , Células-Tronco/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/citologia , Animais , Glicemia/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Neovascularização Fisiológica/efeitos dos fármacos , Pâncreas/metabolismo , Ratos Wistar , Células-Tronco/metabolismoRESUMO
Oral Squamous Cell Carcinoma (OSSC) is a major life-threatening disease with high incidence in the Southeast Asian countries. Chronic exposure to arecoline causes genetic changes in the epithelial cells of the oral mucosa, induces proliferation through activation of the EGF receptor and promotes downstream COX-2 expression. Taiwanin C, a podophyllotoxin derived from Taiwania cryptomerioides Hayata is known to inhibit COX activity and to hinder PGE2 production in macrophages. In this study a tumor cell line T28 and a non-tumor cell line N28 derived from mice OSCC models were used to study the effect of Taiwanin C on PGE2 associated COX-2 expression and cell cycle regulators. Taiwanin C activated p21 protein expression, down-regulated cell cycle regulatory proteins, elevated apoptosis and down-regulated p-PI3K/p-Akt survival mechanism in T28 oral cancer cells. Our results therefore emphasize the therapeutic potential of Taiwanin C against arecoline-induced oral cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Lactonas/farmacologia , Lignanas/farmacologia , Neoplasias Bucais/patologia , Inibidores de Fosfoinositídeo-3 Quinase , 4-Nitroquinolina-1-Óxido/toxicidade , Animais , Arecolina/toxicidade , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos C57BL , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/metabolismoRESUMO
Osteosarcoma (OS) is a tumor entity that can cause a large number of cancer-related deaths. Although chemotherapy can decrease proliferation and increase apoptosis of human OS cells, the clinical prognosis remains poor. Fisetin is a flavonol found in fruits and vegetables and is reported to inhibit cell growth in numerous cancers. But the molecular mechanism underlying fisetin in human OS cells is not clear. It is known that sterile-alpha motif and leucine zipper containing kinase (ZAK), a kinase in the MAP3K family, is involved in various cell processes, including proliferation and apoptosis. In our lab, we have demonstrated that overexpression of ZAK can induce apoptosis in human OS cells. In the previous studies, MAP4K, the upstream of MAP3K, can act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Turning on the Hippo pathway can decrease proliferation and otherwise cause cell apoptosis in cancer cells. In this study, we found that fisetin can upregulate ZAK expression to induce the Hippo pathway and mediate the activation of JNK/ERK, the downstream of ZAK, to trigger cell apoptosis via AP-1 dependent manner in human OS cells. These findings reveal a novel molecular mechanism underlying fisetin effect on human OS cells.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/metabolismo , Flavonoides/farmacologia , Sistema de Sinalização das MAP Quinases , Osteossarcoma/metabolismo , Proteínas Quinases/metabolismo , Apoptose , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonóis , Via de Sinalização Hippo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase Quinases , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Cardiac fibrosis is a common pathophysiological process observed during chronic and stress-induced acceleration of cardiac aging. Fibrosis is a necessary process during wound healing and tissue repair. However, its deposition in organs would proceed to scarring and organ damage. Here Alpinate Oxyphyllae Fructus (AOF), a Chinese medicine extract was used to protect aging heart from collagen accumulation. About 8 weeks old, male SD rats were randomly divided into (i) Control, (ii) D-galactose induced aging (IA), (iii) IA + AOF 50 (AOF low, AL), (iv) IA + AOF 100 (AOF medium, AM), (v) IA + AOF 150 (AOF high, AH) mg/kg/day, AOF was administered orally. After 8 weeks rats were sacrificed and hearts were collected. Results showed collagen deposition and up-regulation of matrix metalloproteinases-MMP-2 and -9 in D-galactose-induced aging rats. Furthermore, western blotting and immunostaining were also confirmed the upregulation of TGF-ß1 mediated fibrosis in aging induced rats. However, collagen deposition and fibrosis were significantly decreased by AOF treatments (AM and AH). AOF treatments salvaged the cardiac fibrosis. Hence, AOF might be a potential therapeutic agent in the prevention of cardiac fibrosis associated with aging. The protective effects of AOF might have promising results in anti-aging treatments.
Assuntos
Envelhecimento/efeitos dos fármacos , Alpinia/química , Medicamentos de Ervas Chinesas/farmacologia , Coração/efeitos dos fármacos , Miocárdio/patologia , Substâncias Protetoras/farmacologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Colágeno/metabolismo , Medicamentos de Ervas Chinesas/isolamento & purificação , Fibrose , Frutas/química , Galactose , Masculino , Metaloproteinase 2 da Matriz/genética , Miocárdio/metabolismo , Substâncias Protetoras/isolamento & purificação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/genéticaRESUMO
Carthamus tinctorius L. (Compositae) is used in Chinese medicine to treat heart disease and inflammation. In our previous study, we found that C. tinctorius L. inhibited lipopolysaccharides (LPS)-induced tumor necrosis factor-alpha (TNF-α) activation, JNK expression, and apoptosis in H9c2 cardiomyoblast cells. The present study was performed to investigate the protective effect of C. tinctorius extract (CTF) on LPS-challenged H9c2 myocardioblast cell and to explore the possible underlying mechanism. Cell viability assay showed that LPS treatment decreased the cell viability of H9c2 cell, whereas CTF treatment reversed LPS cytotoxicity in a dose-dependent manner, especially in the LPS + CTF 25 (µg/mL) group. LPS treatment-induced apoptosis was determined by transferase-mediated dUTP nick end labeling assay, and by Western blot. LPS-induced apoptotic bodies were decreased following CTF treatment. Expression of TNF-α, FAS-L, FAS, FADD, caspase-8, BID, and t-BID was significantly increased in LPS-treated H9c2 cells. In contrast, it was significantly suppressed by the administration of CTF extract. In addition, CTF treatment activates antiapoptotic proteins, Bcl-2 and p-Bad, and downregulates Bax, cytochrome-c, caspase-9, caspase-3, and apoptosis-inducing factor expression. Furthermore, CTF exerted cytoprotective effects by activating insulin-like growth factor-I (IGF-I) signaling pathway leading to downregulation of the apoptotic proteins involved in FAS death receptor pathway. In addition, AG1024 and IGF-I receptor (IGF-IR) inhibitor and siRNA silencing reverses the effect of CTF implying that CTF functions through the IGF-IR pathway to inhibit LPS-induced H9c2 apoptosis. These results suggest that treatment with CTF extract prevented the LPS-induced apoptotic response through IGF-I pathway.
Assuntos
Apoptose/efeitos dos fármacos , Carthamus tinctorius/química , Extratos Vegetais/farmacologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor fas/metabolismo , Animais , Carthamus tinctorius/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Oxaliplatin (OXA), is a third generation platinum drug used as first-line chemotherapy in colorectal cancer (CRC). Cancer cells acquires resistance to anti-cancer drug and develops resistance. ATP-binding cassette (ABC) drug transporter ABCG2, one of multidrug resistance (MDR) protein which can effectively discharge a wide spectrum of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular concentration of these drugs. Role of ABCG2 and plausible molecular signaling pathways involved in Oxaliplatin-Resistant (OXA-R) colon cancer cells was evaluated in the present study. OXA resistant LoVo cells was developed by exposing the colon cells to OXA in a dose-dependent manner. Development of multi drug resistance in OXA-R cells was confirmed by exposing the resistance cells to oxaliplatin, 5-FU, and doxorubicin. OXA treatment resulted in G2 phase arrest in parental LoVo cells, which was overcome by OXA-R LoVo cells. mRNA and protein expression of ABCG2 and phosphorylation of NF-κB was significantly higher in OXA-R than parental cells. Levels of ER stress markers were downregulated in OXA-R than parental cells. OXA-R LoVo cells exposed to NF-κB inhibitor QNZ effectively reduced the ABCG2 and p-NF-κB expression and increased ER stress marker expression. On other hand, invasion and migratory effect of OXA-R cells were found to be decreased, when compared to parental cells. Metastasis marker proteins also downregulated in OXA-R cells. ABCG2 inhibitor verapamil, downregulate ABCG2, induce ER stress markers and induces apoptosis. In vivo studies in nude mice also confirms the same.