RESUMO
Most patients with differentiated thyroid cancer have a good prognosis after radioactive iodine-131 treatment, but there are still a small number of patients who are not sensitive to radioiodine treatment and may subsequently show disease progression. Therefore, radioactive-iodine refractory differentiated thyroid cancer treated with radioiodine usually shows reduced radioiodine uptake. Thus, when sodium iodine symporter expression, basolateral membrane localization and recycling degradation are abnormal, radioactive-iodine refractory differentiated thyroid cancer may occur. In recent years, with the deepening of research into the pathogenesis of this disease, an increasing number of molecules have become or are expected to become therapeutic targets. The application of corresponding inhibitors or combined treatment regimens for different molecular targets may be effective for patients with advanced radioactive-iodine refractory differentiated thyroid cancer. Currently, some targeted drugs that can improve the progression-free survival of patients with radioactive-iodine refractory differentiated thyroid cancer, such as sorafenib and lenvatinib, have been approved by the FDA for the treatment of radioactive-iodine refractory differentiated thyroid cancer. However, due to the adverse reactions and drug resistance caused by some targeted drugs, their application is limited. In response to targeted drug resistance and high rates of adverse reactions, research into new treatment combinations is being carried out; in addition to kinase inhibitor therapy, gene therapy and rutin-assisted iodine-131 therapy for radioactive-iodine refractory thyroid cancer have also made some progress. Thus, this article mainly focuses on sodium iodide symporter changes leading to the main molecular mechanisms in radioactive-iodine refractory differentiated thyroid cancer, some targeted drug resistance mechanisms and promising new treatments.
Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/radioterapia , Radioisótopos do Iodo/uso terapêutico , Sorafenibe/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Intervalo Livre de Progressão , Adenocarcinoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Acute kidney injury (AKI) is closely linked to the pathogenesis of sepsis. Oxidative stress can affect the development of AKI by increasing damage to renal tubular epithelial cells. Astragaloside IV (AS-IV) is a natural saponin widly verified beneficial for ameliorating sepsis-induced kidney injury. However, the underlying mechanisms of AS-IV on relieving oxidative stress in renal tubular epithelial cells are yet to be established. PURPOSE: We aimed to investigate whether AS-IV could attenuate mitochondrialdysfunction and apoptosis in renal tubular epithelial cells and reveal its underlying mechanisms. METHODS: For the in vivo study, mice were divided into four groups (n=6): sham+saline, CLP+saline, CLP+ASIV- low dosage (5 mg/kg), CLP+AS-IV-high dosage (10 mg/kg), After 6 h or 24 h of treatment, the renal injuries were assessed based on related parameters of blood, protein and histopathological examination. Immunohistochemistry and ELISA were used to examine renal function. The molecular mechanism of AS-IV inhibited apoptosis and mitochondrial damage were monitored by flow cytometry and western blot analysis in HK-2 cells. RESULTS: We found that AS-IV ameliorates renal vacuolization, brush border loss, mitochondrial ultrastructure changes in sepsis-induced AKI, and the apoptosis and oxidative damage were greatly mitigated by AS-IV (10 mg/kg)-treated group. Abnormal changes in mitochondrial morphology and mitochondrial membrane potential were alleviated, and the expression of mitochondrial complex protein I (NDUFB8) and mitochondrial complex protein II (SDHB8) increased with (10 mg/kg)-treated group. Tubular epithelial cell apoptosis in AS-IV (20 µM)-treated cells was reduced by the Bax and cleaved caspase3 pathway. CONCLUSION: These studies demonstrated that AS-IV protects against sepsis-induced kidney tubular injury by alleviating oxidative stress, mitochondrial dysfunction possibly associated with the restored cleaved caspase3 pathway.
Assuntos
Injúria Renal Aguda , Saponinas , Sepse , Camundongos , Animais , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Saponinas/farmacologia , Saponinas/uso terapêutico , Saponinas/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Apoptose , Mitocôndrias/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Células Epiteliais/metabolismoRESUMO
Lignans found in the botanical extract of the Traditional Chinese Medicine Sambucus williamsii Hance exhibit protective effects on trabecular bone mass and mechanical strength of cortical bone of ovariectomized rats. A novel approach was adapted using HSQC NMR methods to estimate the total amount of these bioactives in a complex mixture. It was determined that lignans possessing the hydroxy- or oxybenzyl carbon signal were bioactive. These compounds were readily identified and assigned in a defined region of the 13C NMR spectrum at 80-90 ppm and calculated as 10-15% of the lignan-rich fraction of S. williamsii. Comparison of the peak heights of the oxybenzyl-substituted carbon resonance signals of the lignans in the botanical extract was made against those of a standard lignan pinoresinol. The application of this simple and reliable NMR method can be used to estimate amounts of related compounds and chemical families in complex mixtures or botanical extracts and offers measurable scientific evidence in quality processes. This is of particular importance for registration requirements of botanical drugs and in complex mixtures of botanical extracts.
Assuntos
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Misturas Complexas/química , Lignanas/análise , Sambucus/química , Animais , Linhagem Celular , CamundongosRESUMO
PURPOSE: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. METHODS: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. RESULTS: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. CONCLUSION: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions.
Assuntos
Antibacterianos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Imunomodulação/efeitos dos fármacos , Pneumonia Estafilocócica/prevenção & controle , Polygonum/química , Substâncias Protetoras/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/química , Quimiocina CCL2/análise , Contagem de Colônia Microbiana , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Interleucina-6/análise , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/patologia , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análiseRESUMO
Abstract Purpose: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. Methods: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. Results: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. Conclusion: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions.
Assuntos
Animais , Pneumonia Estafilocócica/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Substâncias Protetoras/farmacologia , Polygonum/química , Imunomodulação/efeitos dos fármacos , Antibacterianos/farmacologia , Pneumonia Estafilocócica/patologia , Pneumonia Estafilocócica/tratamento farmacológico , Fatores de Tempo , Ensaio de Imunoadsorção Enzimática , Líquido da Lavagem Broncoalveolar/química , Imuno-Histoquímica , Contagem de Colônia Microbiana , Reprodutibilidade dos Testes , Interleucina-6/análise , Fator de Necrose Tumoral alfa/análise , Resultado do Tratamento , Quimiocina CCL2/análise , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BLRESUMO
The acute lung injury (ALI) is a leading cause of morbidity and mortality in critically ill patients. Amygdalin is derived from the bitter apricot kernel, an efficacious Chinese herbal medicine. Although amygdalin is used by many cancer patients as an antitumor agent, there is no report about the effect of amygdalin on acute lung injury. Here we explored the protective effect of amygdalin on ALI using lipopolysaccharide (LPS)-induced murine model by detecting the lung wet/dry ratio, the myeloperoxidase (MPO) in lung tissues, inflammatory cells in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines production, as well as NLRP3 and NF-κB signaling pathways. The results showed that amygdalin significantly reduced LPS-induced infiltration of inflammatory cells and the production of TNF-α, IL-1ß, and IL-6 in the BALF. The activity of MPO and lung wet/dry ratio were also attenuated by amygdalin. Furthermore, the western blotting analysis showed that amygdalin remarkably inhibited LPS-induced NF-κB and NLRP3 activation. These findings indicate that amygdalin has a protective effect on LPS-induced ALI in mice. The mechanism may be related to the inhibition of NF-κB and NLRP3 signaling pathways.
Assuntos
Amigdalina/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Amigdalina/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Ischemia/reperfusion injury (IRI) has lzong been an area of concern and focus of investigations. Erythropoietin (EPO) exhibits multiple protective effects, and selenium is an antioxidant trace element in the body, however, there have been no reports concerning the effects of EPO combined with sodium selenite on IRI. In the present study, a mouse model of renal IRI (RIRI) was pretreated with EPO and sodium selenite to determine the most appropriate combination ratio of the two for further investigation. The results revealed that EPO and sodium selenite had synergistic protective effects in RIRI. EPO was identified as the predominant treatment component, with sodium selenite serving as an adjuvant, and combination treatment was markedly more effective, compared with treatment with either drug alone. The optimal ratio of treatment was 10:1 (10 IU EPO: 1 µg sodium selenite). The results indicated that RIRI markedly induced renal injury, as evidenced by elevated levels of blood urea nitrogen (BUN), as well as higher pathological scores, based on hematoxylin and eosin staining. Pretreatment with EPO and sodium selenite significantly decreased serum expression levels of BUN and malonaldehyde, and increased the expression levels of superoxide dismutase, glutathione peroxidase and nitric oxide (NO), compared with the model group. Furthermore, cotreatment with EPO and sodium selenite upregulated the protein expression levels of phosphatidylinositol3 kinase (PI3K) in renal tissue samples. Together, the results suggested that coadministration of EPO and sodium selenite effectively ameliorates IRIinduced renal injury by reducing oxidative stress and activating the PI3K/NO signaling pathway.
Assuntos
Eritropoetina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Selenito de Sódio/uso terapêutico , Animais , Nitrogênio da Ureia Sanguínea , Sinergismo Farmacológico , Quimioterapia Combinada , Eritropoetina/administração & dosagem , Glutationa Peroxidase/metabolismo , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Substâncias Protetoras/administração & dosagem , Selenito de Sódio/administração & dosagem , Superóxido Dismutase/metabolismoRESUMO
Previous studies have implicated erythropoietin (EPO) signaling in the regulation of glucose metabolism. Whether EPO can be used treat diabetes and the underlying mechanism remain to be elucidated. The present study aimed to investigate whether EPO affects glucose metabolism, and the underlying mechanisms, in experimental diabetic rats. The effects of EPO (300 U/kg three times a week for 4 weeks) on glucose metabolism, hematopoietic function, blood selenium content and the ultrastructure of pancreatic ßcells were investigated in low dose (25 mg/kg body weight) streptozotocininduced experimental diabetic rats provided with a highfat diet. The results demonstrated that EPO significantly decreased the fasting blood glucose, the area under the curve of the oral glucose tolerance and insulin tolerance tests and Lalanine gluconeogenesis. Ultrastructural examination of the pancreatic islets revealed that EPO prevented the dysfunction of pancreatic ßcells in experimental diabetic rats, ameliorated cytoplasmic vacuolation and fragmentation of mitochondria, and increased the number of secretory granules. EPO administration increased the activities of superoxide dismutase and glutathione peroxidase, and decreased the level of malondialdehyde. Additionally, EPO increased blood selenium in the diabetic rats and produced a hematopoietic effect. These results indicated that EPO modulated glucose metabolism and improved pancreatic ßcells damage by increasing antioxidation. The detailed mechanisms underlying these effects require further investigation.