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1.
Life Sci ; 258: 118153, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738361

RESUMO

AIMS: Obesity-related glomerulopathy (ORG) is characterized by glomerulomegaly with or without focal and segmental glomerulosclerosis lesions. Isothiocyanate sulforaphane (SFN) can protect kidneys from ORG-related damages. In this study, we investigated the effects of SFN as a preventive therapy or intervention for ORG to reveal its mechanism of action. MAIN METHODS: We established a mouse obesity model with preventive SFN or N-acetylcysteine treatment for 2 months. Thereafter, we used nuclear factor erythroid 2-related factor 2-deficient (Nrf2-/-) and wild type mice in our ORG model with SFN treatment. Finally, we generated a corresponding mouse podocyte model in vitro. The body weight, wet weight of perirenal-and peritesticular fat, and urinary albumin/creatinine ratio were assessed. We used periodic acid-Schiff staining and electron microscopy to assess the function of the kidneys and podocytes. In addition, we evaluated the expression of Nrf2 and podocyte-specific proteins by western blotting. KEY FINDINGS: Treatment with SFN reduced body weight, organ-associated fat weight, and urinary albumin/creatinine ratio in both the preventive treatment and disease intervention regimens. SFN treated mice exhibited higher expression levels of podocyte-specific proteins and better podocyte function. However, treatment with SFN did not affect these parameters in obese Nrf2-/- mice. Light chain 3 of microtubule-associated protein 1-II and metallothionein had higher expression in the wild type than in the Nrf2-/- mice. SIGNIFICANCE: Treatment with SFN limited ORG-induced damage by enhancing podocyte autophagy via Nrf2.


Assuntos
Isotiocianatos/uso terapêutico , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/complicações , Substâncias Protetoras/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Nefropatias/metabolismo , Glomérulos Renais/citologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Podócitos/citologia , Podócitos/efeitos dos fármacos , Podócitos/metabolismo
2.
Chem Biol Interact ; 329: 109213, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32739323

RESUMO

Phytoestrogens are plant-derived substances with a similar structure to 17-beta-estradiol, which have protective roles in estrogen-dependent diseases. Isoflavones, the most well-known subgroup of phytoestrogens, play protective roles against chemicals-induced liver injuries through several molecular mechanisms. Hepatoprotective effects of isoflavones are, partly, associated with their antioxidant, anti-inflammatory, immunomodulatory, and anti-fibrotic properties. Besides, isoflavones can reduce gut-derived endotoxins, accelerate alcohol metabolism, stimulate detoxification of hepatotoxic chemicals, suppress the bioactivation of these chemicals, inhibit hepatocytes apoptosis, and restore autophagy activity during chemicals-induced liver diseases. This review provides a summary of the molecular mechanisms underlying the hepatoprotective effects of isoflavones. It seems that further studies are needed to investigate the hepatoprotective potential of isoflavones in patients with different stages of chemicals-induced liver injuries.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Isoflavonas/metabolismo , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Inflamação/prevenção & controle , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia
3.
PLoS One ; 15(8): e0237086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764782

RESUMO

Paramylon is a novel ß-glucan that is stored by Euglena gracilis Z, which is a unicellular photosynthesizing green alga with characteristics of both animals and plants. Recent studies have indicated that paramylon functions as an immunomodulator or a dietary fiber. Currently, chronic kidney disease (CKD) is a global health problem, and there is no effective preventive treatment for CKD progression. However, paramylon may suppress the progression of CKD via the elimination of uremic toxins or modulation of gut microbiota, leading to the alleviation of inflammation. The aim of this study was to evaluate the effect of paramylon in CKD rat model. Eight-week-old male Wistar rats with a 5/6 nephrectomy were given either a normal diet or a diet containing 5% paramylon for 8 weeks. Proteinuria was measured intermittently. Serum and kidney tissues were harvested after sacrifice. We performed a renal molecular and histopathological investigation, serum metabolome analysis, and gut microbiome analysis. The results showed that paramylon attenuated renal function, glomerulosclerosis, tubulointerstitial injury, and podocyte injury in the CKD rat model. Renal fibrosis, tubulointerstitial inflammatory cell infiltration, and proinflammatory cytokine gene expression levels tended to be suppressed with paramylon treatment. Further, paramylon inhibited the accumulation of uremic toxins, including tricarboxylic acid (TCA) cycle-related metabolites and modulated a part of CKD-related gut microbiota in the CKD rat model. In conclusion, we suggest that paramylon mainly inhibited the absorption of non-microbiota-derived uremic solutes, leading to protect renal injury via anti-inflammatory and anti-fibrotic effects. Paramylon may be a novel compound that can act against CKD progression.


Assuntos
Glucanos/farmacologia , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Euglena gracilis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Glucanos/isolamento & purificação , Glucanos/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Rim/imunologia , Rim/patologia , Masculino , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , Proteinúria/sangue , Proteinúria/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Toxinas Biológicas/sangue , Toxinas Biológicas/metabolismo
4.
PLoS One ; 15(8): e0236879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790676

RESUMO

Benign prostatic hyperplasia (BPH) is a progressive pathological condition associated with proliferation of prostatic tissues, prostate enlargement, and lower-urinary tract symptoms. However, the mechanism underlying the pathogenesis of BPH is unclear. The aim of this study was to investigate the protective effects of a combination of Stauntonia hexaphylla and Cornus officinalis (SC extract) on a testosterone propionate (TP)-induced BPH model. The effect of SC extract was examined in a TP-induced human prostate adenocarcinoma cell line. Male Sprague-Dawley rats were randomly divided into 5 groups (n = 6) for in vivo experiments. To induce BPH, all rats, except those in the control group, were administered daily with subcutaneous injections of TP (5 mg/kg) and orally treated with appropriate phosphate buffered saline/drugs (finasteride/saw palmetto/SC extract) for 4 consecutive weeks. SC extract significantly downregulated the androgen receptor (AR), prostate specific antigen (PSA), and 5α-reductase type 2 in TP-induced BPH in vitro. In in vivo experiments, SC extract significantly reduced prostate weight, size, serum testosterone, and dihydrotestosterone (DHT) levels. Histologically, SC extract markedly recovered TP-induced abnormalities and reduced prostatic hyperplasia, thereby improving the histo-architecture of TP-induced BPH rats. SC extract also significantly downregulated AR and PSA expression, as assayed using immunoblotting. Immunostaining revealed that SC extract markedly reduced the 5α-reductase type 2 and significantly downregulated the expression of proliferating cell nuclear antigen. In addition, immunoblotting of B-cell lymphoma 2 (Bcl-2) family proteins indicated that SC extract significantly downregulated anti-apoptotic Bcl-2 and markedly upregulated pro-apoptotic B cell lymphoma-associated X (Bax) expression. Furthermore, SC treatment significantly decreased the Bcl-2/Bax ratio, indicating induced prostate cell apoptosis in TP-induced BPH rats. Thus, our findings demonstrated that SC extract protects against BPH by inhibiting 5α-reductase type 2 and inducing prostate cell apoptosis. Therefore, SC extract might be useful in the clinical treatment of BPH.


Assuntos
Apoptose/efeitos dos fármacos , Colestenona 5 alfa-Redutase/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/prevenção & controle , Substâncias Protetoras/uso terapêutico , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Cornus/química , Cornus/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Folhas de Planta/metabolismo , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/etiologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ranunculales/química , Ranunculales/metabolismo , Ratos , Ratos Sprague-Dawley , Propionato de Testosterona/efeitos adversos
5.
Khirurgiia (Mosk) ; (7): 76-81, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32736467

RESUMO

OBJECTIVE: To evaluate symptom-modifying effects of a two-month parenteral therapy with chondroitin sulfate («Mucosat¼) in patients with knee and/or hip osteoarthritis (OA) in various combinations of adjuvant therapy. MATERIAL AND METHODS: There were 70 patients with primary and/or post-traumatic unilateral/bilateral knee and/or hip osteoarthritis (Kellgren-Lawrence grade I-II). Pain syndrome severity was assessed as ≥ 50 mm (100-mm VAS), total Leken's index - ≥ 5 points. The main group comprised 40 patients who received Mucosat for 60 days. NSAIDs were additionally prescribed in 9 (22.5%) of these patients. The control group included 30 patients with intra-articular injection of hyaluronic acid. All patients underwent clinical and functional examination (rating scales VAS, Leken's total index, WOMAC index, EQ-5D health questionnaire), laboratory diagnosis (IL-1, IL-6, TNF-α), X-ray examination, assessment of adverse events at 5 visits. RESULTS AND CONCLUSION: Administration of chondroitin sulfate is associated with reduced local pain syndrome and functional normalization of musculoskeletal system. Prolonged pain-free period with high safety profile due to reduced need for NSAIDs is an advantage of Mucosat therapy. Thus, this drug may be recommended for initial therapy. A combination of chondroitin sulfate with intra-articular injection of hyaluronic acid may be perspective for optimization of therapy and secondary prevention of exacerbations of OA. Further research is required.


Assuntos
Sulfatos de Condroitina/uso terapêutico , Ácido Hialurônico/uso terapêutico , Osteoartrite do Quadril/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Artralgia/tratamento farmacológico , Artralgia/etiologia , Sulfatos de Condroitina/administração & dosagem , Humanos , Ácido Hialurônico/administração & dosagem , Injeções Intra-Articulares , Osteoartrite do Quadril/complicações , Osteoartrite do Joelho/complicações , Substâncias Protetoras/administração & dosagem , Resultado do Tratamento
7.
Braz J Med Biol Res ; 53(7): e9271, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520202

RESUMO

Montelukast sodium is an effective and well-tolerated anti-asthmatic drug. Long non-coding RNAs (lncRNAs) are involved in the treatment of asthma. Therefore, this study aimed to investigate the effect of montelukast sodium on children with cough-variant asthma (CVA) and the role of lncRNA prostate cancer gene expression marker 1 (PCGEM1) in drug efficacy. The efficacy of montelukast sodium was evaluated by assessing the release of inflammatory factors and pulmonary function in CVA children after a 3-month treatment. An ovalbumin (OVA)-sensitized mouse model was developed to simulate asthmatic conditions. PCGEM1 expression in clinical peripheral blood samples and lung tissues of asthmatic mice was determined. Asthmatic mice experienced nasal inhalation of PCGEM1 overexpression with simultaneous montelukast sodium to investigate the roles of PCGEM1 in asthma treatment. The NF-κB axis after PCGEM1 overexpression was detected to explore the underling mechanisms. Consequently, montelukast sodium contributed to reduced levels of pro-inflammatory factors and improved pulmonary function in CVA children. PCGEM1 was poorly expressed in OVA-sensitized asthmatic mice and highly expressed in CVA children with response to the treatment. PCGEM1 overexpression enhanced the anti-inflammatory effects and promoted effects on pulmonary function of montelukast sodium in CVA children and OVA-sensitized asthmatic mice. Furthermore, PCGEM1 inhibited the activation of the NF-κB axis. This study demonstrated the anti-inflammatory and lung-protective effects of montelukast sodium on CVA, which was strengthened by overexpression of PCGEM1. Findings in this study highlighted a potential anti-asthmatic target of montelukast sodium.


Assuntos
Acetatos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Tosse/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Quinolinas/uso terapêutico , RNA Longo não Codificante/metabolismo , Animais , Asma/sangue , Criança , Pré-Escolar , Tosse/sangue , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
8.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 73-76, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476376

RESUMO

OBJECTIVE: To find if edaravone can play a protective role in a mouse model of pulmonary oxygen toxicity and explore the intervention mechanism. METHODS: Thirty male C57BL/6 mice were randomly divided into 3 groups(Air +Vehicle, Hyperbaric oxygen(HBO) +Vehicle and HBO + Edaravone). Mice were either given edaravone (5 mg/(kg·d)) in sterilized water or a sterilized water vehicle for 3 days before oxygen exposure. Mice in HBO groups were exposed to 0.23 MPa hyperoxia (≥95% O2) for 6 h. Lung tissues were collected and the wet/dry ratio of lung were analyzed. For histologic analysis, lung sections were stained with hematoxylin and eosin (HE). Proinflammatory cytokine levels and antioxidant enzyme activities in lungs were determined by using ELISA kits. The expression levels of pro-apoptosis protein were determined with Western blot analysis. RESULTS: Edaravone treatment could significantly reduce lung permeability, decrease tissue pro-apoptosis protein (cleaved-caspase3) and inflammation (IL-1ß). However, edaravone treatment had no effect on antioxidant enzyme activities. CONCLUSION: These results showed that edaravone treatment had a protective role in pulmonary oxygen toxicity through curbing inflammation and apoptosis.


Assuntos
Edaravone/uso terapêutico , Hiperóxia/tratamento farmacológico , Oxigênio/toxicidade , Substâncias Protetoras/uso terapêutico , Animais , Apoptose , Inflamação , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
10.
Curr Diabetes Rev ; 16(8): 820-832, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442089

RESUMO

BACKGROUND: We thought to delve deeper into seven meta-analyses of major clinical trials focusing on Glucagon-Like Peptide-One Receptor Agonist (GLP-1 RA) cardioprotective effect. AIM: We explored the role of GLP-1 RA in cardiovascular risk protection as the primary outcome in subjects with type 2 diabetes mellitus. METHODOLOGY: The current review has explored and critically appraised seven meta-analyses of placebo- controlled randomized clinical trials (RCT-s) involving GLP-1 RA used in diabetes that has exhibited major cardiovascular events as the primary outcome. RESULTS: Based on the participants-intervention-comparison and outcomes (PICO), the total number of the participants in this review were (138750), the intervention was conducted with GLP-1 RA, the comparator was a placebo and the outcome was major cardiovascular events. The overall evidence for the cardioprotective effect of GLP-1 RA in diabetes was very clear in subjects with the cardiovascular risk of varying degrees. Most of the currently reviewed meta-analyses have not shown cardioprotection with GLP-1 RA in subjects with diabetes exhibiting high cardiovascular risk or medical history of cardiovascular diseases. Patient variability, in addition to potency parameters, will be the key to a successful member of the class. There will be avenues for selection of a candidate based on the suitability to patient preferences and characteristics. CONCLUSION: The RCT-s for GLP-1 RA should characterize cardiovascular risk in subjects with diabetes such that disparities between established cardiovascular risk (high, moderate and low) or medical history of cardiovascular disease have been accounted for in subgroup analysis.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Substâncias Protetoras/uso terapêutico , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco
11.
Elife ; 92020 04 06.
Artigo em Inglês | MEDLINE | ID: covidwho-38616

RESUMO

The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARS- CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). The angiotensin converting enzyme-1-angiotensin II-angiotensin AT1 receptor pathway contributes to the pathophysiology of ARDS, whereas activation of the ACE-2-angiotensin(1-7)-angiotensin AT2 receptor and the ACE-2-angiotensin(1-7)-Mas receptor pathways have been shown to be protective. Here we propose and discuss therapeutic considerations how to increase soluble ACE-2 in plasma in order for ACE-2 to capture and thereby inactivate SARS-CoV-2. This could be achieved by administering recombinant soluble ACE-2. We also discuss why and how ACEIs and ARBs provide cardiovascular, renal and also pulmonary protection in SARS-CoV-2- associated ARDS. Discontinuing these medications in COVID-19 patients may therefore potentially be harmful.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pulmão/metabolismo , Pulmão/virologia , Pandemias , Pneumonia Viral/epidemiologia , Substâncias Protetoras/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos
12.
Chem Biol Interact ; 324: 109098, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278740

RESUMO

This study evaluates the possible protective effects of gallic acid (GaA) and ferulic acid (FeA) against an experimentally induced liver fibrosis by thioacetamide (TAA) in rats. Animals were divided into: Control group, GaA group (20 mg/kg/day, p.o), FeA (20 mg/kg/day, p.o), TAA group (receiving 250 mg/kg twice/week, I.P), TAA + GaA group, TAA + FeA group (received the same previous doses) and TAA+silymarin group (received silymarin at 100 mg/kg/day+TAA as mentioned above). After 6 consecutive weeks, animals were sacrificed and the assessment of liver functions, oxidative stress biomarkers and histopathological examination of the liver tissues were performed. In addition, the effect on TGF-ß1/Smad3 signaling and the expression of miR-21, miR-30 and miR-200 were evaluated. The results showed that administration of GaA or FeA with TAA induced a significant reduction in serum ALT, AST and ALP activities and protected the integrity of liver tissues. Furthermore, they increased the activities of the hepatic antioxidant enzymes; superoxide dismutase and catalase while decreased malondialdehyde content to a normal level. The hepatic expression of TGF-ß1, phosphorylated and total Smad3 proteins were significantly decreased. In addition, miR-21 expression was downregulated while miR-30 and miR-200 expressions were upregulated by administration of gallic acid or ferulic acid. In conclusion, gallic and ferulic acids exhibit hepatoprotective and antioxidant effects against TAA-induced liver fibrosis in rats. These effects are mediated through inhibition of TGF-ß1/Smad3 signaling and differentially regulating the hepatic expression level of miR-21, miR-30 and miR-200.


Assuntos
Ácidos Cumáricos/uso terapêutico , Ácido Gálico/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Substâncias Protetoras/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Regulação para Baixo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , MicroRNAs/metabolismo , Ratos Wistar , Proteína Smad3/metabolismo , Tioacetamida , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
13.
Elife ; 92020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32250244

RESUMO

The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARS- CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). The angiotensin converting enzyme-1-angiotensin II-angiotensin AT1 receptor pathway contributes to the pathophysiology of ARDS, whereas activation of the ACE-2-angiotensin(1-7)-angiotensin AT2 receptor and the ACE-2-angiotensin(1-7)-Mas receptor pathways have been shown to be protective. Here we propose and discuss therapeutic considerations how to increase soluble ACE-2 in plasma in order for ACE-2 to capture and thereby inactivate SARS-CoV-2. This could be achieved by administering recombinant soluble ACE-2. We also discuss why and how ACEIs and ARBs provide cardiovascular, renal and also pulmonary protection in SARS-CoV-2- associated ARDS. Discontinuing these medications in COVID-19 patients may therefore potentially be harmful.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pulmão/metabolismo , Pulmão/virologia , Pandemias , Pneumonia Viral/epidemiologia , Substâncias Protetoras/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos
14.
Am J Clin Oncol ; 43(6): 446-451, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32235164

RESUMO

OBJECTIVE: We compared the outcomes in soft tissue sarcoma (STS) treated with olaratumab and doxorubicin (OD) versus doxorubicin, ifosfamide, and mesna (AIM) to assess whether OD could supersede AIM in STS therapy. METHODS: A single-institution, retrospective study of STS treated for advanced disease with OD or AIM in 2013 to 2017 was conducted. Demographic and clinical parameters were compared by Fisher's exact test. Kaplan-Meier and Cox analyses examined progression-free survival (PFS) and overall survival (OS). Adverse events were compared. RESULTS: Thirty patients (13 OD, 17 AIM) were included. OD was administered more commonly after first-line therapy (54% OD vs. 6% AIM, P=0.0005). The 2 groups did not differ in other parameters. Median OS [OD: 14.2 mo, 95% confidence interval (CI): 7.1-not reached; AIM 19.9 mo, 95% CI 9.5-35.5; hazard ratio: 0.99, 95% CI: 0.38-2.59, P=0.99] and PFS (OD: 2.6 mo, 95% CI: 1.3-7; AIM 6.4 mo, 95% CI: 1.5-14.5; hazard ratio: 0.57, 95% CI: 0.26-1.24, P=0.16) were not statistically different, although median values favored AIM. Grade 3 to 4 neutropenia, but not febrile neutropenia, was more frequent with OD. CONCLUSIONS: OD and AIM did not differ with respect to either OS or PFS. Although this study's size initially appeared the most likely explanation, lack of significant activity of olaratumab was subsequently reported in the phase III trial of OD. Our results suggest that future conditional oncology drug approvals should be accompanied by mandated registries to monitor outcomes of patients treated after conditional approval, but before full approval.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/administração & dosagem , Ifosfamida/administração & dosagem , Mesna/uso terapêutico , Substâncias Protetoras/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Resultado do Tratamento , Adulto Jovem
15.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(2): 204-209, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32275007

RESUMO

OBJECTIVE: To investigate the role of Ribociclib in sepsis induced-acute kidney injury (AKI) and its possible mechanisms. METHODS: (1) Twenty adult male C57BL/6 mice were divided into sham operation group (Sham group; only open the abdomen without ligating or perforating the cecum, administered with sodium lactate buffer 12 hours before the sham operation), Ribociclib control group (administered with 150 mg/kg Ribociclib), cecal ligation and puncture (CLP) group (sepsis model induced by CLP; lactate buffer was given by intragastric administration 12 hours before CLP), and Ribociclib pretreatment group (administered with 150 mg/kg Ribociclib 12 hours before CLP) according to random number table, with 5 mice in each group. Kidneys were harvested 12 hours after the operation. Pathological changes in kidney were observed by hematoxylin-eosin (HE) staining. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in mice kidney homogenate were measured by enzyme linked immunosorbent assay (ELISA). Western Blot was used to detect the expression of cell cycle-related protein phosphorylate retinoblastoma protein (p-Rb), apoptosis-related protein Bcl-2 and Bax. (2) Mouse renal tubular epithelial (TCMK-1) cell line was used for in vitro experiment. The cells were divided into control group, Ribociclib group (treated with 5 µmol/L Ribociclib for 24 hours), lipopolysaccharide (LPS) group (treated with 200 mg/L LPS for 6 hours), Ribociclib+LPS group (replaced with the medium containing 5 µmol/L Ribociclib and 200 mg/L LPS for 6 hours after exposing with 5 µmol/L Ribociclib for 18 hours). Inflammatory cytokines in cell culture medium were detected by ELISA. The expression of p-Rb, Bcl-2 and Bax, autophagy-related proteins microtubule associated protein 1 light chain LC3b (LC3b II, LC3b I) and p62, phosphate protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR) were measured by Western Blot. RESULTS: (1) Animal experiments showed that, compared with the Sham group, the kidney tissue of mice were significantly damaged, the levels of TNF-α and IL-6 were increased, the expressions of p-Rb and Bcl-2/Bax ratio were decreased in kidney tissue in CLP group; but there was no significant difference in indexes between Ribociclib control group and Sham group. Compared with the CLP group, kidney injury in mice pretreated with Ribociclib was significantly ameliorated, the pathological score was significantly decreased (1.48±0.16 vs. 2.68±0.16, P < 0.01), the levels of TNF-α and IL-6 in kidney homogenate were significantly decreased [TNF-α (ng/g): 340.55±34.96 vs. 745.08±58.86, IL-6 (mg/g): 17.33±1.01 vs. 114.20±20.49, both P < 0.01], the expression of p-Rb was furtherly decreased (p-Rb/ß-tubulin: 0.14±0.01 vs. 0.73±0.06, P < 0.01), Bcl-2/Bax ratio was increased (0.89±0.06 vs. 0.62±0.10, P < 0.01). (2) In vitro experiments showed that, compared with the control group, the releases of TNF-α and IL-6 were increased, the expression of p-Rb was decreased, the ratios of Bcl-2/Bax and LC3b II/I were decreased, the expressions of p62, p-AKT and p-mTOR were increased in LPS group; the expression of p-Rb was decreased after Ribociclib treatment in TCMK-1 cells. Compared with the LPS group, TNF-α and IL-6 were decreased [TNF-α (ng/L): 2.73±0.23 vs. 4.96±0.10, IL-6 (ng/L): 36.05±5.83 vs. 53.78±24.08, both P < 0.01], the expression of p-Rb was furtherly decreased (p-Rb/ß-tubulin: 0.25±0.05 vs. 0.65±0.05, P < 0.01), the ratios of Bcl-2/Bax and LC3b II/I were increased (Bcl-2/Bax: 1.01±0.07 vs. 0.73±0.05, LC3b II/I: 2.08±0.31 vs. 1.04±0.01, both P < 0.05), the expressions of p62, p-AKT and p-mTOR were decreased (p62/ß-tubulin: 0.59±0.01 vs. 1.09±0.08, p-AKT/ß-tubulin: 0.61±0.03 vs. 1.20±0.06, p-mTOR/ß-tubulin: 0.50±0.05 vs. 1.15±0.08, all P < 0.01) in the Ribociclib+LPS group. CONCLUSIONS: Ribociclib pretreatment ameliorated sepsis-induced AKI and AKT/mTOR pathway may be involved in the protective role of Ribociclib on kidney.


Assuntos
Lesão Renal Aguda , Aminopiridinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Purinas/uso terapêutico , Sepse , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa
16.
Clin Sci (Lond) ; 134(4): 379-388, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32064497

RESUMO

Alport syndrome is a rare genetic disease that results in disordered basement membrane type IV collagen resulting in occular and auditory defects as well of progressive kidney disease. Although no 'cure' currently exists, therapeutic blockade of the renin-angiotensin-aldosterone system can slow the progression to end-stage kidney disease (ESKD). Clinical trials for treatments in preventing chronic kidney disease have largely been negative over the last two decades until recent trials have shown positive cardiovascular and renal outcomes of sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with diabetes mellitus. Although marketed as medications for Type 2 diabetes, SGLT2 inhibitors have been found to have additional properties that are nephroprotective which makes them a potential candidate for treatment for those with other forms of progressive kidney disease. This review discusses the evidence for the use of SGLT2 inhibitors as a potential treatment in Alport syndrome that may slow the progression of chronic kidney disease and prevent patients reaching ESKD.


Assuntos
Nefrite Hereditária/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Taxa de Filtração Glomerular , Humanos , Nefrite Hereditária/fisiopatologia , Substâncias Protetoras/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
17.
Biochem Biophys Res Commun ; 524(2): 354-359, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32001002

RESUMO

Diabetes mellitus is a metabolic disorder that can lead to blood-brain barrier (BBB) disruption and cognitive decline. However, the mechanisms of BBB breakdown in diabetes are still unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects on vascular structure and functions. In the current study, we showed increased vascular permeability of the BBB, which was accompanied by upregulation of sEH and downregulation of 14,15-EET. Moreover, the sEH inhibitor t-AUCB restored diabetic BBB integrity in vivo, and 14,15-EET prevented ROS accumulation and MEC injury in vitro. t-AUCB or 14,15-EET treatment provoked AMPK/HO-1 activation under diabetic conditions in vivo and in vitro. Thus, we suggest that decreased EET degradation by sEH inhibition might be a potential therapeutic approach to attenuate the progression of BBB injury in diabetic mice via AMPK/HO-1 pathway activation.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Diabetes Mellitus Tipo 2/complicações , Epóxido Hidrolases/antagonistas & inibidores , Substâncias Protetoras/uso terapêutico , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/metabolismo , Heme Oxigenase-1/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
J Dairy Sci ; 103(4): 2947-2955, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32008775

RESUMO

Colorectal cancer (CRC) is known to be a life-threatening disease and commonly leads to metastasis in the liver. Fermented milk acts as an effective carrier for probiotic strains, whose consumption improves host health. Our previous study indicated that fermented milk that included a synbiotic combination of Lactobacillus gasseri 505 (505) and Cudrania tricuspidata leaf extract (CT) resulted in significantly greater anti-oxidative effects than fermented milk without CT. Therefore, we hypothesized that fermented milk containing CT and 505 (FCT) could result in hepatoprotective effects against CRC-induced liver metastasis. Liver inflammation and CRC were induced in male C57BL/6J mice, using azoxymethane/dextran sodium sulfate, and 505, CT, and FCT were administered to the 3 sample-treated 505, CT, and FCT groups, respectively, for 10 wk. The results showed that FCT treatment significantly reduced serum aspartate aminotransferase and alanine aminotransferase concentrations and elevated albumin concentrations. Moreover, the results of histological analysis showed that hepatic steatosis was notably reduced in the FCT group. Among the 3 sample-treated groups, the expression of mRNA associated with enzymes showing anti-oxidative activities, such as superoxide dismutase, catalase, and glutathione reductase, was the highest in the FCT-treated mice. In addition, FCT administration resulted in the greatest anti-inflammatory activity, as inflammatory marker levels (i.e., tumor necrosis factor-α, cyclooxygenase-2, myeloperoxidase, and nuclear factor kappa-light-chain enhancer of activated B cells) were significantly downregulated at the mRNA level and the expression of proteins associated with the nuclear factor kappa-light-chain enhancer of activated B cells and mitogen-activated protein kinase signaling pathways was suppressed by FCT. Therefore, this study demonstrated that fermented milk containing novel synbiotics has the potential to prevent hepatic toxicity induced because of CRC owing to its enhanced anti-oxidative and anti-inflammatory activities.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Lactobacillus gasseri , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas Experimentais/secundário , Moraceae/química , Extratos Vegetais/uso terapêutico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/patologia , Produtos Fermentados do Leite , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Fermentação , Lactobacillus gasseri/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Leite , Probióticos , Substâncias Protetoras/uso terapêutico , Simbióticos
19.
Med Sci Monit ; 26: e920211, 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927559

RESUMO

BACKGROUND The aim of this study was to investigate the mechanisms underlying the potential effects of hydrogen-rich water (HW) on articular cartilage in a rat osteoarthritis (OA) model. MATERIAL AND METHODS A rat model of OA was established using the modified Hulth method, and rats were forced to exercise for 30 min every day 1 week after surgery for 7 weeks. Mankin's method was used to score the severity of OA. The animals were assigned into the OA group, OA+HW group, and sham operation group. After 8 weeks, the animals in the OA group had a Mankin score >8 points, and HW was administered into the knee joint. After 2 weeks of treatment, articular cartilage was obtained for pathological examination, consisting of hematoxylin and eosin, toluidine blue, and Hoechst staining, as well as quantitative real-time PCR and Western blot analyses. This combination of pharmacological and molecular biological analyses was performed to examine the mechanism underlying the protective effect of HW on articular cartilage. RESULTS The antioxidant effects of HW suppressed oxidative damage, which may have aided the inhibition of ECM-degrading enzymes (MMP3, MMP13, ADAMT4, and ADAMT5), the upregulation of Col II and aggrecan expression, and the downregulation of COX-2, iNOS, and NO expression. The results of HE staining indicated intra-articular treatment of HW attenuated cartilage degradation. However, Hoechst staining in the OA group indicated the nuclei of the fragmented chondrocytes were condensed compared to the sham operation group, and this effect was inhibited by HW. CONCLUSIONS HW showed a protective effect against the progression of OA in an animal model, which may have been mediated by its anti-oxidant and anti-apoptotic activities.


Assuntos
Apoptose/efeitos dos fármacos , Cartilagem Articular/patologia , Matriz Extracelular/metabolismo , Hidrogênio/uso terapêutico , Osteoartrite/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Água/farmacologia , Proteínas ADAM/metabolismo , Agrecanas/metabolismo , Animais , Cartilagem Articular/efeitos dos fármacos , Caspase 3/metabolismo , Colágeno Tipo II/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Metaloproteinases da Matriz/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/patologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
20.
Int J Mol Sci ; 21(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936141

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was suppressor of cytokine signaling 3 (Socs3), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, Socs3, was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/prevenção & controle , Peptídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Colágeno , Modelos Animais de Doenças , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
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