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1.
Invest Ophthalmol Vis Sci ; 63(1): 4, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34982146

RESUMO

Purpose: Netarsudil, a Rho kinase inhibitor with norepinephrine transport inhibitory effect, lowers intraocular pressure, however, its effect on axon damage remains to be elucidated. The aim of the current study was to investigate the effect of netarsudil on TNF-induced axon loss and to examine whether it affects phosphorylated-AMP-activated kinase (p-AMPK) and autophagy in the optic nerve. Methods: Intravitreal administration of TNF or TNF with netarsudil was carried out on rats and quantification of axon number was determined. Electron microscopy determined autophagosome numbers. Localization of p-AMPK expression was examined by immunohistochemistry. The changes in p62, LC3-II, and p-AMPK levels were estimated in the optic nerve by immunoblot analysis. The effect of an AMPK activator A769662 or an AMPK inhibitor dorsomorphin on axon number was evaluated. Results: Morphometric analysis revealed apparent protection by netarsudil against TNF-induced axon degeneration. Netarsudil increased autophagosome numbers inside axons. Netarsudil treatment significantly upregulated optic nerve LC3-II levels in both the TNF-treated eyes and the control eyes. Increased p62 protein level induced by TNF was significantly ameliorated by netarsudil. The netarsudil administration alone lessened p62 levels. Netarsudil significantly upregulated the optic nerve p-AMPK levels. A769662 exhibited obvious axonal protection against TNF-induced damage. A769662 treatment upregulated LC3-II levels and the increment of p62 level induced by TNF was significantly ameliorated by A769662. Immunohistochemical analysis revealed that p-AMPK is present in axons. Netarsudil-mediated axonal protection was significantly suppressed by dorsomorphin administration. Conclusions: Netarsudil upregulated p-AMPK and autophagy. Netarsudil-mediated axonal protection may be associated with upregulated p-AMPK.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Axônios/efeitos dos fármacos , Benzoatos/farmacologia , Degeneração Neural/prevenção & controle , Nervo Óptico/efeitos dos fármacos , Fator de Necrose Tumoral alfa/toxicidade , beta-Alanina/análogos & derivados , Quinases Associadas a rho/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Axônios/enzimologia , Axônios/patologia , Compostos de Bifenilo/farmacologia , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica , Injeções Intravítreas , Masculino , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/metabolismo , Degeneração Neural/enzimologia , Nervo Óptico/ultraestrutura , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pironas/farmacologia , Ratos , Ratos Wistar , Proteína Sequestossoma-1/metabolismo , Tiofenos/farmacologia , beta-Alanina/farmacologia
2.
J Int Med Res ; 50(1): 3000605211067909, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34986674

RESUMO

Advances in cancer therapy have resulted in more cancer therapy-related cardiac dysfunction (CTRCD), which is the main cause of death in older female survivors of breast cancer. Traditionally, guideline-recommended medications for heart failure, such as beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), are commonly used to prevent or attenuate CTRCD. However, sometimes their effectiveness is not satisfactory. Recently, the drug combination of sacubitril plus valsartan has been proven to be more beneficial for heart failure with reduced ejection fraction in the long term compared with an ACEI/ARB alone. However, there is a lack of evidence of the efficacy and safety of this drug combination in CTRCD. We report a case of worsening CTRCD, despite treatment with traditional medications, in which the patient improved after changing perindopril to sacubitril/valsartan. The patient's heart function greatly improved after changing this ACEI to sacubitril/valsartan. Changing an ACEI/ARB to sacubitril/valsartan in patients with worsening chemotherapy-induced heart failure is appropriate. Further studies with a high level of evidence are required to assess the efficacy and safety of sacubitril/valsartan for CTRCD.


Assuntos
Insuficiência Cardíaca , Neoplasias , Idoso , Aminobutiratos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Compostos de Bifenilo , Combinação de Medicamentos , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Volume Sistólico , Tetrazóis/efeitos adversos , Resultado do Tratamento , Valsartana
3.
J Eur Acad Dermatol Venereol ; 36 Suppl 1: 66-69, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34855253

RESUMO

A 78-year-old woman was referred to our skin cancer centre with three previous incomplete resections in the left cavum conchae of a deep-infiltrating locally advanced, but still asymptomatic basal cell carcinoma (BCC). The patient noted furthermore two rapidly growing exophytic lesions in the left preauricular and cervical area in the last weeks. The clinical and histological distinction of locally advanced from metastatic cutaneous squamous cell carcinoma (CSCC) lesions was challenging. Imaging analysis with CT scans showed, however, an involvement of the parotid gland as well as multiple small lymph node metastases. The interdisciplinary tumour board decision at our institution recommended a systemic treatment with the PD1-antibody cemiplimab. After 13 cycles with cemiplimab at a dose of 350 mg intravenously every 3-weeks, the patient showed a complete response of the two CSCC lesions with histological confirmation. However, the BCC of the left ear appeared to be unchanged and still asymptomatic. The interdisciplinary tumour board considered this tumour to be no candidate for a curative resection or irradiation. Therefore, the patient was exposed to the hedgehog inhibitor sonidegib with a conventional dose of 200 mg orally per day. After 3 months of treatment, the tumour showed a markable regression and a complete response was confirmed by 3-punch biopsies from this preoperated lesion. Both cemiplimab and sonidegib were excellently tolerated with almost no adverse events apart from a mild fatigue (CTC grade 1) over the first 3 weeks of the cemiplimab therapy. There were no laboratory abnormalities found.


Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Idoso , Anticorpos Monoclonais Humanizados , Compostos de Bifenilo , Carcinoma Basocelular/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Células Epiteliais , Feminino , Proteínas Hedgehog , Humanos , Piridinas , Neoplasias Cutâneas/tratamento farmacológico
4.
Biochim Biophys Acta Biomembr ; 1864(1): 183778, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34537215

RESUMO

Tannins belong to plant secondary metabolites exhibiting a wide range of biological activity. One of the important aspects of the realization of the biological effects of tannins is the interaction with lipids of cell membranes. In this work we studied the interaction of two hydrolysable tannins: 1,2,3,4,6-penta-O-galloyl-ß-d-glucose (PGG) and 1,2-di-O-galloyl-4,6-valoneoyl-ß-d-glucose (T1) which had the same number of both aromatic rings (5) and hydroxyl groups (15) but differing in flexibility due to the presence of valoneoyl group in the T1 molecule with DMPC (dimyristoylphosphatidylcholine) lipid nano-vesicles (liposomes). Tannins-liposomes interactions were investigated using fluorescence spectroscopy, differential scanning calorimetry, laser Doppler velocimetry, dynamic light scattering and Fourier Transform Infra-Red spectroscopy. It was shown that more flexible PGG molecules stronger decreased the microviscosity of the liposomal membranes and increased the values of negative zeta potential in comparison with the more rigid T1. Both compounds diminished the phase transition temperature of DMPC membranes, interacted with liposomes via PO groups of head of phospholipids and their hydrophobic regions. These tannins neutralized DPPH free radicals with the stoichiometry of the reaction equal 1:1. The effects of the studied compounds on liposomes were discussed in relation to tannin quantum chemical parameters calculated by molecular modeling.


Assuntos
Compostos de Bifenilo/química , Taninos Hidrolisáveis/química , Lipossomos/química , Lipídeos de Membrana/química , Picratos/química , Varredura Diferencial de Calorimetria , Dimiristoilfosfatidilcolina/química , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/metabolismo , Lipídeos de Membrana/metabolismo
5.
Yonsei Med J ; 63(1): 16-25, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34913280

RESUMO

PURPOSE: Tumor radioresistance and dose-limiting toxicity restrict the curative potential of radiotherapy, requiring novel approaches to overcome the limitations and augment the efficacy. Here, we investigated the effects of signal transducer and activator of transcription 3 (STAT3) activation and autophagy induction by irradiation on antiapoptotic proteins and the effectiveness of the BH3 mimetic ABT-737 as a radiosensitizer using K-ras mutant non-small cell lung cancer (NSCLC) cells and a KrasG12D:p53fl/fl mouse (KP mouse) model. MATERIALS AND METHODS: A549 and H460 cells were irradiated, and the expression of Bcl-2 family proteins, JAK/STAT transcriptional pathway, and autophagic pathway were evaluated by immunoblotting. The radiosensitizing effects of ABT-737 were evaluated using A549 and H460 cell lines with clonogenic assays and also by a KP mouse model with microcomputed tomography and immunohistochemistry. RESULTS: In A549 and H460 cells and mouse lung tissue, irradiation-induced overexpression of the antiapoptotic molecules Bcl-xL, Bcl-2, Bcl-w, and Mcl-1 through JAK/STAT transcriptional signaling induced dysfunction of the autophagic pathway. After treatment with ABT-737 and exposure to irradiation, the number of surviving clones in the cotreatment group was significantly lower than that in the group treated with radiation or ABT-737 alone. In the KP mouse lung cancer model, cotreatment with ABT-737 and radiation-induced significant tumor regression; however, body weight changes in the combination group were not significantly different, suggesting that combination treatment did not cause systemic toxicity. CONCLUSION: These findings supported the radiosensitizing activity of ABT-737 in preclinical models, and suggested that clinical trials using this strategy may be beneficial in K-ras mutant NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Apoptose , Compostos de Bifenilo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Camundongos , Nitrofenóis , Piperazinas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Radiação Ionizante , Sulfonamidas , Microtomografia por Raio-X , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Hazard Mater ; 421: 126758, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34352527

RESUMO

Organophosphorus compounds were proposed to impair immune surveillance and increase the total burden of pathogens. However, scarce attention has been paid to the effects of organophosphate flame retardants (OPFRs) on neutrophils. Previous literature outlined that neutrophil extracellular traps (NETs) death (NETosis) is associated with autophagy-related signaling. Here we found that 20 µM diphenyl phosphate (DPHP) could promote NETs formation via assessing markers of NETs and the morphological changes. Concurrently, flow cytometry and western blot analysis revealed that DPHP-triggered NETs formation was associated with reactive oxygen species (ROS) burst and activation of extracellular signal-regulated kinase (ERK) and p38. Additionally, the results revealed that autophagy occurred in DPHP-triggered NETs formation, manifested as enhanced LC3B protein expressions and reduced p62 protein expressions. Mechanism dissection revealed that inhibition of autophagy by 3-methyladenine (3-MA) alleviated the ROS burst and subsequent NETosis caused by DPHP. Conversely, autophagy enhancer Rapamycin (Rapa) augmented the above effects of DPHP, including the generation of ROS and NETosis. Collectively, these data suggested ERK/p38 signaling and ROS burst might be an important cause of DPHP-triggered NETs formation, while suppression of excessive autophagy could rescue these actions. These observations provided a theoretical basis for the treatment and prevention of OPFRs-induced immunotoxicity.


Assuntos
Armadilhas Extracelulares , Autofagia , Compostos de Bifenilo , MAP Quinases Reguladas por Sinal Extracelular , Organofosfatos , Fosfatos , Espécies Reativas de Oxigênio
7.
Cancer Lett ; 524: 151-160, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34655667

RESUMO

Members of the PI3K signaling pathway, especially PIK3CA, the gene encoding the catalytic subunit of the PI3K complex, are highly mutated and amplified in various cancer types, including non-small cell lung cancer. Although PI3K inhibitors have been used in clinics for follicular lymphoma and chronic lymphocytic leukemia, no agents targeting PI3K aberrations in lung cancer have been approved by the FDA so far. In this study, we observed that PIK3CA-E545K, the most common mutation in lung cancer, harbored a modest induction of stem-like properties in lung epithelial cells, and drove development of adenocarcinoma autochthonously when paired with p53 loss in a murine mouse model. We also found that PIK3CA-mutant of amplified lung cancer cells were sensitive to EZH2 inhibition. EZH2 inhibition synergized with PI3K inhibition in human cancer cells in vitro and worked together efficiently in vivo. Mechanistically, EZH2 inhibition cooperated with PI3K inhibition to produce a more potent suppression of phospho-AKT downstream of PI3K. This study suggests a promising combination therapy to combat lung cancers with PIK3CA mutation or amplification. Both copanlisib, the PI3K inhibitor, and tazemetostat, the EZH2 inhibitor, are FDA-approved, which should enhance the clinical translation of this work.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Morfolinas/farmacologia , Mutação , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Hypertension ; 79(1): 261-270, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34739764

RESUMO

Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6-8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hemorragia/fisiopatologia , Rim/inervação , Simpatectomia/métodos , Tetrazóis/administração & dosagem , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Hemodinâmica/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Ovinos
9.
Biomolecules ; 11(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34944506

RESUMO

Renin-angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion-reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood-brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion-reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion-reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury.


Assuntos
Angiotensina II/administração & dosagem , Angiotensina I/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Pia-Máter/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Tetrazóis/administração & dosagem , Angiotensina I/efeitos adversos , Angiotensina II/efeitos adversos , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Feminino , Masculino , Microcirculação/efeitos dos fármacos , Microscopia de Fluorescência , Fragmentos de Peptídeos/efeitos adversos , Pia-Máter/efeitos dos fármacos , Pia-Máter/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Tetrazóis/farmacologia
10.
PLoS One ; 16(12): e0259896, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34972101

RESUMO

Magnolol is a bioactive polyphenolic compound commonly found in Magnolia officinalis. The aim of this study is to clarify the contribution of the magnolol additive on the growth performance of Linwu ducklings aging from 7 to 28 d, comparing to the effects of antibiotic additive (colistin sulphate). A total of 325, 7-d-old ducklings were assigned to 5 groups. Each group had 5 cages with 13 ducklings in each cage. The ducklings in different groups were fed with diets supplemented with 0, 100, 200 and 300 mg/kg magnolol additive (MA) (Control, MA100, MA200 and MA300) and 30 mg/kg colistin sulphate (CS30) for 3 weeks, respectively. Parameters regarding to the growth performance, intestinal mucosal morphology, serum biochemical indices, antioxidant and peroxide biomarkers and the expression levels of antioxidant-related genes were evaluated by one way ANOVA analysis. The results showed that 30 mg/kg colistin sulphate, 200 and 300 mg/kg magnolol additive improved the average final weight (P = 0.045), average daily body weight gain (P = 0.038) and feed/gain ratios (P = 0.001) compared to the control group. 200 and 300 mg/kg magnolol additive significantly increased the villus height/crypt depth ratio of ileum, compared to the control and CS30 groups (P = 0.001). Increased serum level of glucose (P = 0.011) and total protein (P = 0.006) were found in MA200 or MA300 group. In addition, comparing to the control and CS30 groups, MA200 or MA300 significantly increased the levels of superoxide dismutase (P = 0.038), glutathione peroxidase (P = 0.048) and reduced glutathione (P = 0.039) in serum. Moreover, the serum and hepatic levels of 8-hydroxy-2'-deoxyguanosine (P = 0.043 and 0.007, respectively) were lower in all MA groups compared to those of the control and CS30 group. The hepatic mRNA expression levels of superoxide dismutase-1, catalase and nuclear factor erythroid-2-related factor 2/erythroid-derived CNC-homology factor were also increased significantly in MA200 and MA300 groups (P < 0.05). Taken together, these data demonstrated that MA was an effective feed additive enhancing the growth performance of Linwu ducklings at 7 to 28 d by improving the antioxidant and intestinal mucosal status. It suggested that MA could be a potential ingredient to replace the colistin sulphate in diets.


Assuntos
Antioxidantes/metabolismo , Compostos de Bifenilo/farmacologia , Patos/crescimento & desenvolvimento , Lignanas/farmacologia , Animais , Biomarcadores/sangue , Dieta , Patos/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Nutrientes , Peróxidos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
Int J Mol Sci ; 22(24)2021 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-34948151

RESUMO

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from Magnolia grandiflora, represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl4). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-ß (TGF-ß1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl4-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-ß1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-ß1/SMAD signaling and autophagy in HSCs.


Assuntos
Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Intoxicação por Tetracloreto de Carbono , Células Estreladas do Fígado , Lignanas/farmacologia , Cirrose Hepática , Fígado/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Intoxicação por Tetracloreto de Carbono/metabolismo , Intoxicação por Tetracloreto de Carbono/patologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos
12.
Rev Port Cardiol (Engl Ed) ; 40(12): 975-983, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34922707

RESUMO

Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with high rates of hospitalization and death. It also has a negative impact on patients' functional capacity and quality of life, as well as on healthcare costs. In recent years, new HFrEF prognosis-modifying drugs have emerged, leading to intense debate within the international scientific community toward a paradigm shift for the management of HFrEF. In this article, we report the contribution of a Portuguese HF expert panel to the ongoing debate. Based on the most recently published clinical evidence, and the panel members' clinical judgment, three key principles are highlighted: (i) sacubitril/valsartan should be preferred as first-line therapy for HFrEF, instead of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (ii) the four foundation HFrEF drugs are the angiotensin receptor/neprilysin inhibitor, beta-adrenergic blocking agents, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, regardless of the presence of type-2 diabetes mellitus; (iii) these four HFrEF drug classes should be introduced over a short-term period of four to six weeks, guided by a safety protocol, followed by a dose up-titration period of 8 weeks.


Assuntos
Insuficiência Cardíaca , Aminobutiratos , Compostos de Bifenilo , Consenso , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Prognóstico , Qualidade de Vida , Volume Sistólico , Tetrazóis
13.
Artigo em Inglês | MEDLINE | ID: mdl-34948736

RESUMO

With climate change increasing global temperatures, more workers are exposed to hotter ambient temperatures that exacerbate risk for heat injury and illness. Continuously monitoring core body temperature (TC) can help workers avoid reaching unsafe TC. However, continuous TC measurements are currently cost-prohibitive or invasive for daily use. Here, we show that Kenzen's wearable device can accurately predict TC compared to gold standard TC measurements (rectal probe or gastrointestinal pill). Data from four different studies (n = 52 trials; 27 unique subjects; >4000 min data) were used to develop and validate Kenzen's machine learning TC algorithm, which uses subject's real-time physiological data combined with baseline anthropometric data. We show Kenzen's TC algorithm meets pre-established accuracy criteria compared to gold standard TC: mean absolute error = 0.25 °C, root mean squared error = 0.30 °C, Pearson r correlation = 0.94, standard error of the measurement = 0.18 °C, and mean bias = 0.07 °C. Overall, the Kenzen TC algorithm is accurate for a wide range of TC, environmental temperatures (13-43 °C), light to vigorous heart rate zones, and both biological sexes. To our knowledge, this is the first study demonstrating a wearable device can accurately predict TC in real-time, thus offering workers protection from heat injuries and illnesses.


Assuntos
Temperatura Corporal , Dispositivos Eletrônicos Vestíveis , Algoritmos , Benzimidazóis , Compostos de Bifenilo , Temperatura Alta , Humanos , Tetrazóis
14.
Proc Natl Acad Sci U S A ; 118(51)2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34903661

RESUMO

Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial-capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial-vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.


Assuntos
Quimiocina CX3CL1/metabolismo , Retinopatia Diabética/patologia , Microglia/fisiologia , Retina/patologia , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Quimiocina CX3CL1/farmacologia , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/metabolismo , Perfilação da Expressão Gênica , Camundongos , Microglia/metabolismo , Neurônios/fisiologia , Pericitos/patologia , Ratos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Retina/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/patologia , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia , Tetrazóis/farmacologia , Vasoconstrição/efeitos dos fármacos
15.
N Engl J Med ; 385(20): 1845-1855, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34758252

RESUMO

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/tratamento farmacológico , Ramipril/uso terapêutico , Valsartana/uso terapêutico , Idoso , Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Doenças Cardiovasculares/mortalidade , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hipotensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Modelos de Riscos Proporcionais , Ramipril/efeitos adversos , Volume Sistólico , Valsartana/efeitos adversos , Disfunção Ventricular Esquerda/etiologia
16.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 506-510, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816662

RESUMO

Objective: To investigate the synergistic effects of magnolol and gefitinib on non-small cell lung cancer A549 cells. Methods: A549 cells were treated with Magnolol (6.25~500 µmol/L) or gefitinib (6.25~500 µmol/L) for 24 h, respectively, and the cell viability was detected by cell counting Kit-8 (CCK-8) experiment (n=3). Magnolol 100 µmol/L and gefitinib 5 µmol/L were selected in the following experiments (n=3, 24 h). Control group, magnolol group, gefitinib group and magnolol+gefitinib group were set up for factorial analysis. Colony formation experiment was applied to detect the cell proliferation. Western blot was used to detect protein expressions. Flow cytometry was applied to test cell apoptosis and sorting CD44+ and CD133+ cells. Results: Compared with the control group, the colony formation rate of Magnolol or Gefitinib groups was decreased significantly (P<0.05); the apoptosis rate was increased significantly (P<0.05); the number of CD44+ and CD133+ cells was reduced significantly (P<0.05); the expressions of Ki67, PCNA, and stem cell marker proteins SOX2 and OCT4 were down-regulated (P<0.05); and the ratio of Bax/Bcl-2 was increased significantly (P<0.05). Compared with the Magnolol group or Gefitinib group, the Magnolol+Gefitinib group further promoted the above changes (P<0.05), and the apoptosis rate, the ratio of Bax/Bcl-2, SOX2 and OCT4 all showed interactions between magnolol and gefitinib (P<0.05). Conclusion: Magnolol and gefitinib promote the apoptosis of A549 cells and inhibit its stem cell-like properties, and the effect of the two combined is better than separated administration. Magnolol and gefitinib have interactive effects on A549 cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células A549 , Apoptose , Compostos de Bifenilo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Gefitinibe/farmacologia , Humanos , Lignanas , Neoplasias Pulmonares/tratamento farmacológico
18.
JAMA ; 326(19): 1919-1929, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34783839

RESUMO

Importance: There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%). Objective: To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. Design, Setting, and Participants: A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019). Interventions: Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor. Main Outcomes and Measures: Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. Results: Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%). Conclusions and Relevance: Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03066804.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Valsartana/uso terapêutico , Idoso , Aminobutiratos/efeitos adversos , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacologia , Biomarcadores/sangue , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacologia , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Volume Sistólico , Valsartana/efeitos adversos , Valsartana/farmacologia , Teste de Caminhada
19.
Phytochemistry ; 192: 112972, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34624729

RESUMO

Apple replant disease (ARD) is a severe soil-borne disease frequently observed in apple tree nurseries and orchards worldwide. One of the responses of apple trees to ARD is the formation of biphenyl and dibenzofuran phytoalexins in their roots. However, there is no information on whether or not these phytoalexins are exuded into the soil. To answer this open question, a model system was established using the ARD-sensitive apple rootstock M26 (Malus × domestica Borkh. Rosaceae) and GC-MS analysis in combination with an in-house GC-MS database including retention indices. We have detected a total of 35 phytoalexins, i.e. 10 biphenyls and 25 dibenzofurans in root samples, thereby adding eight compounds to the previously reported 27 phytoalexins of Malinae species. When in vitro cultured M26 plantlets were treated with yeast extract, all the 35 phytoalexins were formed in the roots and 85.2% of the total phytoalexin amount was exuded into the culture medium. In roots of M26 plants grown in ARD soil in pot, 26 phytoalexins were detected and their exudation was demonstrated using two independent approaches of collecting root exudates. In a modified dipping experiment and a soil-hydroponic hybrid setup, the exudation rate was 39.5% and 20.6%, respectively. The exudation rates for individual phytoalexins differed, indicating controlled exudation processes. The exuded phytoalexins may play an important role in shaping the soil microbiome, which appears to greatly influence the development and severity of ARD.


Assuntos
Malus , Benzofuranos , Compostos de Bifenilo , Dibenzofuranos , Raízes de Plantas , Sesquiterpenos , Solo
20.
Food Funct ; 12(19): 8920-8931, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606549

RESUMO

The effect of adding the chokeberry fruit additive to rape honey was studied with regard to the physicochemical properties and biological activity. Two samples of dried powdered fruits were used to enrich the honey (1 and 4% v/v) during creaming. The obtained products were characterized in terms of sugar content, acidity, conductivity, total phenolic, flavonoid and anthocyanin contents and HPTLC polyphenol profiles. The antioxidant properties of enriched honeys were studied in vitro (FRAP, DPPH, and ABTS) and in vivo using a S. cerevisiae model. The inhibitory effect against 5 bacterial strains and coronavirus surrogate bacteriophage phi6 was tested. The addition of chokeberry significantly modified the physicochemical properties of honey and enhanced its antioxidant potential (from 3 to 15 times). Using HPTLC analysis, the occurrence of flavonoids, phenolic acids, and anthocyanins in chokeberry enriched honey was determined. The modified honey protected yeast cells against H2O2-induced oxidative stress when used as a pretreatment agent. All tested bacteria were susceptible to enriched honey in a dose-dependent manner. The antiviral potential of enriched honey against the model bacteriophage was discovered for the first time. In terms of numerous health benefits determined, honey enriched with Aronia melanocarpa fruits can be considered as an interesting novel functional food, which may increase the consumption of chokeberry superfruits.


Assuntos
Frutas , Alimento Funcional , Mel , Photinia , Extratos Vegetais/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Humanos , Picratos/química , Extratos Vegetais/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos
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