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1.
Nat Commun ; 12(1): 5458, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531390

RESUMO

Treatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide.


Assuntos
Adenina/análogos & derivados , Alanina/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Organofosfatos/farmacologia , Pró-Fármacos/farmacologia , Tenofovir/análogos & derivados , Tenofovir/farmacologia , Adenina/química , Adenina/farmacocinética , Adenina/farmacologia , Alanina/química , Alanina/farmacocinética , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Estabilidade de Medicamentos , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Masculino , Nanopartículas/química , Organofosfatos/química , Organofosfatos/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Tenofovir/química , Tenofovir/farmacocinética , Equivalência Terapêutica
2.
Expert Rev Hematol ; 14(9): 819-830, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34375536

RESUMO

INTRODUCTION: Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy. AREAS COVERED: The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism. EXPERT OPINION: Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.


Assuntos
Adenina/análogos & derivados , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/efeitos adversos , Adenina/farmacologia , Adenina/uso terapêutico , Idoso , COVID-19/complicações , Gerenciamento Clínico , Interações Medicamentosas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Masculino , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia
3.
Nat Commun ; 12(1): 4651, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330898

RESUMO

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.


Assuntos
Adenocarcinoma/metabolismo , Fosfatase 6 de Especificidade Dupla/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Humanos , Indóis/farmacologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas p21(ras)/genética , Estresse Fisiológico/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299380

RESUMO

Artificial activation of oocytes is an important step for successful parthenogenesis and somatic cell nuclear transfer (SCNT). Here, we investigated the initiation of DNA synthesis and in vivo development of canine PA embryos and cloned embryos produced by treatment with 1.9 mM 6-dimethylaminopurine (6-DMAP) for different lengths of time. For experiments, oocytes for parthenogenesis and SCNT oocytes were cultured for 4 min in 10 µM calcium ionophore, and then divided into 2 groups: (1) culture for 2 h in 6-DMAP (DMAP-2h group); (2) culture for 4 h in DMAP (DMAP-4h group). DNA synthesis was clearly detected in all parthenogenetic (PA) embryos and cloned embryos incorporated BrdU 4 h after activation in DMAP-2h and DMAP-4h groups. In vivo development of canine parthenogenetic fetuses was observed after embryo transfer and the implantation rates of PA embryos in DMAP-2h were 34%, which was significantly higher than those in DMAP-4h (6.5%, p < 0.05). However, in SCNT, there was no significant difference in pregnancy rate (DMAP-2h: 41.6% vs. DMAP-4h: 33.3%) and implantation rates (DMAP-2h: 4.94% vs. DMAP-4h: 3.19%) between DMAP-2h and DMAP-4h. In conclusion, the use of DMAP-2h for canine oocyte activation may be ideal for the in vivo development of PA zygotes, but it was not more effective in in vivo development of canine reconstructed SCNT oocytes. The present study demonstrated that DMAP-2h treatment on activation of canine parthenogenesis and SCNT could effectively induce the onset of DNA synthesis during the first cell cycle.


Assuntos
Adenina/análogos & derivados , Replicação do DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Adenina/farmacologia , Animais , Clonagem de Organismos/métodos , Cães , Transferência Embrionária/métodos , Feminino , Técnicas de Transferência Nuclear , Oócitos/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Gravidez
5.
Phytochemistry ; 190: 112842, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34214924

RESUMO

A phytochemical investigation on the flowers of Sophora davidii resulted in the isolation of three unusual matrine-adenine hybrids, sophovicines A-C, together with biogenetically related analogue sophocarpine. Their structures and absolute configurations were determined by NMR analysis, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) data. Since sophovicines represent the first example of matrine-adenine hybrids, a putative biosynthetic pathway toward sophovicines A-C was proposed. In addition, computational molecular modeling suggested that compounds sophovicines B and C may have potent activities against human cytomegalovirus (HCMV). So, the inhibit effects of isolates on HCMV were evaluated. The results show that sophovicines B and C can inhibit HCMV replication effectively with IC50 values of 7.12 and 7.32 µM, respectively.


Assuntos
Sophora , Adenina/farmacologia , Alcaloides , Citomegalovirus , Humanos , Estrutura Molecular , Quinolizinas/farmacologia
7.
Aging (Albany NY) ; 13(12): 16072-16087, 2021 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-34120890

RESUMO

Hepatocellular carcinoma (HCC) serves as a prevailing global malignancy with severe mortality and extremely unsatisfactory prognosis, in which autophagy is a fundamental process in liver cancer pathogenesis, but the mechanisms are poorly understood. MicroRNAs (miRNAs) serve as a type of well-recognized non-coding regulators and contribute to the modulation of liver cancer development, from the aspects of diagnosis, progression, and therapy. Here, we aimed to investigate the function of hsa_microRNA-513b-5p (miR-513b-5p) in regulating autophagy during HCC progression. Specifically, our data showed that miR-513b-5p mimic reduced the LC3-II and beclin1 expression but enhanced p62 expression in HCC cells. MiR-513b-5p repressed liver cancer cell proliferation, migration/invasion, and induced apoptosis in vitro. Crucially, miR-513b-5p attenuated tumor growth of liver cancer cells in vivo. In the mechanical investigation, we identified that PIK3R3 mRNA 3'UTR was targeted by miR-513b-5p and miR-513b-5p suppressed PIK3R3 expression. PIK3R3 overexpression partly reversed miR-513b-5p-mediated autophagy, proliferation, and apoptosis of liver cancer cells. Consequently, we concluded that miR-513b-5p repressed autophagy during the malignant progression of HCC by targeting PIK3R3. MiR-513b-5p may be applied as a therapeutic target for HCC.


Assuntos
Autofagia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Progressão da Doença , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , MicroRNAs/genética , Invasividade Neoplásica
8.
Am J Physiol Renal Physiol ; 321(1): F106-F119, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34121452

RESUMO

Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice (n = 5-9 mice/sex/group) were randomly allocated to CKD groups (0.2-0.15% adenine-supplemented diet or 5/6 Nx surgery) or the corresponding control groups (casein diet or sham surgery). Following the induction of CKD, the glomerular filtration rate was reduced to a similar level in both adenine and 5/6 Nx mice (adenine diet-fed male mice: 81.1 ± 41.9 µL/min vs. 5/6 Nx male mice: 160 ± 80.9 µL/min, P = 0.5875; adenine diet-fed female mice: 112.9 ± 32.4 µL/min vs. 5/6 Nx female mice: 107.0 ± 45.7 µL/min, P = 0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e., p-cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas Ca2+ homeostasis was disturbed in male mice with both CKD models. Compared with control mice, muscle mass and myofiber cross-sectional areas of the extensor digitorum longus and soleus muscles were ∼18-24% smaller in male CKD mice regardless of the model but were not different in female CKD mice (P > 0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19-24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy. However, the adenine diet model demonstrated superior performance with regard to mortality (∼20-50% mortality for 5/6 Nx vs. 0% mortality for the adenine diet, P < 0.05 for both sexes) compared with the 5/6 Nx surgical model.NEW & NOTEWORTHY Numerous preclinical models of chronic kidney disease have been used to evaluate skeletal muscle pathology; however, direct comparisons of popular models are not available. In this study, we compared adenine-induced nephropathy and 5/6 nephrectomy models. Both models produced equivalent levels of muscle atrophy and mitochondrial impairment, but the adenine model exhibited lower mortality rates, higher consistency in uremic toxin levels, and dysregulated phosphate homeostasis compared with the 5/6 nephrectomy model.


Assuntos
Adenina/farmacologia , Taxa de Filtração Glomerular/genética , Músculo Esquelético/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Nefrectomia/métodos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Uremia/fisiopatologia
9.
Sci Adv ; 7(25)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34134991

RESUMO

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , COVID-19/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , eIF-2 Quinase/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Apoptose/fisiologia , COVID-19/etiologia , COVID-19/patologia , Linhagem Celular , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Células Epiteliais/virologia , Feminino , Humanos , Indóis/farmacologia , Pulmão/virologia , Masculino , Camundongos Transgênicos , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética
10.
Aging (Albany NY) ; 13(12): 16381-16403, 2021 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-34175838

RESUMO

Cardiac senescence is associated with cardiomyopathy which is a degenerative disease in the aging process of the elderly. The present study investigates using multiple experimental approaches whether the natural flavone acacetin could attenuate myocardial senescence in C57/BL6 mice and H9C2 rat cardiac cells induced by D-galactose. We found that the impaired heart function in D-galactose-induced accelerated aging mice was improved by oral acacetin treatment in a dose-dependent manner. Acacetin significantly countered the increased serum advanced glycation end products, the myocardial telomere length shortening, the increased cellular senescence marker proteins p21 and p53, and the reduced mitophagy signaling proteins PINK1/Parkin and Sirt6 expression in aging mice. In H9C2 rat cardiac cells, acacetin alleviated cell senescence induced by D-galactose in a concentration-dependent manner. Acacetin decreased p21 and p53 expression, up-regulated PINK1/Parkin, LC3II/LC3I ratio, pLKB1, pAMPK and Sirt6, and reversed the depolarized mitochondrial membrane potential in aging cardiac cells. Mitophagy inhibition with 3-methyladenine or silencing Sirt6 abolished the protective effects of acacetin against cardiac senescence. Further analysis revealed that acacetin effect on Sirt6 was mediated by Sirt1 activation and increase of NAD+/NADH ratio. These results demonstrate that acacetin significantly inhibits in vivo and in vitro cardiac senescence induced by D-galactose via Sirt1-mediated activation of Sirt6/AMPK signaling pathway, thereby enhancing mitophagy and preserving mitochondrial function, which suggests that acacetin may be a drug candidate for treating cardiovascular disorders related to aging.


Assuntos
Envelhecimento/patologia , Flavonas/farmacologia , Mitofagia/efeitos dos fármacos , Miocárdio/patologia , Acetilação , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Cardiotônicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Galactose , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , Sirtuínas/metabolismo
11.
PLoS Biol ; 19(6): e3001281, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34077419

RESUMO

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.


Assuntos
Autofagia , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas de Ligação a Tacrolimo/metabolismo , Quinases da Família src/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Camundongos , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores
12.
Biomolecules ; 11(6)2021 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070807

RESUMO

This work aimed to investigate whether treatment with the antidiabetic drug metformin would affect adenine-induced chronic kidney disease (CKD) in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Rats were randomly divided into eight groups, and given either normal feed, or feed mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also simultaneously treated orally with metformin (200 mg/kg/day). Rats given adenine showed the typical signs of CKD that included detrimental changes in several physiological and traditional and novel biochemical biomarkers in plasma urine and kidney homogenates such as albumin/creatinine ratio, N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, 8-isoprostane, adiponectin, cystatin C, as well as plasma urea, creatinine, uric acid, indoxyl sulfate, calcium, and phosphorus. Several indices of inflammation and oxidative stress, and renal nuclear factor-κB and nuclear factor erythroid 2-related factor 2 levels were also measured. Histopathologically, adenine caused renal tubular necrosis and fibrosis. The activation of the intracellular mitogen-activated protein kinase signaling pathway was inhibited in the groups that received metformin and STZ together, with or without adenine induced-CKD. Induction of diabetes worsened most of the actions induced by adenine. Metformin significantly ameliorated the renal actions induced by adenine and STZ when these were given singly, and more so when given together. The results suggest that metformin can be a useful drug in attenuating the progression of CKD in both diabetic and non-diabetic rats.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Rim/metabolismo , Metformina/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Adenina/efeitos adversos , Adenina/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Rim/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia
13.
Carbohydr Polym ; 268: 118247, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34127226

RESUMO

Atherosclerotic cardiovascular disease became one of the major causes of morbidity and mortality worldwide. As a sulfated polysaccharide with anti-inflammatory and hypolipidemic activities, fucoidan can induce autophagy. We show here that fucoidan reduces lipid accumulation in foam cells, which is one of the causes of atherosclerosis. Further studies show that fucoidan promotes autophagy showed by the expression of p62/SQSTM1 and microtubule-associated protein light chain 3 (LC3) II, which can be blocked by autophagy inhibitors 3-MA and bafilomycin A1. In addition, the expression of transcription factor EB (TFEB), master regulator of autophagy and lysosome function, is upregulated after the treatment with fucoidan. Moreover, the knockout of TFEB with small interfering RNA suppressed the effect of fucoidan. Together, fucoidan reduces lipid accumulation in foam cells by enhancing autophagy through the upregulation of TFEB. In view of the role of foam cells in atherosclerosis, fucoidan can be valuable for the treatment of atherosclerosis.


Assuntos
Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Células Espumosas/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Polissacarídeos/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Macrolídeos/farmacologia , Camundongos , Células RAW 264.7
14.
Aging (Albany NY) ; 13(12): 15964-15989, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031264

RESUMO

A traditional Chinese medicinal fungus, Antrodia salmonea (AS), with antioxidant properties is familiar in Taiwan but anti-cancer activity of AS in human colon cancer is ambiguous. Hence, we explored the anti-cancer activity of AS in colon cancer cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that AS showed a remarkable effect on cell viability in colon cancer cells; SW620, HCT116, and HT29. Annexin V/propidium iodide (PI) stained cells indicated that AS induced both early/late apoptosis in SW620 cells. Additionally, cells treated with AS induced caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, mitochondrial dysfunction, and Bcl-2 associated X (Bax)/B-cell lymphoma (Bcl-2) dysregulation. Microtubule- associated protein 1A/1B-light chain 3B (LC3-II) accumulation, sequestosome 1 (p62/SQSTM1) activation, autophagy related 4B cysteine peptidase (ATG4B) inactivation, acidic vesicular organelles (AVOs) formation, and Beclin-1/Bcl-2 dysregulation revealed that AS-induced autophagy. Interestingly, cells pretreated with 3-methyladenine (3-MA) strengthened AS-induced caspase-3/apoptosis. Suppression of apoptosis by z-Val-Ala-Asp fluoromethyl ketone (Z-VAD-FMK) did not however block AS-induced autophagy, suggesting that autophagy was not attenuated by the AS-induced apoptosis. Application of N-acetylcysteine (NAC) prevented AS-induced cell death, caspase-3 activation, LC3-II accumulation, and AVOs formation, indicating that AS-induced apoptosis and autophagy was mediated by reactive oxygen species (ROS). Furthermore, AS-induced cytoprotective autophagy and apoptosis through extracellular signal-regulated kinase (ERK) signaling cascades. Moreover, in vivo data disclosed that AS inhibited colitis-associated tumorigenesis in azoxymethane (AOM)-dextran sodium sulphate (DSS)-treated mice. For the first time, we report the anti-cancer properties of this potentially advantageous mushroom for the treatment of human colon cancer.


Assuntos
Apoptose , Autofagia , Neoplasias do Colo/patologia , Citoproteção , Polyporales/química , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Azoximetano , Proteína Beclina-1/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Colite/induzido quimicamente , Colite/complicações , Neoplasias do Colo/etiologia , Citoproteção/efeitos dos fármacos , Sulfato de Dextrana , Progressão da Doença , Humanos , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos ICR , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/metabolismo
15.
Aging (Albany NY) ; 13(11): 15151-15163, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035183

RESUMO

Acute myocardial injury (AMI) is often secondary to sepsis, which is a life-threatening disease associated with severe cardiac inflammation. Narciclasine, a plant alkaloid isolated from different members of the Amaryllidaceae family, has been extensively characterized as an antitumor and anti-inflammatory compound. In addition, autophagy is critical for sepsis-induced myocardial injury. However, the role and mechanism of autophagy by which narciclasine confers cardioprotection are still unclear. The present study aimed to investigate the underlying mechanism by which narciclasine affects the pathogenesis of sepsis-induced myocardial injury. Narciclasine effectively attenuated LPS-induced myocardial inflammation in vitro and in vivo. In addition, narciclasine protected cardiac function and suppressed the expression of inflammatory cytokines in LPS-induced heart tissue. Furthermore, narciclasine upregulated LPS-induced autophagic activity, and the autophagy inhibitor 3-MA abrogated narciclasine-mediated protection against LPS-induced AMI. Importantly, narciclasine exerted an inhibitory effect on the JNK signaling pathway, and JNK activity was tightly associated with narciclasine-induced autophagy and the consequent protective effects during AMI. Taken together, our findings indicate that narciclasine protects against LPS-induced AMI by inducing JNK-dependent autophagic flux; hence, narciclasine may be an effective and novel agent for the clinical treatment of sepsis-induced myocardial injury.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Autofagia , Miocárdio/patologia , Fenantridinas/farmacologia , Sepse/complicações , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Alcaloides de Amaryllidaceae/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Inflamação/patologia , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenantridinas/uso terapêutico , Regulação para Cima/efeitos dos fármacos
16.
Cell Stem Cell ; 28(9): 1614-1624.e5, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33951479

RESUMO

DNA base editors and prime editing technology enable therapeutic in situ correction of disease-causing alleles. These techniques could have broad applications for ex vivo editing of cells prior to transplantation in a range of diseases, but it is critical that the target population is efficiently modified and engrafts into the host. Chemically derived hepatic progenitors (CdHs) are a multipotent population capable of robust engraftment and hepatocyte differentiation. Here we reprogrammed hepatocytes from a mouse model of hereditary tyrosinemia type 1 (HT1) into expandable CdHs and successfully corrected the disease-causing mutation using both adenine base editors (ABEs) and prime editors (PEs). ABE- and PE-corrected CdHs repopulated the liver with fumarylacetoacetate hydrolase-positive cells and dramatically increased survival of mutant HT1 mice. These results demonstrate the feasibility of precise gene editing in transplantable cell populations for potential treatment of genetic liver disease.


Assuntos
Adenina , Hepatopatias , Adenina/farmacologia , Animais , Edição de Genes , Hepatócitos , Hepatopatias/terapia , Camundongos
17.
Neurochem Res ; 46(8): 2033-2045, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34021889

RESUMO

Autophagy, a process for self-degradation of intracellular components and dysfunctional organelles, is closely related with neurodegenerative diseases. It has been shown that cadmium (Cd) induces neurotoxicity partly by impairing autophagy. However, the underlying mechanism is not fully elucidated. In this study, we show that Cd induced expansion of autophagosomes with a concomitant abnormal expression of autophagy-related (Atg) proteins in PC12 cells and primary murine neurons. 3-MA, a classical inhibitor of autophagy, attenuated Cd-induced expansion of autophagosomes and apoptosis in the cells. Further investigation demonstrated that Cd activated JNK pathway contributing to autophagosome expansion-dependent neuronal apoptosis. This is supported by the findings that pharmacological inhibition of JNK with SP600125 or expression of dominant negative c-Jun markedly attenuated Cd-induced expansion of autophagosomes and abnormal expression of Atg proteins, as well as apoptosis in PC12 cells and/or primary neurons. Furthermore, we noticed that chelating intracellular free Ca2+ ([Ca2+]i) with BAPTA/AM profoundly blocked Cd-elicited activation of JNK pathway and consequential expansion of autophagosomes, abnormal expression of Atg proteins, and apoptosis in the neuronal cells. Similar events were also seen following prevention of [Ca2+]i elevation with EGTA or 2-APB, implying a Ca2+-dependent mechanism involved. Taken together, the results indicate that Cd impairs autophagy leading to apoptosis by Ca2+-dependent activation of JNK signaling pathway in neuronal cells. Our findings highlight that manipulation of intracellular Ca2+ level and/or JNK activity to ameliorate autophagy may be a promising intervention against Cd-induced neurotoxicity and neurodegeneration.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cádmio/toxicidade , Cálcio/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Antracenos/farmacologia , Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Células PC12 , Ratos
18.
J Bone Miner Metab ; 39(4): 572-582, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33818629

RESUMO

INTRODUCTION: PTH1-34 can stimulate osteoblast formation, which contributes to the improvement of bone loss. PTH1-34 can activate autophagy, and autophagy plays a key role in osteoblast formation. This study aimed to explore the role of autophagy in PTH1-34-regulated osteoblastogenesis. MATERIALS AND METHODS: In this study, the mice treated with ovariectomy (OVX mice) were used to observe the effect of PTH1-34 on the formation and autophagy of osteoblasts in trabecular bone in vivo. Osteoblast precursor cell line MC3T3-E1 was treated with PTH1-34, and then the autophagic parameters of osteoblast precursors (including autophagic proteins and autophagosome formation) were detected using Western Blotting and Transmission Electron Microscopy. Next, after using autophagic pharmacological inhibitor (3-MA) and silencing vectors of autophagic molecule Beclin1 to downregulate autophagic activity, the parameters related to osteogenesis (including ALP staining intensity, ALP activity, cell proliferation and osteoblastic protein expression) were evaluated using corresponding assays. RESULTS: In vivo results showed that PTH1-34 not only improved bone loss caused by OVX but also restored Beclin1 expression and autophagic activity of immature osteoblasts in bone tissues. In vitro assays also showed that treatment of PTH1-34 enhanced the autophagy in osteoblast precursors. Moreover, under PTH1-34 intervention, the upregulated osteogenic parameters were reversed by autophagic inhibition with 3-MA. Of note, Beclin1 silencing can recover the osteogenic activity enhanced by PTH1-34. CONCLUSION: PTH1-34 can enhance the autophagic activity of osteoblast precursors, which is involved in PTH1-34-regulated osteoblast formation. Furthermore, Beclin1, as a key autophagic regulator, plays a pivotal role in PTH1-34-regulated osteoblast precursor autophagy and osteoblastogenesis.


Assuntos
Autofagia , Proteína Beclina-1/metabolismo , Osteoblastos/metabolismo , Hormônio Paratireóideo/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Benzilaminas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células , Estradiol/farmacologia , Feminino , Camundongos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ovariectomia , Quinazolinas/farmacologia , Ratos Sprague-Dawley
19.
Aging (Albany NY) ; 13(9): 12955-12972, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33929971

RESUMO

Breast cancer is the most common malignancy in women all around the world, especially in many countries in Asia. However, antitumor drugs with unique curative effects and low toxic side-effects have not been found yet. Warangalone is an isoflavone extracted from the Cudrania tricuspidata fruit, and is reported to possess anti-inflammatory and anti-cancer activity. The purpose of this study was to determine the effects of warangalone on breast cancer cells. In this study, we found that warangalone decreased the viability of breast cancer cells by increasing the generation of reactive oxygen species (ROS) resulting in mitochondrial damage and decreased mitochondrial membrane potential (MMP). Warangalone induced mitochondrial apoptosis by increasing the BAX/BCL-2 ratio. Warangalone activated mitophagy via upregulation of PINK1 and Parkin expression and co-localization. The combination of warangalone and autophagy inhibitors or PINK1 siRNA increased the degree of cell apoptosis compared to treatment with warangalone alone. Warangalone damages mitochondria via ROS, thereby triggering PINK1/Parkin-mediated mitophagy and inducing mitochondrial apoptosis. However, autophagy/mitophagy protects against warangalone-induced mitochondrial apoptosis. A combination of warangalone and autophagy/mitophagy inhibitors may be a potential treatment for breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Isoflavonas/farmacologia , Mitofagia/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoflavonas/uso terapêutico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitofagia/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
20.
Biochem Biophys Res Commun ; 555: 182-189, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33823364

RESUMO

Autophagy and apoptosis, as major modes of cell death, play critical roles in cellular homeostasis. Our previous study demonstrated that the cross-talk between autophagy and apoptosis regulated cadmium-induced testicular injury and self-recovery, influencing male fertility. However, the underlying mechanism remains blurry. Herein, our subfertility rat model indicated that cadmium-induced autophagy and apoptosis were ameliorated by the activation of SIRT3 and blunted by the inhibition of SIRT3 in rat testis. Further, generating SIRT3 overexpression and knockdown models in TM3 mouse Leydig cells, we found that melatonin (SIRT3 activator) and overexpression of SIRT3 rescued cadmium-induced autophagy and apoptosis in TM3 cells. Knockdown of SIRT3 induced autophagy and apoptosis, which failed to be reversed by melatonin in TM3 cells. Taken together, SIRT3 functions as a pivotal protective factor in testicular Leydig cells injury, and melatonin regulates the cross-talk between autophagy and apoptosis by SIRT3, ameliorating cadmium-induced testicular injury.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Células Intersticiais do Testículo/metabolismo , Melatonina/metabolismo , Sirtuína 3/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cádmio/toxicidade , Células Cultivadas , Técnicas de Silenciamento de Genes , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Melatonina/farmacologia , Camundongos , Ratos Sprague-Dawley , Sirtuína 3/genética , Sirtuínas/metabolismo , Testículo/citologia , Testículo/efeitos dos fármacos , Testículo/metabolismo
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