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1.
Food Chem ; 399: 133799, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35998490

RESUMO

Flesh quality is evaluated according to nutritional value and sensory quality. Cinnamaldehyde (CIN) improves mammalian meat quality, but research relating this to aquaculture is scarce. In this study, five doses of CIN (0, 36, 72, 108, 144 mg/kg diet) were fed to grass carp (Ctenopharyngodon idella) for 60 days. The results show that CIN supplementation increased nutritional value by increasing crude protein content. CIN also improved the sensory quality by increasing the pH and collagen content, decreasing shear force, lactate, and cooking loss. These changes may be related to changes in muscle fiber growth by increasing myofiber diameter. The increased myofiber diameter induced by CIN is associated with TOR mRNA and protein levels, and down-regulated FOXO3a mRNA levels, which might be associated with PTP1B/IGF1/PI3K/AKTs-TOR/FOXO3a signaling. Based on muscle crude protein content, optimal CIN supplementation dosage was 88.01 mg/kg.


Assuntos
Carpas , Doenças dos Peixes , Acroleína/análogos & derivados , Ração Animal/análise , Animais , Carpas/genética , Carpas/metabolismo , Dieta , Suplementos Nutricionais , Doenças dos Peixes/genética , Proteínas de Peixes/metabolismo , Imunidade Inata , Mamíferos/genética , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/genética , Transdução de Sinais
2.
Anal Cell Pathol (Amst) ; 2022: 9303081, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090016

RESUMO

Background: GPNMB is a newly discovered tumour-promoting factor that may promote tumour cell progression by activating the PI3K/AKT pathway by EGFR. However, there are insufficient studies about GPNMB in ESCC. This study investigated the relationship between GPNMB and EGFR/PI3K pathway genes in ESCC. Methods: The expression levels of GPNMB, EGFR, p-PI3K, and Ki-67 were examined using immunohistochemistry. Statistical analysis was done by SPSS 22.0 and R. Results: GPNMB mRNA expression is higher in ESCC compared with paracancerous tissues. The expression of EGFR, PIK3CA, PIK3CB, and AKT1 was increased in GPNMB upregulated samples. GPNMB expression was positively correlated with EGFR, p-PI3K, and Ki-67 expression. GPNMB was expressed higher in the AJCC III stage, lymph node metastasis, and moderately poorly differentiated patients. EGFR was higher expressed in patients with vascular invasion; p-PI3K expression in Kazak was higher than that in Han; Ki-67 expression was higher in tumour size ≥ 3 cm. Patients with high expression of GPNMB, p-PI3K, and Ki-67 had worse OS. p-PI3K, Ki-67, nerve invasion, and lymphatic metastasis were independent risk factors, and postoperative adjuvant therapy was a protective factor in ESCC. Conclusion: As a tumour-promoting factor, GPNMB is expected to be a potential target for ESCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Carcinoma de Células Escamosas/metabolismo , Classe I de Fosfatidilinositol 3-Quinases , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Antígeno Ki-67 , Metástase Linfática , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico
3.
Oxid Med Cell Longev ; 2022: 4622520, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092165

RESUMO

Cardiac microvascular endothelial cell ischemia-reperfusion (CMEC I/R) injury occurs in approximately 50% of acute myocardial infarction patients subjected to successful revascularization therapy. This injury leads to cardiac microcirculatory system dysfunctions, which seriously affect cardiac functions and long-term prognostic outcomes. Previously, we elucidated the role of lysine-specific demethylase 3A (KDM3A) in protecting cardiomyocytes from I/R injury; however, its roles in CMEC I/R injuries have yet to be fully established. In this study, hypoxia/reoxygenation (H/R) treatment significantly impaired CMEC functions and induced their pyroptosis, accompanied by KDM3A downregulation. Then, gain- and loss-of-function assays were performed to investigate the roles of KDM3A in CMEC H/R injury in vitro. KDM3A knockout enhanced CMEC malfunctions and accelerated the expressions of pyroptosis-associated proteins, such as NLRP3, cleaved-caspase-1, ASC, IL-1ß, GSDMD-N, and IL-18. Conversely, KDM3A overexpression developed ameliorated alternations in CMEC H/R injury. In vivo, KDM3A knockout resulted in the deterioration of cardiac functions and decreased the no-reflow area as well as capillary density. Mechanistically, KDM3A activated the PI3K/Akt signaling pathway and ameliorated I/R-mediated CMEC pyroptosis. In conclusion, KDM3A is a promising treatment target for alleviating CMEC I/R injury.


Assuntos
Traumatismo por Reperfusão Miocárdica , Piroptose , CME-Carbodi-Imida/metabolismo , Células Endoteliais/metabolismo , Humanos , Isquemia/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Microcirculação , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
4.
Commun Biol ; 5(1): 974, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109592

RESUMO

Leydig cells in fetal testes play crucial roles in masculinizing fetuses through androgen production. Gene knockout studies have revealed that growth factors are implicated in fetal Leydig cell (FLC) differentiation, but little is known about the mechanisms regulating this process. We investigate this issue by characterizing FLC progenitor cells using single-cell RNA sequencing. The sequence datasets suggest that thymosin ß10 (Tmsb10) is transiently upregulated in the progenitors. While studying the function of Tmsb10, we reveal that platelet-derived growth factor (PDGF) regulates ciliogenesis through the RAS/ERK and PI3K/AKT pathways, and thereby promotes desert hedgehog (DHH)-dependent FLC differentiation. Tmsb10 expressed in the progenitor cells induces their differentiation into FLCs by suppressing the RAS/ERK pathway. Through characterizing the transiently expressed Tmsb10 in the FLC progenitors, this study unveils the molecular process of FLC differentiation and shows that it is cooperatively induced by DHH and PDGF.


Assuntos
Androgênios , Sistema de Sinalização das MAP Quinases , Androgênios/metabolismo , Feto , Humanos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Timosina
5.
PLoS One ; 17(9): e0270306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36112580

RESUMO

Obesity is a leading global health problem contributing to various chronic diseases, including type II diabetes mellitus (T2DM). The aim of this study was to investigate whether blueberries, yoghurt, and their respective bioactive components, Cyanidin-3-O-ß-glucoside (C3G) and peptides alone or in combinations, alter the expression of genes related to glucose metabolism in skeletal muscles from diet-induced obese mice. In extensor digitorum longus (EDL), yoghurt up-regulated the expression of activation of 5'adenosine monophosphate-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3 kinase (PI3K) and glucose transporter 4 (GLUT4), and down-regulated the expression of angiotensin II receptor type 1 (AGTR-1). The combination of blueberries and yoghurt down-regulated the mRNA expression of AGTR-1 and Forkhead box protein O1 (FoxO1) in the EDL. Whereas the combination of C3G and peptides down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression in the EDL. In the soleus, blueberries and yoghurt alone, and their combination down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression. In summary blueberries and yoghurt, regulated multiple genes associated with glucose metabolism in skeletal muscles, and therefore may play a role in the management and prevention of T2DM.


Assuntos
Mirtilos Azuis (Planta) , Diabetes Mellitus Tipo 2 , Proteínas Quinases Ativadas por AMP/metabolismo , Monofosfato de Adenosina/metabolismo , Animais , Antocianinas/metabolismo , Antocianinas/farmacologia , Mirtilos Azuis (Planta)/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Suplementos Nutricionais , Proteína Forkhead Box O1/metabolismo , Expressão Gênica , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Camundongos Obesos , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/metabolismo , RNA Mensageiro/metabolismo , Receptores de Angiotensina/metabolismo , Iogurte
6.
Cell Death Dis ; 13(9): 794, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115854

RESUMO

PI3K/AKT signaling pathway plays an important role in regulating the tumorigenesis, recurrence, and metastasis of breast cancer (BC). In this study, we discovered a circRNA with protein-coding potential, which we named circSEMA4B. CircSEMA4B could encode a novel protein, SEMA4B-211aa. Both circSEMA4B and SEMA4B-211aa were remarkably downregulated in BC tissues and cell lines. Low expression of circSEMA4B was positively associated with TNM stage, tumor size, lymph node metastasis, and distant metastasis of BC patients. The functional investigation showed that circSEMA4B and SEMA4B-211aa could significantly inhibit the proliferation and migration of BC in vivo and in vitro. Of note, SEMA4B-211aa inhibited the generation of PIP3 by binding to p85, thereby inhibiting the phosphorylation of AKT (Thr308). CircSEMA4B inhibited the phosphorylation of AKT (Ser473) through miR-330-3p/PDCD4 axis. Taken together, circSEMA4B is a novel negative regulator of PI3K/AKT signaling pathway, providing novel mechanistic insights into the underlying mechanisms of BC.


Assuntos
Neoplasias da Mama , MicroRNAs , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Circular , Proteínas de Ligação a RNA/metabolismo
7.
Sci Rep ; 12(1): 15628, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115905

RESUMO

Previously, our group has demonstrated establishment of Cancer Stem Cell (CSC) models from stem cells in the presence of conditioned medium of cancer cell lines. In this study, we tried to identify the factors responsible for the induction of CSCs. Since we found the lipid composition could be traced to arachidonic acid cascade in the CSC model, we assessed prostaglandin E2 (PGE2) as a candidate for the ability to induce CSCs from induced pluripotent stem cells (iPSCs). Mouse iPSCs acquired the characteristics of CSCs in the presence of 10 ng/mL of PGE2 after 4 weeks. Since constitutive Akt activation and pik3cg overexpression were found in the resultant CSCs, of which growth was found independent of PGE2, chronic stimulation of the receptors EP-2/4 by PGE2 was supposed to induce CSCs from iPSCs through epigenetic effect. The bioinformatics analysis of the next generation sequence data of the obtained CSCs proposed not only receptor tyrosine kinase activation by growth factors but also extracellular matrix and focal adhesion enhanced PI3K pathway. Collectively, chronic stimulation of stem cells with PGE2 was implied responsible for cancer initiation enhancing PI3K/Akt axis.


Assuntos
Dinoprostona , Neoplasias , Animais , Ácido Araquidônico/metabolismo , Meios de Cultivo Condicionados/farmacologia , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Camundongos , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
8.
Biomed Res Int ; 2022: 5481552, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119923

RESUMO

Chronic kidney disease (CKD) is identified as a widespread chronic progressive disease jeopardizing public health which characterized by gradually loss of renal function. However, there is no efficient therapy to prevail over this disease. Our study was attempting to reveal hirudin's regulation to renal fibrosis as well as the molecular mechanism. We built renal fibrosis models on both cell and animal levels, which were subsequently given with hirudin disposal; then, we performed the transwell assay to estimate the cells' migration and had our detection to relevant proteins with western blot and immunofluorescence. Finally, we commenced both the identification and the determination to the hirudin targeted proteins and its downstream signaling pathways with the methods of network pharmacology. And the results turned out that when it was compared with the model group, the group with hirudin addition came with the suppression in the migration of renal tubular epithelial cells NRK-52E and with a conspicuous decline in the expressions of fibronectin, N-cadherin, vimentin, TGF-ß, and snail. After that, we predicted that there were 17 hirudin target points mainly involving in the PI3K-AKT signaling pathway. Our outcomes of the animal level demonstrated that the conditions of interstitial fibrosis, severe tubular dilatation or atrophy, inflammatory cell infiltration, and massive accumulation of interstitial collagen in the model group were withdrawn after the addition of hirudin. In addition, p-PDGFRß, p-PI3K, and p-AKT protein expressions were significantly reduced, and the PI3K/AKT pathway was downregulated after hirudin treatment in the model group of NRK-52E cells and animals. Therefore, we had our conclusion that hirudin is capable of suppressing the PI3K-AKT signaling pathway as well as the EMT by decreasing PDGFRß phosphorylation.


Assuntos
Nefropatias , Proteínas Proto-Oncogênicas c-akt , Animais , Caderinas/metabolismo , Regulação para Baixo , Transição Epitelial-Mesenquimal , Fibronectinas/metabolismo , Fibrose , Hirudinas/farmacologia , Nefropatias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Vimentina/metabolismo
9.
Oxid Med Cell Longev ; 2022: 8672969, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120596

RESUMO

Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). However, effective therapeutic drugs for IDD remain to be further explored. Inflammatory cytokines play a pivotal role in the onset and progression of IDD. Dihydroartemisinin (DHA) has been well reported to have powerful anti-inflammatory effects, but whether DHA could ameliorate the development of IDD remained unclear. In this study, the effects of DHA on extracellular matrix (ECM) metabolism and cellular senescence were firstly investigated in nucleus pulposus cells (NPCs) under tumor necrosis factor alpha (TNFα)-induced inflammation. Meanwhile, AKT agonist sc-79 was used to determine whether DHA exerted its actions through regulating PI3K/AKT and NF-κB signaling pathways. Next, the therapeutic effects of DHA were tested in a puncture-induced rat IDD model. Finally, we detected the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens. We demonstrated that DHA ameliorated the imbalance between anabolism and catabolism of extracellular matrix and alleviated NPCs senescence induced by TNFα in vitro. Further, we illustrated that DHA mitigated the IDD progression in a puncture-induced rat model. Mechanistically, DHA inhibited the activation of PI3K/AKT and NF-κB signaling pathways induced by TNFα, which was undermined by AKT agonist sc-79. Molecular docking predicted that DHA bound to the PI3K directly. Intriguingly, we also verified the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens, suggesting that DHA may qualify itself as a promising drug for mitigating IDD.


Assuntos
Artemisininas , Degeneração do Disco Intervertebral , Animais , Anti-Inflamatórios/farmacologia , Artemisininas/farmacologia , Citocinas/metabolismo , Degeneração do Disco Intervertebral/patologia , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia
10.
J Ethnopharmacol ; 299: 115658, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36075273

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia argyi H. Lév. & Vaniot (Asteraceae), also called "Chinese mugwort", is frequently used as a herbal medicine in China, Japan, Korea, and eastern parts of Russia. It is known as "ai ye" in China and "Gaiyou" in Japan. In ancient China, the buds and leaves of A. argyi were commonly consumed before and after Tomb-sweeping Day. It is used to treat malaria, hepatitis, cancer, inflammatory diseases, asthma, irregular menstrual cycle, sinusitis, and pathologic conditions of the kidney and liver. Although A. argyi extract (AAE) has shown anti-tumor activity against various cancers, the therapeutic effect and molecular mechanism of AAE remains to be further studied in lung cancer. AIM OF THE STUDY: This study aimed to demonstrate the anti-tumor effect of AAE and its associated biological mechanisms in CL1-0 parent and gemcitabine-resistant (CL1-0-GR) lung cancer cells. EXPERIMENTAL PROCEDURE: Human lung cancer cells CL1-0 and CL1-0-GR cells were treated with AAE. Cell viability was assessed using the MTT, colony, and spheroid formation assays. Migration, invasion, and immunofluorescence staining were used to determine the extent of epithelial- mesenchymal transition (EMT). JC-1 and MitoSOX fluorescent assays were performed to investigate the effect of AAE on mitochondria. Apoptosis was detected using the TUNEL assay and flow cytometry with Annexin V staining. RESULT: We found that A. argyi significantly decreased cell viability and induced apoptosis, accompanied by mitochondrial membrane depolarization and increased ROS levels in both parent cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0-GR). AAE-induced apoptosis is regulated via the PI3K/AKT and MAPK signaling pathways. It also prevents CL1-0 and CL1-0-GR cancer cell invasion, migration, EMT, colony formation, and spheroid formation. In addition, AAE acts cooperative with commercial chemotherapy drugs to enhance tumor spheroid shrinkage. CONCLUSION: Our study provides the first evidence that A. argyi treatment suppresses both parent and gemcitabine-resistant lung cancer cells by inducing ROS, mitochondrial membrane depolarization, and apoptosis, and reducing EMT. Our finding provides insights into the anti-cancer activity of A. argyi and suggests that A. argyi may serve as a chemotherapy adjuvant that potentiates the efficacy of chemotherapeutic agents.


Assuntos
Artemisia , Neoplasias Pulmonares , Anexina A5/metabolismo , Anexina A5/farmacologia , Anexina A5/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
11.
Biomed Pharmacother ; 153: 113389, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076477

RESUMO

Alzheimer's disease (AD) is a brain disease that causes problems in memory, thinking, and behavior. Allantoin has been shown to have antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we aimed to investigate the effect and mechanism of action of allantoin on AD-related memory impairment. We investigated the effect of allantoin on an amyloid ß1-42 peptide (Aß1-42)-induced AD model in rats and evaluated its memory-enhancing effect using the Morris water maze test. Pathological changes in the hippocampus and cortex were examined by hematoxylin-eosin staining. The expression of the phosphorylated Tau protein and PI3K/Akt/GSK-3ß signaling pathway was analyzed by western blotting. The results of the water maze test showed that after treatment with allantoin, the rats could reduce their swimming time and travel distances to find the platform. Allantoin treatment also increased the time spent in the quadrant in which the platform was located. Histological assessment showed that Aß1-42 could cause morphological alterations in nerve cells in the hippocampal CA1 region, and that allantoin could repair the damage to these cells. Western blotting revealed that allantoin treatment increased the expression of p-PI3K, p-Akt, and p-GSK-3ß and decreased p-Tau in the hippocampus and cortex of rats. These effects were inhibited by LY294002. These findings showed that allantoin could improve cognitive impairment in Aß1-42-induced rats by activating the PI3K/Akt/GSK-3ß signaling pathway to reduce abnormal hyperphosphorylation of Tau. Thus, allantoin may be a potential therapeutic agent for neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Alantoína/metabolismo , Alantoína/farmacologia , Alantoína/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Proteínas tau/metabolismo
12.
Biomed Pharmacother ; 153: 113474, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076499

RESUMO

Tumor cells can secret various cytokines and chemokines, which affect the tumor cells themselves and the neighboring cells. Here, we observed that human ovarian cancer (OC) cells developed resistance to paclitaxel treatment following culture with the conditioned medium (CM) derived from paclitaxel-resistant OC (OCTR) cells. A cytokine array revealed that both OCTR cells secreted large amounts of CC chemokine ligand 2 (CCL2). CCL2 and its receptor, CCR2, were overexpressed in OCTR cells. CCL2 expression was associated with worse progression-free survival in patients with ovarian cancer. The inhibition of the CCL2/CCR2 axis suppressed the chemoresistance induced by OCTR-CM. The enhanced expression and production of CCL2 in OC cells were mediated via the NF-κB pathway, and stimulated the activation of the PI3K/Akt pathway, which resulted in the development of paclitaxel resistance in OC cells. Additionally, the OCTR cells significantly increased the migration of macrophages, which was also associated with the overproduction of CCL2 in chemoresistant cancer cells. The macrophages stimulated by OCTR cells expressed high levels of markers of M2 phenotype, and their CM significantly decreased the paclitaxel responsiveness of OC cells. The administration of a CCR2 inhibitor to a murine model significantly improved the paclitaxel sensitivity. These data suggested that apart from inducing chemoresistance in OC cells by acting as an autocrine factor, CCL2 also functions as a chemokine that induces the chemotaxis of macrophages, which may contribute to chemoresistance. Therefore, targeting the CCL2/CCR2 signaling axis may improve the therapeutic response of patients with ovarian cancer to paclitaxel.


Assuntos
Comunicação Autócrina , Neoplasias Ovarianas , Animais , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Ligantes , Macrófagos/metabolismo , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo
13.
Nat Commun ; 13(1): 5415, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109503

RESUMO

Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling. Our results show that SIRT6 levels are increased during glucocorticoid-induced reduction of myotube size and during skeletal muscle atrophy in mice. Notably, overexpression of SIRT6 spontaneously decreases the size of primary myotubes in a cell-autonomous manner. On the other hand, SIRT6 depletion increases the diameter of myotubes and protects them against glucocorticoid-induced reduction in myotube size, which is associated with enhanced protein synthesis and repression of atrogenes. In line with this, we find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid-induced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor-mediated increase in IGF2 expression. The increased activation, in turn, leads to nuclear exclusion and transcriptional repression of the FoxO transcription factor, a key activator of muscle atrophy. Further, we find that pharmacological inhibition of SIRT6 protects against glucocorticoid-induced muscle wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of SIRT6 in glucocorticoid-induced muscle atrophy.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Sirtuínas , Animais , Cromatina , Glucocorticoides/farmacologia , Mamíferos/metabolismo , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Fatores de Transcrição
14.
Front Immunol ; 13: 854432, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110864

RESUMO

Natural killer (NK) cells are crucial for immune responses to viral infections. CD160 is an important NK cell activating receptor, with unknown function in HIV infection. Here, we found that CD160 expression was reduced on NK cells from HIV-infected individuals and its expression was negatively correlated with HIV disease progression. Further, GLUT1 expression and glucose uptake were higher in CD160+ NK cells, and the results of RNA-seq and flow cytometry demonstrated that CD160 positively regulated glucose metabolism through the PI3K/AKT/mTOR/s6k signaling pathway, thereby enhancing NK cell function. Moreover, we determined that reduced CD160 expression on NK cells could be attributed to the higher plasma levels of TGF-ß1 in HIV-infected individuals. Overall, these results highlight the vital role of CD160 in HIV disease progression and regulation of glucose metabolism, indicating a potential target for HIV immunotherapy.


Assuntos
Infecções por HIV , Antígenos CD/metabolismo , Progressão da Doença , Proteínas Ligadas por GPI/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos , Células Matadoras Naturais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Imunológicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
15.
Hum Exp Toxicol ; 41: 9603271221125928, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36113040

RESUMO

To elucidate the effect of tricin in cerebral ischemia/reperfusion (I/R) injury and examine its possible underlying mechanisms. Rats were randomly divided into Sham (exposed the right internal carotid arteries), I/R, and tricin (administered at various doses) groups. After the cerebral I/R injury model was established, a Morris water maze test and a tetrazolium chloride assay were performed. Apoptosis and autophagy were assessed in the nerve cells of hippocampus tissue, and the levels of inflammatory markers within animal serum were detected. Proteins related to apoptosis and the PI3K/Akt pathway were evaluated. To further investigate the mechanisms by which tricin affects brain damage, mouse neuroblastoma cells N2a were divided into control, oxygen-glucose deprivation and reoxygenation (OGD/R), tricin, PI3K/Akt activator, and tricin + PI3K/Akt inhibitor groups. The cell viability, apoptosis, inflammatory factors, and PI3K/Akt pathway related proteins in N2a cells were also detected. The results revealed that I/R-induced learning and memory dysfunction was improved by tricin treatment. The area of cerebral infarction, the levels of apoptosis and autophagy in nerve cells, and the serum inflammatory marker content were all decreased following tricin treatment. Additionally, the expression of Beclin-1 protein was downregulated, while the expression of Bcl-2 protein, p-PI3K/PI3K and p-Akt/Akt was upregulated after tricin treatment. Mechanistically, tricin or PI3K/Akt activator ameliorated OGD/R-induced apoptosis, autophagy, and inflammation. However, these effects were reversed following PI3K/Akt inhibitor treatment in OGD/R-induced N2a cells. In summary, this study suggested that tricin can against I/R-induced brain injury by inhibiting autophagy, apoptosis and inflammation, and activating the PI3K/Akt signaling pathway.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Apoptose , Autofagia , Proteína Beclina-1 , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Cloretos/farmacologia , Flavonoides , Glucose/farmacologia , Inflamação/tratamento farmacológico , Camundongos , Neurônios/metabolismo , Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
16.
Front Public Health ; 10: 969070, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36051999

RESUMO

Objective: We performed a pan-cancer analysis to explore the potential mechanisms of FAT4 in 33 different tumors. Methods: In this study, we selected 33 types of cancers based on the datasets of TCGA (the cancer genome atlas). We analyzed the expression of FAT4 in tumor and normal tissues. Meanwhile, we analyzed the expression levels of FAT4 in tissues from tumors of different stages. Kaplan-Meier survival analysis, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), immune infiltration analysis, Gene set enrichment analysis (GSEA), and FAT4-related gene enrichment analysis were performed. Results: FAT4 expression in most tumor tissues was lower than in corresponding control tissues. FAT4 expression was different in different stages of bladder cancer (BLCA), kidney clear cell carcinoma (KIRC), and breast cancer (BRCA). In addition, the expression level of FAT4 in different types of tumors has an important impact on the prognosis of patients. FAT4 might influence the efficacy of immunotherapy via tumor burden and microsatellite instability. We observed a statistically positive correlation between cancer-associated fibroblasts and FAT4 expression in most tumors. GSEA of BLCA indicated that low FAT4 expression groups were mainly enriched in calcium signaling pathway and chemokine signaling pathway. GSEA analysis of KIRC suggested low FAT4 expression groups were mainly involved in olfactory transduction and oxidative phosphorylation. Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that the role of FAT4 in the pathogenesis of cancer may be related to human papillomavirus infection, Hippo signaling pathway, PI3K-Akt signaling pathway, etc. Gene Ontology (GO) enrichment analysis further showed that most of these genes were related to the pathways or cell biology, such as peptidyl-tyrosine phosphorylation, cell junction assembly, protein tyrosine kinase activity, etc. Conclusion: Our study summarized and analyzed the antitumor effect of FAT4 in different tumors comprehensively, which aided in understanding the role of FAT4 in tumorigenesis from the perspective of clinical tumor samples. Pan-cancer analysis showed that FAT4 to be novel biomarkers for various cancers prognosis.


Assuntos
Caderinas/metabolismo , Neoplasias , Fosfatidilinositol 3-Quinases , Proteínas Supressoras de Tumor/metabolismo , Caderinas/genética , Linhagem Celular Tumoral , Humanos , Instabilidade de Microssatélites , Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Supressoras de Tumor/genética
17.
FASEB J ; 36(10): e22522, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36052752

RESUMO

Spermatogenesis is a highly coordinated process that initiates shortly after birth and continues throughout the lifespan of male animals. Foxo1 is a transcription factor and is involved in many biological processes. It has been reported that the inactivation of Foxo1 in gonocytes during the embryonic stage causes the defects of spermatogenesis. In the present study, we found that the inactivation of Foxo1 in spermatogonia after birth also caused germ cell loss and male infertility. We found that the initiation of meiosis was not affected; however, the germ cell development was arrested after meiosis and lack of mature spermatozoa in the cauda epididymis. We also found that the proliferation of Foxo1-deficient spermatogonia stem cells was significantly reduced under in vitro conditions. Further study revealed that inactivation of Pten in postnatal spermatogonia using Stra8-Cre did not affect germ cell development and the subcellular location of FOXO1 in Pten-deficient spermatogonia. This study demonstrated that Foxo1 was involved in the development of spermatogonia after birth and the function of Foxo1 was probably not regulated by PI3K/PTEN signaling.


Assuntos
Fosfatidilinositol 3-Quinases , Espermatogônias , Animais , Masculino , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/fisiologia , Espermatogênese/fisiologia , Espermatogônias/metabolismo , Testículo/metabolismo
18.
Oxid Med Cell Longev ; 2022: 5772509, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105481

RESUMO

Objective: Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) remains a hopeful therapeutic approach for bone defect reconstruction. Herein, we investigated the effects and mechanisms of leukemia inhibitory factor (LIF) in the function and viability of hypoxic BMSCs as well as bone defect repair. Methods: The effects of LIF on apoptosis (flow cytometry, TUNEL staining), mitochondrial activity (JC-1 staining), proliferation (colony formation, EdU staining), and differentiation (CD105, CD90, and CD29 via flow sorting) were examined in hypoxic BMSCs. LIF, LIFR, gp130, Keap1, Nrf2, antioxidant enzymes (SOD1, catalase, GPx-3), bone-specific matrix proteins (ALP, BSP, OCN), PI3K, and Akt were detected via immunoblotting or immunofluorescent staining. BMSCs combined with biphasic calcium phosphate scaffolds were implanted into calvarial bone defect mice, and the therapeutic effect of LIF on bone defect was investigated. Results: Hypoxic BMSCs had increased apoptosis and oxidative stress and reduced mitochondrial activity. Additionally, LIF, LIFR, and gp130 were upregulated and PI3K/Akt activity was depressed in hypoxic BMSCs. Upregulated LIF alleviated apoptosis and oxidative stress and heightened mitochondrial activity and PI3K/Akt signaling in hypoxic BMSCs. Additionally, LIF overexpression promoted self-renewal and osteogenic differentiation of BMSCs with hypoxic condition. Mechanically, LIF facilitated self-renewal and differentiation as well as attenuated oxidative stress of BMSCs through enhancing PI3K/AKT signaling activity. Implantation of LIF-overexpressed BMSC-loaded BCP scaffolds promoted osteogenesis as well as alleviated oxidative stress and apoptosis through PI3K/Akt signaling. Conclusion: Our findings demonstrate that LIF facilitates self-renewal and differentiation and attenuates oxidative stress of BMSCs by PI3K/AKT signaling.


Assuntos
Osteogênese , Fosfatidilinositol 3-Quinases , Animais , Receptor gp130 de Citocina/metabolismo , Hipóxia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator Inibidor de Leucemia/farmacologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
19.
Can Respir J ; 2022: 8437348, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091328

RESUMO

Introduction: Vascular smooth muscle cells (VSMCs) are highly involved in airway vascular remodeling in asthma. Objectives: This study aimed to investigate the mechanisms underlying the effects of a disintegrin and metalloproteinase-33 (ADAM33) gene on the migration capacity and inflammatory cytokine secretion of VSMCs. Methods: Human aortic smooth muscle cells (HASMCs) were transfected with lentiviral vectors carrying short hairpin RNA (shRNA) targeting ADAM33 or negative control vectors. The migration capacity of HASMCs was evaluated by a transwell assay. The levels of secreted inflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA) kits. Reverse transcription-quantitative polymerase chain reaction and Western blot assays were performed to detect mRNA and protein expression levels. Results: Silencing of ADAM33 significantly inhibited the migration of HASMCs. The expression of tumor necrosis factor alpha (TNF-α) in the supernatant of HASMCs was decreased, while that of interferon gamma (IFN-γ) was increased after the transfection of shRNA targeting ADAM33. Insufficient ADAM33 expression also suppressed the expression levels of phosphatidylinositol 3-kinase (PI3K), phospho-protein kinase B (AKT), phospho-mammalian target of rapamycin (mTOR), Rho-associated protein kinases, phospho-forkhead box protein O1 (FOXO1), and cyclin D1, but it did not affect the levels of AKT, mTOR, or Rho. Conclusion: Silencing of the ADAM33 gene inhibited HASMC migration and regulated inflammatory cytokine secretion via targeting the PI3K/AKT/mTOR pathway and its downstream signaling. These data contribute to a better understanding of the regulatory mechanisms of airway vascular remodeling in asthma.


Assuntos
Asma , Proteínas Proto-Oncogênicas c-akt , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteínas ADAM/farmacologia , Remodelação das Vias Aéreas , Asma/genética , Asma/metabolismo , Movimento Celular , Células Cultivadas , Citocinas , Humanos , Músculo Liso Vascular/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinase/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/farmacologia , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologia , Remodelação Vascular
20.
Front Endocrinol (Lausanne) ; 13: 965167, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093083

RESUMO

The prevalence of maternal obesity during pregnancy is associated with the risk of gestational diabetes, preeclampsia, and cardiomyopathy. Environmental factors such as active lifestyles and apelin may lead to beneficial changes. In rats, apelin and exercise (45 to 65% VO2max for 6 to 9 weeks) during pregnancy increase brown adipose tissue (BAT) proteins such as Cidea, Elovl3, UCP1, PRDM16, and PGC-1α in males and females fetuses, while white adipose tissue (WAT) is reduced. In humans and animals, apelin and exercise stimulate the expression of the glucose transporters (GLUT1/2/4) in the muscle and adipose tissue through the PI3K/Akt and AMPK pathways. Hence, exercise and apelin may are known as regulators of energy metabolism and be anti-obesity and anti-diabetic properties. In mice, exercise also creates a short-term hypoxic environment in the pregnant mother, activating HIF-1, VEGF, and VEGFR, and increasing angiogenesis. Exercise and apelin also increase vasodilation, angiogenesis, and suppression of inflammation through the L-arginine/eNOS/NO pathway in humans. Exercise can stimulate the ACE2-Ang-(1-7)-Mas axis in parallel with inhibiting the ACE-Ang II-AT1 pathway. Exercise and apelin seem to prevent preeclampsia through these processes. In rats, moderate-intensity exercise (60 to 70% VO2max for 8 weeks) and apelin/APJ also may prevent pathological hypertrophy in pregnancy by activating the PI3K/Akt/mTOR/p70S6K pathway, PI3k-Akt-ERK1/2-p70S6K pathway, and the anti-inflammatory cytokine IL-10. Since pre-clinical studies have been more on animal models, future research with scientific guidelines should pay more attention to human specimens. In future research, time factors such as the first, second, and third trimesters of pregnancy and the intensity and duration of exercise are important variables that should be considered to determine the optimal intensity and duration of exercise.


Assuntos
Pré-Eclâmpsia , Proteínas Quinases S6 Ribossômicas 70-kDa , Tecido Adiposo Marrom/metabolismo , Animais , Apelina , Feminino , Humanos , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Pré-Eclâmpsia/prevenção & controle , Gravidez , Proteínas Proto-Oncogênicas c-akt , Ratos
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