RESUMO
During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.
Assuntos
Apoptose , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/química , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Células HCT116 , Células HeLa , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Domínios Proteicos , Proteólise , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Transcription factors are a specialized group of proteins that play important roles in regulating gene expression in human. These proteins control the transcription and translation of genes by binding to specific sites on DNA, thereby regulating key biological processes such as cell differentiation, proliferation, immune response, and neural development. Moreover, transcription factors are also involved in apoptosis and the pathogenesis of various diseases. By investigating transcription factors, researchers can uncover the mechanisms of gene regulation in organisms and develop more effective methods for preventing and treating human diseases. In the present study, the Virtual Inference of Protein-activity by Enriched Regulon algorithm was utilized to calculate the protein activity of transcription factors, and the metabolic-related protein activity were used for classifying bladder cancer patients into different subtype. To identify chemotherapy drugs with clinical benefits, the differences in prognosis and drug sensitivity between two distinct subtypes of bladder cancer patients were investigated. Simultaneously, the master regulators that display varying levels of transcription factor activity between two different bladder cancer subtypes were explored. Additionally, the potential transcriptional regulatory mechanisms and targets of these factors were investigated, thereby generating novel insights into bladder cancer research at the transcriptional regulation level.
RESUMO
Diabetes stands as one of the most prevalent chronic diseases globally. The conventional methods for diagnosing diabetes are frequently overlooked until individuals manifest noticeable symptoms of the condition. This study aimed to address this gap by collecting comprehensive datasets, including 1000 instances of blood routine data from diabetes patients and an equivalent dataset from healthy individuals. To differentiate diabetes patients from their healthy counterparts, a computational framework was established, encompassing eXtreme Gradient Boosting (XGBoost), random forest, support vector machine, and elastic net algorithms. Notably, the XGBoost model emerged as the most effective, exhibiting superior predictive results with an area under the receiver operating characteristic curve (AUC) of 99.90% in the training set and 98.51% in the testing set. Moreover, the model showcased commendable performance during external validation, achieving an overall accuracy of 81.54%. The probability generated by the model serves as a risk score for diabetes susceptibility. Further interpretability was achieved through the utilization of the Shapley additive explanations (SHAP) algorithm, identifying pivotal indicators such as mean corpuscular hemoglobin concentration (MCHC), lymphocyte ratio (LY%), standard deviation of red blood cell distribution width (RDW-SD), and mean corpuscular hemoglobin (MCH). This enhances our understanding of the predictive mechanisms underlying diabetes. To facilitate the application in clinical and real-life settings, a nomogram was created based on the logistic regression algorithm, which can provide a preliminary assessment of the likelihood of an individual having diabetes. Overall, this research contributes valuable insights into the predictive modeling of diabetes, offering potential applications in clinical practice for more effective and timely diagnoses.
Assuntos
Diabetes Mellitus , Aprendizado de Máquina , Humanos , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Feminino , Masculino , Máquina de Vetores de Suporte , Algoritmos , Curva ROC , Pessoa de Meia-Idade , Índices de Eritrócitos , AdultoRESUMO
The perception of facial expression plays a crucial role in social communication, and it is known to be influenced by various facial cues. Previous studies have reported both positive and negative biases toward overweight individuals. It is unclear whether facial cues, such as facial weight, bias facial expression perception. Combining psychophysics and event-related potential technology, the current study adopted a cross-adaptation paradigm to examine this issue. The psychophysical results of Experiments 1A and 1B revealed a bidirectional cross-adaptation effect between overweight and angry faces. Adapting to overweight faces decreased the likelihood of perceiving ambiguous emotional expressions as angry compared to adapting to normal-weight faces. Likewise, exposure to angry faces subsequently caused normal-weight faces to appear thinner. These findings were corroborated by bidirectional event-related potential results, showing that adaptation to overweight faces relative to normal-weight faces modulated the event-related potential responses of emotionally ambiguous facial expression (Experiment 2A); vice versa, adaptation to angry faces relative to neutral faces modulated the event-related potential responses of ambiguous faces in facial weight (Experiment 2B). Our study provides direct evidence associating overweight faces with facial expression, suggesting at least partly common neural substrates for the perception of overweight and angry faces.
Assuntos
Expressão Facial , Preconceito de Peso , Humanos , Sobrepeso , Ira/fisiologia , Potenciais Evocados/fisiologia , Emoções/fisiologiaRESUMO
Aurora kinases (AURKs) are mitotic kinases important for regulating cell cycle progression. Small-molecule inhibitors of AURK have shown promising antitumor effects in multiple cancers; however, the utility of these inhibitors as inducers of cancer cell death has thus far been limited. Here, we examined the role of the Bcl-2 family proteins in AURK inhibition-induced apoptosis in colon cancer cells. We found that alisertib and danusertib, two small-molecule inhibitors of AURK, are inefficient inducers of apoptosis in HCT116 and DLD-1 colon cancer cells, the survival of which requires at least one of the two antiapoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1. We further identified Bcl-xL as a major suppressor of alisertib- or danusertib-induced apoptosis in HCT116 cells. We demonstrate that combination of a Bcl-2 homology (BH)3-mimetic inhibitor (ABT-737), a selective inhibitor of Bcl-xL, Bcl-2, and Bcl-w, with alisertib or danusertib potently induces apoptosis through the Bcl-2 family effector protein Bax. In addition, we identified Bid, Puma, and Noxa, three BH3-only proteins of the Bcl-2 family, as mediators of alisertib-ABT-737-induced apoptosis. We show while Noxa promotes apoptosis by constitutively sequestering Mcl-1, Puma becomes associated with Mcl-1 upon alisertib treatment. On the other hand, we found that alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into truncated Bid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor-induced apoptosis and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells.
Assuntos
Antineoplásicos , Apoptose , Aurora Quinases , Proteína bcl-X , Humanos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Aurora Quinases/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Células HCT116 , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Salmonella exhibits a strong inducible acid tolerance response (ATR) under weak acid conditions, and can also induce high-risk strains that are highly toxic, acid resistant, and osmotic pressure resistant to aquatic products. However, the induction mechanism is not yet clear. Therefore, this study aims to simulate the slightly acidic, low-temperature, and high-protein environment during squid processing and storage. Through λRed gene knockout, exploring the effects of low-acid induction, long-term low-temperature storage, and two-component regulation on Salmonella ATR. In this study, we found the two-component system, PhoP/PhoQ and PmrA/PmrB in Salmonella regulates the amino acid metabolism system and improves bacterial acid tolerance by controlling arginine and lysine. Compared with the two indicators of total biogenic amine and diamine content, biogenic amine index and quality index were more suitable for evaluating the quality of aquatic products. The result showed that low-temperature treatment could inhibit Salmonella-induced ATR, which further explained the ATR mechanism from the amino acid metabolism.
Assuntos
Arginina , Diaminas , Animais , Decapodiformes , Salmonella/genética , Aminas BiogênicasRESUMO
BACKGROUND: Pancreatic cancer (PC) is a fatal human malignancy with a poor prognosis. Corosolic acid (CRA) is a triterpenoid, has been reported to have inhibitory effects on tumor growth. However, the role of CRA on PC has not been explored. Here, we aimed to uncover the molecular mechanisms of CRA in PC progression. METHODS: Cell viability, lactate dehydrogenase (LDH) release, cell apoptosis and senescence were detected by cell counting kit-8 (CCK-8), LDH, flow cytometry and senescence associated-ß-galactosidase (SA-ß-gal) assay. Levels of relevant proteins and oxidative stress (OS) markers were evaluated by Western blot and enzyme-linked immunosorbent assay (ELISA). A xenograft tumor model was established to explore the in vivo effects of CRA on PC. RESULTS: We found that CRA inhibited PC cell viability and promoted LDH release in a dose-dependent manner, but had no significant effect on human normal pancreatic ductal epithelial cells HPDE6C7. CRA increased OS-induced cell apoptosis and senescence in HAPC and SW1990 cells. And CRA decreased the levels of anti-apoptotic protein Bcl-2, and elevated the expression of pro-apoptotic protein Bax and senescence-associated proteins P21 and P53. Besides, CRA decreased tumor growth in xenograft models. Furthermore, CRA inactivated the Janus kinase-2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in HAPC and SW1990 cells. Functional experiments demonstrated that activation of the JAK2/STAT3 pathway by the JAK2 activator coumermycin A1 (C-A1) or the STAT3 activator colivelin (col) reduced the contribution effect of OS, apoptosis and senescence by CRA. CONCLUSION: Taken together, our findings indicated that CRA exerted anti-cancer effects in PC by inhibiting the JAK2/STAT3 pathway.
Assuntos
Neoplasias Pancreáticas , Triterpenos , Humanos , Fator de Transcrição STAT3 , Neoplasias Pancreáticas/tratamento farmacológico , Estresse Oxidativo , Triterpenos/farmacologia , Apoptose , Janus Quinase 2RESUMO
BACKGROUND: Incentive spirometry (IS) as a routine respiratory therapy during the perioperative period has been widely used in clinical practice. However, the impact of IS on patients with perioperative lung cancer remains controversial. This review aimed to evaluate the efficacy of IS in perioperative pulmonary rehabilitation for patients with lung cancer. METHODS: Cochrane Library, PubMed, Web of Science, Ovid, CINAHL, Chinese National Knowledge Infrastructure, Weipu, and Wanfang Databases were searched from inception to 30 November 2023. Only randomized controlled trials were included in this systematic review. The PRISMA checklist served as the guidance for conducting this review. The quality assessment of the included studies was assessed by the Cochrane risk-of-bias tool. The meta-analysis was carried out utilizing Review Manager 5.4. Furthermore, sensitivity analysis and subgroup analysis were also performed. RESULTS: Nine studies recruited 1209 patients met our inclusion criteria. IS combined with other respiratory therapy techniques was observed to reduce the incidence of postoperative pulmonary complications, enhance pulmonary function, curtail the length of hospital stay, and lower the Borg score. Nevertheless, no improvements were found in the six-minute walk distance or quality of life score. CONCLUSIONS: Although IS demonstrates benefits as a component of comprehensive intervention measures for perioperative patients with lung cancer, it proves challenging to determine the precise impact of IS as a standalone component within the comprehensive intervention measures. Therefore, further researches are required to better understand the effectiveness of IS isolation and its interactions when integrated with additional respiratory therapies for these patients. CLINICAL TRIAL REGISTRATION: PROSPERO, https://www.crd.york.ac.uk/prospero/ , registry number: CRD42022321044.
Assuntos
Neoplasias Pulmonares , Complicações Pós-Operatórias , Espirometria , Humanos , Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Qualidade de Vida , Assistência Perioperatória/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tempo de Internação , Terapia Respiratória/métodosRESUMO
Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor-induced apoptosis on the mitochondria.
Assuntos
Apoptose/fisiologia , Hexoquinase/metabolismo , Mitocôndrias/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular , Ciclosporina/farmacologia , Dactinomicina/farmacologia , Doxorrubicina/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína Ligante Fas/farmacologia , Deleção de Genes , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hexoquinase/genética , Humanos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genéticaRESUMO
The mechanism of Bax/Bak activation remains a central question in mitochondria-dependent apoptotic signaling. While it is established that all proapoptotic Bcl-2 homology 3 (BH3)-only proteins bind and neutralize the anti-apoptotic Bcl-2 family proteins, how this neutralization leads to Bax/Bak activation has been actively debated. Here, genome editing was used to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and those that lack the entire Bcl-2 family (Bcl-2 allKO). Although the OctaKO cells were resistant to most apoptotic stimuli tested, they underwent Bax/Bak-dependent and p53/Rb-independent apoptosis efficiently when both Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins, were inactivated or eliminated. Strikingly, when expressed in the Bcl-2 allKO cells, both Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) through their respective helix 9, and this association triggered their homo-oligomerization/activation. Together, these results strongly suggest that the OMM, not BH3-only proteins or p53/Rb, is the long-sought-after direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins.
Assuntos
Apoptose/genética , Membranas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica/genética , Inativação Gênica , Células HCT116 , Células HeLa , Humanos , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismoRESUMO
Ferroptosis has been implicated in the pathogenesis of secondary brain injury following intracerebral hemorrhage (ICH), and regulating this process is considered a potential therapy for alleviating further brain injury. A previous study showed that CDGSH iron sulfur domain 2 (CISD2) can inhibit ferroptosis in cancer. Thus, we investigated the effects of CISD2 on ferroptosis and the mechanisms underlying its neuroprotective role in mice after ICH. CISD2 expression markedly increased after ICH. CISD2 over-expression significantly decreased the number of Fluoro-Jade C-positive neurons and alleviated brain edema and neurobehavioral deficits at 24 h after ICH. In addition, CISD2 over-expression up-regulated the expression of p-AKT, p-mTOR, ferritin heavy chain 1, glutathione peroxidase 4, ferroportin, glutathione, and glutathione peroxidase activity, which are markers of ferroptosis. Additionally, CISD2 over-expression down-regulated the levels of malonaldehyde, iron content, acyl-CoA synthetase long-chain family member 4, transferrin receptor 1, and cyclooxygenase-2 at 24 h after ICH. It also alleviated mitochondrial shrinkage and decreased the density of the mitochondrial membrane. Furthermore, CISD2 over-expression increased the number of GPX4-positive neurons following ICH induction. Conversely, knockdown of CISD2 aggravated neurobehavioral deficits, brain edema, and neuronal ferroptosis. Mechanistically, MK2206, an AKT inhibitor, suppressed p-AKT and p-mTOR and reversed the effects of CISD2 over-expression on markers of neuronal ferroptosis and acute neurological outcome. Taken together, CISD2 over-expression alleviated neuronal ferroptosis and improved neurological performance, which may be mediated through the AKT/mTOR pathway after ICH. Thus, CISD2 may be a potential target to mitigate brain injury via the anti-ferroptosis effect after ICH.
Assuntos
Edema Encefálico , Lesões Encefálicas , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Edema Encefálico/metabolismo , Peroxidação de Lipídeos , Hemorragia Cerebral/metabolismo , Lesões Encefálicas/patologia , Serina-Treonina Quinases TOR/metabolismo , Ferro/metabolismo , Neurônios/metabolismo , Enxofre/metabolismo , Enxofre/farmacologiaRESUMO
MAIN CONCLUSION: Auto-fluorescent condensed tannins specifically accumulated in mesophyll cells of non-salt secretor mangroves are involved in the compartmentation of Na+ and osmotic regulation, contributing to their salt tolerance. Salinity is a major abiotic stress affecting the distribution and growth of mangrove plants. The salt exclusion mechanism from salt secretor mangrove leaves is quite known; however, salt management strategies in non-salt secretor leaves remain unclear. In this study, we reported the auto-fluorescent inclusions (AFIs) specifically accumulated in mesophyll cells (MCs) of four non-salt secretor mangroves but absent in three salt secretors. The AFIs increased with the leaf development under natural condition, and applied NaCl concentrations applied in the lab. The AFIs in MCs were isolated and identified as condensed tannin accretions (CTAs) using the dye dimethyl-amino-cinnamaldehyde (DMACA), specific for condensed tannin (CT), both in situ leaf cross sections and in the purified AFIs. Fluorescence microscopy and transmission electron microscope (TEM) analysis indicated that the CTAs originated from the inflated chloroplasts. The CTAs had an obvious membrane and could induce changes in shape and fluorescence intensity in hypotonic and hypertonic NaCl solutions, suggesting CTAs might have osmotic regulation ability and play an important role in the osmotic regulation in MCs. The purified CTAs were labeled by the fluorescent sodium-binding benzofuran isophthalate acetoxymethyl ester (SBFI-AM), confirming they were involved in the compartmentation of excess Na+ in MCs. This study provided a new view on the salt resistance-associated strategies in mangroves.
Assuntos
Células do Mesofilo , Proantocianidinas , Tolerância ao Sal , Cloreto de Sódio/farmacologia , Folhas de Planta/fisiologia , SalinidadeRESUMO
Fish skin gelatin is an important functional product in the food, cosmetics, and biomedicine industries, and establishing a green and effective fish skin gelatin extraction method is an effective way to obtain high-quality gelatin and improve its production efficiency. In this study, a trypsin method was used to extract the skin gelatin of sea perch, tilapia, and grass carp, and the microstructures of skin gelatin of these three fish species were analyzed, with such functional characteristics as thermal stability, gel strength, and emulsifying properties measured. The study results show that the skin gelatin of sea perch and tilapia obtained through the trypsin method has a relatively big molecular mass, a dense network structure, and a stable trihelix conformation. In addition, the skin gelatin of these three fish species has a relatively high ß-turn content in the secondary structure, good gel strength, and water absorption properties. The compositions of the collagen-associated proteins in the skin gelatins of these three fish species extracted with the trypsin method are significantly different from each other, with positive effects of decorin and biglycan on the stability of the network structure of gelatin and a certain damaging effect of metalloendopeptidase on the network structure of gelatin. The skin gelatin of tilapia has high thermal stability and good emulsifying performance. Therefore, this gelatin type has bright application prospects in such fields as food processing, cosmetics, and drug development. In contrast, the skin gelatin of grass carp has poor functional properties. Therefore, there are significant differences among the structures and functions of skin gelatin extracted from different kinds of fish through the trypsin method. This finding has provided a useful reference for the production of customized fish gelatin according to demand.
Assuntos
Carpas , Percas , Tilápia , Animais , Gelatina , TripsinaRESUMO
Renal arteriovenous malformation (RAVM) is a rare pathology. It may present with heamturia, hypertension, and congestive heart failure. Digital subtraction angiography (DSA) is the standard diagnostic choice, and endovascular embolization is a preferred procedure of management in most cases. The feeding branches of RAVM are reported to originate from renal arteries. In this report, a 43-year-old female with recurrent massive hematuria and left flank pain was described. Renal angiography revealed double renal arteries supplying the left kidney and multiple renal arteriovenous fistula formation around the renal pelvis. Embolization with coils and gelfoam was performed after which her hematuria subsided. One month later, the patient was readmitted to our hospital due to the relapse of massive hematuria following heavy physical activities. DSA found another feeding artery of the RAVM originating from the aorta around the 4th lumbar vertebra. After embolization of this arterial feeder, hematuria settled. There was no recurrence during a 10-month follow-up. To our knowledge, this is the first case of RAVM with an extrarenal feeding artery, and omission of this scenario can lead to treatment failure.
Assuntos
Malformações Arteriovenosas , Embolização Terapêutica , Nefropatias , Doenças Ureterais , Humanos , Feminino , Adulto , Hematúria/etiologia , Hematúria/terapia , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/terapia , Rim , Nefropatias/complicações , Artéria Renal/diagnóstico por imagem , Falha de Tratamento , Doenças Ureterais/complicações , Embolização Terapêutica/métodosRESUMO
Fatty liver is one of the most pervasive liver diseases worldwide. Probiotics play an important role in the progression of liver disease, but their effects on host regulation are poorly understood. This study investigated the protective effects of lactobacillus gasseri (L. gasseri) against high-cholesterol diet (HCD)-induced fatty liver injury using a zebrafish larvae model. Liver pathology, lipid accumulation, oxidative stress and hepatic inflammation were evaluated to demonstrate the changes in a spectrum of hepatic injury. Moreover, multiple indexes on host gene expression profiles were comprehensively characterized by RNA screening. The results showed that treatment with L. gasseri ameliorated HCD-induced morphological and histological alterations, lipid regulations, oxidative stress and macrophage aggregation in the liver of zebrafish larvae. Furthermore, the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that the core pathways of L. gasseri regulation were interleukin-17 (IL-17) signaling, phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, the regulation of lipolysis and adipocytes and fatty acid elongation and estrogen signaling. The genes at key junction nodes, hsp90aa1.1, kyat3, hsd17b7, irs2a, myl9b, ptgs2b, cdk21 and papss2a were significantly regulated by L. gasseri administration. To conclude, the current research extends our understanding of the protective effects of L. gasseri against fatty liver and provides potential therapeutic options for fatty liver treatment.
Assuntos
Dieta Hiperlipídica , Fígado Gorduroso , Lactobacillus gasseri , Probióticos , Peixe-Zebra , Animais , Colesterol/análise , Colesterol/metabolismo , Dieta/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Lactobacillus gasseri/metabolismo , Lipídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Probióticos/farmacologia , Probióticos/uso terapêutico , Transcriptoma , Peixe-Zebra/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Larva/genéticaRESUMO
Bisphenol A (BPA) is considered to be a threat to marine organisms owning to its widespread usage and potential aquatic toxicity. However, the reproductive toxicity of BPA to transgenerational inheritance in aquatic organisms is still unclarified. In this study, the morphological, histological, and transgenerational changes by BPA in zebrafish testis were investigated. Results showed that BPA caused abnormities in sperm number, activity, and fertility rate. Testicular transcriptional alterations detected by RNA-seq identified 1940 differentially expressed genes (DEGs) after BPA exposure, of which 392 were upregulated and 1548 were downregulated. Gene Ontology analysis showed that acrosin binding, binding of sperm to zona pellucida, and positive regulation of acrosome reaction were significantly enriched in BPA-induced DEGs. Pathway analysis indicated that cell adhesion molecules, steroid hormone biosynthesis and fatty acid biosynthesis, elongation, and metabolism were remarkably changed after BPA treatment. Thus, we deduce here that multi- and transcriptomic changes of chronic exposure to BPA reveals reproductive toxicity in male zebrafish.
Assuntos
Transcriptoma , Peixe-Zebra , Masculino , Animais , Peixe-Zebra/fisiologia , Sêmen , Perfilação da Expressão Gênica , Testículo/metabolismoRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor-mediated extrinsic apoptosis, specifically in cancer cells, and Bid (BH3-interacting domain death agonist) plays an important role in TRAIL-induced apoptosis. Ferroptosis is a newly defined form of regulated cell death known to be distinct from other forms of cell death. However, our previous studies have shown that ferroptosis shares common pathways with other types of programmed cell death such as apoptosis. In this study, we investigated the role of Bid in the crosstalk between the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and TRAIL-induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with the ferroptosis-inducing agents artesunate and erastin in combination with TRAIL, TRAIL-induced activation of caspase-8 was enhanced, and subsequently, the truncation of Bid was increased. Similar results were observed when ovarian adenocarcinoma OVCAR-3 cells were treated with the ferroptotic agents in combination with TRAIL. Results from studies with Bid mutants reveal that the truncation of Bid and the presence of intact BH3 domains are critical for synergistic apoptosis. Nonfunctional Bid mutants were not able to activate the mitochondria-dependent apoptosis pathway, which is required for the conversion of p19 to p17, the active form of caspase-3. These results indicate that Bid plays a critical role in the crosstalk between the ferroptotic agent-induced ER stress response and TRAIL-induced apoptosis.
Assuntos
Apoptose , Neoplasias Ovarianas , Humanos , Feminino , Linhagem Celular Tumoral , Neoplasias Ovarianas/patologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 8/metabolismo , Estresse do Retículo Endoplasmático , Fator de Necrose Tumoral alfa/metabolismoRESUMO
MicroRNA (miRNA)-222-3p is overexpressed in numerous tumors, where it acts as an oncogene. Although miRNA-222 is highly expressed in acute myeloid leukemia (AML), its functions and the mechanisms underlying these functions have not yet been fully elucidated. This study aimed to investigate the regulatory roles of miRNA-222-3p in AML and the molecular mechanisms underlying these roles. In this study, we observed that miRNA-222-3p increased the viability and suppressed the apoptosis of AML cells. Axin2 was demonstrated to be a direct target of miRNA-222-3p, which when overexpressed, inhibited Axin2 expression and stimulated the Wnt/ß-catenin pathway. In contrast, upregulation of Axin2 expression levels reduced the viability and enhanced the apoptosis of AML cells. Moreover, it partially reversed the effects of the miRNA-222-3p mimic on the proliferation and apoptosis of, and modulation of the Wnt/ß-catenin pathway in, AML cells. Taken together, this study provides strong evidence that miRNA-222-3p can serve as a molecular target for AML treatment.
Assuntos
Proteína Axina , Proliferação de Células , Leucemia Mieloide Aguda , MicroRNAs , Apoptose , Proteína Axina/genética , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , MicroRNAs/metabolismo , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismoRESUMO
ABSTRACT: Atherosclerosis (AS) is one of the most common cardiovascular diseases and is the leading cause of arteriosclerotic cardiovascular disease. Bile acids are not only the products of cholesterol metabolism, but also an important class of signaling molecules. Bile acids exert their biological effects through the bile acid receptor signaling pathways. Bile acid receptors are widely distributed in human organs and tissues. The activation of transcriptional and signaling cascades controls bile acid metabolism and synthesis, lipid and carbohydrate metabolism, immune cell expression, and inflammatory responses. A large body of evidence indicates that bile acids play an important role in the initiation and development of AS, and are strongly associated with AS risk factors. The major bile acid receptors, nuclear receptor farnesoid X receptor (liver) and membrane receptor G protein-coupled receptor 5, exhibit anti-atherosclerotic effects. Other nuclear receptors exert different anti-atherosclerotic or pro-atherosclerotic effects. In this review, we summarize the current knowledge on the effects of bile acids and their receptors in AS and explore the pathway of bile acids involved in atherosclerotic lesions. The main research based on animal models or cell/tissue culture experiments is also discussed. This review provides new ideas for the development of novel therapeutic approaches for AS prevention and treatment.
Assuntos
Aterosclerose , Ácidos e Sais Biliares , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Colesterol , Humanos , Lipídeos , Receptores Citoplasmáticos e Nucleares , Receptores Acoplados a Proteínas G/metabolismoRESUMO
BACKGROUND: MiRNA-301b-3p functions as an oncomiRNA or tumor suppressor, and has been reported in various cancer types, including pancreatic, colorectal, oral, hepatocellular and lung cancers. Although the expression of miRNA-301b-3p is upregulated in acute myeloid leukemia (AML), its biological function and precise mechanisms remain unclarified. This study explores the roles of miRNA-301b-3p in AML, with the aim of ascertaining its regulatory action on Wnt/ß-catenin axis by targeting Forkhead box F2 (FOXF2). METHODS: The expression levels of miRNA-301b-3p and FOXF2 were measured by quantitative real-time PCR. The effects of miRNA-301b-3p knockdown and overexpression on cell proliferation were evaluated by CCK8 and cell counting assays, while cell apoptosis was analyzed by flow cytometry. The expression levels of apoptosis-related proteins, including FOXF2, and other targets in Wnt/ß-catenin axis were determined by immunoblotting. Possible interaction between miRNA-301-3p and FOXF2 in AML cells was examined by luciferase reporter assays. RESULTS: MiRNA-301b-3p was dramatically upregulated in AML cells, and showed a negative correlation with FOXF2 expression. Downregulation of miRNA-301b-3p suppressed proliferation and promoted apoptosis in AML cells. MiRNA-301b targeted FOXF2 to regulate Wnt/ß-catenin axis. In the rescue experiments, FOXF2 overexpression partly reversed the effect of miRNA-301b-3p mimic in AML cells. CONCLUSION: The current findings demonstrate that miRNA-301b-3p targets FOXF2 to induce proliferation and inhibit apoptosis in AML cells via regulation of Wnt/ß-catenin axis.