RESUMO
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Research indicates that circulating histones, as pathogenic factors, may represent a therapeutic target for sepsis. However, effectively clearing circulating histones poses a challenge due to their structural similarity to normal blood proteins, their low abundance in the bloodstream, and serious interference from other blood biomacromolecules. Here we design a dodecapeptide-based functional polymer that can selectively adsorb circulating histones from the blood. The peptide, named P1 (HNHHQLALVESY), was discovered through phage display screening and demonstrated a strong affinity for circulating histones while exhibiting negligible affinities for common proteins in the blood, such as human serum albumin (HSA), immunoglobulin G (IgG), and transferrin (TRF). Furthermore, the P1 peptide was incorporated into a functional polymer design, poly(PEGMA-co-P1), which was immobilized onto a silica gel surface through reversible addition-fragmentation chain transfer polymerization. The resulting material was characterized using solid nuclear magnetic resonance, thermogravimetric analysis, and X-ray photoelectron spectroscopy. This material demonstrated the ability to selectively and efficiently capture circulating histones from both model solutions and whole blood samples while also exhibiting satisfactory blood compatibility, good antifouling properties, and resistance to interference. Satisfactory binding affinity and efficient capture capacity toward histone were also observed for the other screened peptide P2 (QMSMDLFGSNFV)-grafted polymer, validating phage display as a reliable ligand screening strategy. These findings present an approach for the specific clearance of circulating histones and hold promise for future clinical applications in blood purification toward sepsis.
RESUMO
BACKGROUND: UNC5A had been reported to play crucial roles in multiple cancers. However, little was known about the associations among UNC5A and glioma. Therefore, we first combined scRNA-seq, proteomics, as well as bulk RNA-seq in order to investigate UNC5A's functions in gliomas. METHODS: Online databases provided scRNA-seq, proteomics, as well as bulk RNA-seq data on UNC5A in gliomas. The following procedures were conducted in order: QRT-PCR, Norman chart, gene set enrichment analysis (GSEA), and univariate/multifactor Cox regression analyses. We further explored the associations among UNC5A and tumor immunity. RESULTS: By comparing gliomas with normal tissues, the TCGA dataset showed a significantly reduced expression of UNC5A, which was also confirmed by GSE50161, GSE4290, and QRT-PCR findings (p < 0.05). In both the TCGA and CGGA datasets, gliomas patients with low-UNC5A expression would have poorer overall survival (OS) prognoses (p < 0.05). ScRNA-seq analysis by the CancerSEA online website presented that UNC5A had a low expression in various glioma clusters and significantly associated with six functional states. Moreover, UNC5A might be a reliable independent biomarker of OS in gliomas patients (p < 0.05). Based on the results of GSEA, UNC5A might be connected to three significant pathways in gliomas. We also successfully created a Norman chart to assess the OS prognoses of these patients. Additionally, in aspects of tumor immunity, the infiltration levels of immune cells in LGG, the immune cell pathways, tumor immune microenvironment, as well as immune checkpoints in both LGG and GBM were revealed to be significantly influenced by UNC5A (p < 0.05). CONCLUSIONS: UNC5A was found to have prognostic and immunological significance in gliomas, offering patients with gliomas new treatment options.
RESUMO
Herein, a luminescent fiber device for detecting ultraviolet (UV) intensity, which comprises a UV probe and a photoelectric converter, is proposed. The UV probe consists of a glass tube filled with luminescent material, which can be used for the efficient radiation conversion of UV radiation to the visible spectral region. The luminescent material, Y2O2S:Eu3+, is mixed with polydimethylsiloxane (PDMS) to form the core of the UV probe. Subsequently, the UV radiation response of the luminescent fiber device is investigated; the experimental results demonstrate that the direction-independent UV detection can be realized by using this luminescent fiber UV detection device while UV light is radiated radially along the UV probe. In addition, since partial discharge (PD) is accompanied by UV radiation, we hope to develop a spectral PD detection scheme based on optical fiber technology, which can broaden the role of optical technology and optical fiber technology in the field of PD detection.
RESUMO
Faced with the escalating challenge of global plastic pollution, this study specifically addresses the research gap in the biodegradation of polystyrene (PS). A PS-degrading bacterial strain was isolated from the gut of Tenebrio molitor, and genomics, molecular docking, and proteomics were employed to thoroughly investigate the biodegradation mechanisms of Pseudomonas putida H-01 against PS. Using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (ATR-FTIR), and contact angle analysis, significant morphological and structural changes in the PS films under the influence of the H-01 strain were observed. The study revealed several potential degradation genes and ten enzymes that were specifically upregulated in the PS degradation environment. Additionally, a novel protein with laccase-like activity, LacQ1, was purified from this strain for the first time, and its crucial role in the PS degradation process was confirmed. Through molecular docking and molecular dynamics (MD) simulations, the interactions between the enzymes and PS were detailed, elucidating the binding and catalytic mechanisms of the degradative enzymes with the substrate. These findings have deepened our understanding of PS degradation.
Assuntos
Biodegradação Ambiental , Simulação de Acoplamento Molecular , Poliestirenos , Poliestirenos/química , Poliestirenos/metabolismo , Pseudomonas putida/metabolismo , Pseudomonas putida/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Genômica , Animais , Simulação de Dinâmica Molecular , Lacase/metabolismo , Lacase/genética , Lacase/químicaRESUMO
N6-methyladenosine (m6A) is one of the most common modifications of RNA in eukaryotic cells and is involved in mRNA metabolism, including stability, translation, maturation, splicing, and export. m6A also participates in the modification of multiple types of non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, thereby affecting their metabolism and functions. Increasing evidence has revealed that m6A regulators, such as writers, erasers, and readers, perform m6A-dependent modification of ncRNAs, thus affecting cancer progression. Moreover, ncRNAs modulate m6A regulators to affect cancer development and progression. In this review, we summarize recent advances in understanding m6A modification and ncRNAs and provide insights into the interaction between m6A modification and ncRNAs in cancer. We also discuss the potential clinical applications of the mechanisms underlying the interplay between m6A modifications and ncRNAs in acute myeloid leukemia (AML). Therefore, clarifying the mutual regulation between m6A modifications and ncRNAs is of great significance to identify novel therapeutic targets for AML and has great clinical application prospects.
Assuntos
Adenosina , Leucemia Mieloide Aguda , RNA não Traduzido , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , AnimaisRESUMO
BACKGROUND: The identification of a novel and effective strategy for the clinical treatment of acute leukemia (AL) is a long-term goal. Minnelide, a water-soluble prodrug of triptolide, has recently been evaluated in phase I and II clinical trials in patients with multiple cancers and has shown promise as an antileukemic agent. However, the molecular mechanism underlying minnelide's antileukemic activity remains unclear. PURPOSE: To explore the molecular mechanisms by which minnelide exhibits antileukemic activity. METHODS: AL cells, primary human leukemia cells, and a xenograft mouse model were treated with triptolide and minnelide. The molecular mechanism was elucidated using western blotting, immunoprecipitation, flow cytometry, GSEA and liquid chromatography-mass spectrometry analysis. RESULTS: Minnelide was highly effective in inhibiting leukemogenesis and improving survival in two complementary AL mouse models. Triptolide, an active form of minnelide, causes cell cycle arrest in G1 phase and induces apoptosis in both human AL cell lines and primary AL cells. Mechanistically, we identified Ars2 as a new chemotherapeutic target of minnelide for AL treatment. We found that triptolide directly targeted Ars2, resulting in the downregulation of miR-190a-3p, which led to the disturbance of PTEN/Akt signaling and culminated in G1 cell cycle arrest and apoptosis. CONCLUSIONS: Our findings demonstrate that targeting Ars2/miR-190a-3p signaling using minnelide could represent a novel chemotherapeutic strategy for AL treatment and support the evaluation of minnelide for the treatment of AL in clinical trials.
Assuntos
Apoptose , Diterpenos , Compostos de Epóxi , MicroRNAs , Fenantrenos , Fenantrenos/farmacologia , Animais , Humanos , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Linhagem Celular Tumoral , Camundongos , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Leucemia/tratamento farmacológico , Organofosfatos/farmacologia , Antineoplásicos Fitogênicos/farmacologiaRESUMO
BACKGROUND: Since cytokine receptor-like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. METHODS: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow-derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno-associated virus (AAV) or AAV containing CRLF1 was determined by morphological, histological, and micro computer tomography (CT) analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were determined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes using real-time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. RESULTS: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondrogenic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and cardiotrophin-like Cytokine (CLC) stimulated catabolic events via STAT3 activation. CONCLUSION: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.
Assuntos
Diferenciação Celular , Condrócitos , Condrogênese , Células-Tronco Mesenquimais , Animais , Coelhos , Células-Tronco Mesenquimais/metabolismo , Condrogênese/genética , Condrócitos/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Citocinas/genética , Fêmur/patologia , Transdução de Sinais , Linhagem Celular , Transplante de Células-Tronco MesenquimaisRESUMO
The anti-obesity effect of conjugated linoleic acid (CLA) has been well elucidated, but whether CLA affects fat deposition by regulating intestinal dietary fat absorption remains largely unknown. Thus, this study aimed to investigate the effects of CLA on intestinal fatty acid uptake and chylomicron formation and explore the possible underlying mechanisms. We found that CLA supplementation reduced the intestinal fat absorption in HFD (high fat diet)-fed mice accompanied by the decreased serum TG level, increased fecal lipids and decreased intestinal expression of ApoB48 and MTTP. Correspondingly, c9, t11-CLA, but not t10, c12-CLA induced the reduction of fatty acid uptake and TG content in PA (palmitic acid)-treated MODE-K cells. In the mechanism of fatty acid uptake, c9, t11-CLA inhibited the binding of CD36 with palmitoyltransferase DHHC7, thus leading to the decreases of CD36 palmitoylation level and localization on the cell membrane of the PA-treated MODE-K cells. In the mechanism of chylomicron formation, c9, t11-CLA inhibited the formation of the CD36/FYN/LYN complex and the activation of the ERK pathway in the PA-treated MODE-K cells. In in vivo verification, CLA supplementation reduced the DHHC7-mediated total and cell membrane CD36 palmitoylation and suppressed the formation of the CD36/FYN/LYN complex and the activation of the ERK pathway in the jejunum of HFD-fed mice. Altogether, these data showed that CLA reduced intestinal fatty acid uptake and chylomicron formation in HFD-fed mice associated with the inhibition of DHHC7-mediated CD36 palmitoylation and the downstream ERK pathway.
Assuntos
Quilomícrons , Dieta Hiperlipídica , Sistema de Sinalização das MAP Quinases , Animais , Masculino , Camundongos , Aciltransferases/metabolismo , Aciltransferases/genética , Antígenos CD36/metabolismo , Antígenos CD36/genética , Quilomícrons/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Absorção Intestinal/efeitos dos fármacos , Ácidos Linoleicos Conjugados/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Herein, a high pressure-sensitive and stable fiber Fabry-Perot (FP) interferometer with nano-diaphragm assembled by H-O catalysis bonding is proposed and demonstrated. In order to assemble a nano-diaphragm-based fiber FP interferometer by H-O catalysis bonding technique, a SiO2 film, introduced as a bridging layer on the nano-diaphragm, can be regarded as a solid adhesive to bridge hollow-core fiber end-face and nano-diaphragm. As thus, by depositing bonded layers on different diaphragm materials, this H-O catalysis bonding technology can be used to for assembling FP interferometer with different materials nano-diaphragms. Experimentally, Si nano-diaphragm is transferred to hollow-core fiber end-face to build a stable fiber FP interferometer without polymeric adhesive. Experimental results reveal that this Si nano-diaphragm-based fiber FP interferometer has a high (79.6 pm/kPa) pressure sensitivity and a low (17.3 pm/°C) temperature sensitivity. Besides that, different materials nano-diaphragm also can be assembled by using this H-O catalysis bonding technique, and the functional FP interferometer can be realized by using functional nano-diaphragm material. Thus, a Pd nano-diaphragm is successfully assembled to build a FP interferometer with a hydrogen concentration measurement capacity. Further investigation will focus on exploitation of multi-material nano-film patterning transfer and different nano-film integration by using this H-O catalysis bonding transfer.
RESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the commonest cancers worldwide. Metastasis is the most common cause of death in patients with CRC. Arenobufagin is an active component of bufadienolides, extracted from toad skin and parotid venom. Arenobufagin reportedly inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in various cancers. However, the mechanism through which arenobufagin inhibits CRC metastasis remains unclear. PURPOSE: This study aimed to elucidate the molecular mechanisms by which arenobufagin inhibits CRC metastasis. METHODS: Wound-healing and transwell assays were used to assess the migration and invasion of CRC cells. The expression of nuclear factor erythroid-2-related factor 2 (Nrf2) in the CRC tissues was assessed using immunohistochemistry. The protein expression levels of c-MYC and Nrf2 were detected by immunoblotting. A mouse model of lung metastasis was used to study the effects of arenobufagin on CRC lung metastasis in vivo. RESULTS: Arenobufagin observably inhibited the migration and invasion of CRC cells by downregulating c-MYC and inactivating the Nrf2 signaling pathway. Pretreatment with the Nrf2 inhibitor brusatol markedly enhanced arenobufagin-mediated inhibition of migration and invasion, whereas pretreatment with the Nrf2 agonist tertbutylhydroquinone significantly attenuated arenobufagin-mediated inhibition of migration and invasion of CRC cells. Furthermore, Nrf2 knockdown with short hairpin RNA enhanced the arenobufagin-induced inhibition of the migration and invasion of CRC cells. Importantly, c-MYC acts as an upstream modulator of Nrf2 in CRC cells. c-MYC knockdown markedly enhanced arenobufagin-mediated inhibition of the Nrf2 signaling pathway, cell migration, and invasion. Arenobufagin inhibited CRC lung metastasis in vivo. Together, these findings provide evidence that interruption of the c-MYC/Nrf2 signaling pathway is crucial for arenobufagin-inhibited cell metastasis in CRC. CONCLUSIONS: Collectively, our findings show that arenobufagin could be used as a potential anticancer agent against CRC metastasis. The arenobufagin-targeted c-MYC/Nrf2 signaling pathway may be a novel chemotherapeutic strategy for treating CRC.
Assuntos
Bufanolídeos , Neoplasias Colorretais , Neoplasias Pulmonares , Animais , Camundongos , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Colorretais/patologia , Linhagem Celular Tumoral , Bufanolídeos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Transição Epitelial-Mesenquimal , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Metástase NeoplásicaRESUMO
Vascular endothelial growth factor B (VEGFB) has been well demonstrated to play a crucial role in regulating vascular function by binding to the VEGF receptors (VEGFRs). However, the specific role of VEGFB and VEGFRs in pubertal mammary gland development remains unclear. In this study, we observed that blocking the VEGF receptors with Axitinib suppressed the pubertal mammary gland development. Meanwhile, the proliferation of mammary epithelial cells (HC11) was repressed by blocking the VEGF receptors with Axitinib. Additionally, knockdown of VEGFR1 rather than VEGFR2 and NRP1 elicited the inhibition of HC11 proliferation, suggesting the essential role of VEGFR1 during this process. Furthermore, Axitinib or VEGFR1 knockdown led to the inhibition of the PI3K/Akt pathway. However, the inhibition of HC11 proliferation induced by Axitinib and or VEGFR1 knockdown was eliminated by the Akt activator SC79, indicating the involvement of the PI3K/Akt pathway. Finally, the knockdown of VEGFB and VEGFR1 suppressed the pubertal development of mice mammary gland with the inhibition of the PI3K/Akt pathway. In summary, the results showed that knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of the PI3K/Akt pathway, which provides a new target for the regulation of pubertal mammary gland development.
Assuntos
Proteínas Proto-Oncogênicas c-akt , Fator B de Crescimento do Endotélio Vascular , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Axitinibe/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular , Proliferação de CélulasRESUMO
INTRODUCTION: The purpose of this research was to settle the role of brucine in pancreatic ductal adenocarcinoma (PDAC) and the mechanisms involved. METHODS: The findings of this study suggest that brucine exerts inhibitory effects on cell growth, clonogenicity, and invasive potential of Panc02 and Mia Paca-2 cells. These effects may be linked to an increase in apoptotic-prone cell population. RESULTS: Gene sequencing data suggests that these effects are mediated through the induction of apoptosis. Experimental evidence further supports the notion that brucine reduces mitochondrial membrane potential and upregulates Bax expression while downregulating Bcl-2 expression. These effects are believed to be a result of brucine-mediated suppression of PI3K/Akt activity, which serves as a regulatory factor of mTOR, Bax, and Bcl-2. Suppression of PI3K activity enhances the tumor-suppressing effects of brucine. CONCLUSION: Overall, these findings suggest that brucine has therapeutic potential as a remedy option for PDAC.
Assuntos
Apoptose , Carcinoma Ductal Pancreático , Mitocôndrias , Neoplasias Pancreáticas , Estricnina , Humanos , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estricnina/farmacologia , Estricnina/análogos & derivadosRESUMO
The antiobesity effect of conjugated linoleic acid (CLA) has been reported. However, the underlying mechanisms have not been fully clarified. Thus, this study aimed to investigate the effects of CLA on thermogenesis of interscapular brown adipose tissue (iBAT) and browning of inguinal subcutaneous white adipose tissue (iWAT) and explore the possible signaling pathway. The in vivo results showed that CLA enhanced the O2 consumption and heat production in HFD (high-fat diet)-fed female mice by roughly 38%. Meanwhile, CLA increased the average iBAT temperature by 2°C at the room temperature and cold exposure, respectively. Correspondingly, CLA caused 1.6- and 2.4-fold increases in the expression of UCP1 (uncoupling protein 1) of BAT and iWAT, respectively, suggesting the activated iBAT thermogenesis and iWAT browning in HFD-fed female mice. Meanwhile, CLA could promote the formation of brown and beige adipocytes in differentiated stromal vascular cells (SVCs) isolated from iBAT and iWAT (the expressions of UCP1 were promoted by about twofold changes). In possible mechanisms, CLA stimulated the expression of CD36 and the activation of the AMPK pathway in mice iBAT and iWAT as well as the differentiated SVCs. However, inhibition of CD36 and AMPK (adenosine 5'-monophosphate-activated protein kinase) abolished the promotive effects of CLA on brown and beige adipocytes formation. Hence, we showed that CLA reduced HFD-induced obesity through enhancing iBAT thermogenesis and iWAT browning via the CD36-AMPK pathway.
Assuntos
Adipócitos Bege , Ácidos Linoleicos Conjugados , Feminino , Animais , Camundongos , Ácidos Linoleicos Conjugados/farmacologia , Proteínas Quinases Ativadas por AMP , Obesidade/tratamento farmacológico , TermogêneseRESUMO
Lignin, a natural organic polymer that is recyclable and inexpensive, serves as one of the most abundant green resources in nature. With the increasing consumption of fossil fuels and the deterioration of the environment, the development and utilization of renewable resources have attracted considerable attention. Therefore, the effective and comprehensive utilization of lignin has become an important global research topic, with the goal of environmental protection and economic development. This review focused on the bacteria and enzymes that can bio-transform lignin, focusing on the main ways that lignin can be utilized to produce high-value chemical products. Bacillus has demonstrated the most prominent effect on lignin degradation, with 89% lignin degradation by Bacillus cereus. Furthermore, several bacterial enzymes were discussed that can act on lignin, with the main enzymes consisting of dye-decolorizing peroxidases and laccase. Finally, low-molecular-weight lignin compounds were converted into value-added products through specific reaction pathways. These bacteria and enzymes may become potential candidates for efficient lignin degradation in the future, providing a method for lignin high-value conversion. In addition, the bacterial metabolic pathways convert lignin-derived aromatics into intermediates through the "biological funnel", achieving the biosynthesis of value-added products. The utilization of this "biological funnel" of aromatic compounds may address the heterogeneous issue of the aromatic products obtained via lignin depolymerization. This may also simplify the separation of downstream target products and provide avenues for the commercial application of lignin conversion into high-value products.
RESUMO
Prism-based surface Plasmon resonance (SPR) system, as one of the leading candidate concepts for scale application and commercial solution, has good stability, high-sensitivity and greater theoretical/technical maturity. Therefore, to take advantage of prism-based SPR system fully, and break up limitations of complicated and bulky traditional prism-based SPR system, optimal and compact design of optical system is an effective solution. Herein, a customizable miniaturized prism-based SPR system is developed by optical system optimization and integrated design, combining portable data acquisition and processing technology (FPGA-based multifunctional data processing). This proposed prism-based SPR system can achieve a miniaturized SPR system, thus, it also can meet the requirements of flexibility configuration and customizable performance to accommodate the various needs of different users and application scenes. Additionally, the customizable features can make it to achieve the best performance optimization and differentiation.
RESUMO
Activin A, a member of the transforming growth factorß (TGFß) superfamily, has been implicated in the tumorigenesis and progression of various cancers. However, it remains unclear whether activin A induces apoptosis in human lung adenocarcinoma cells through the endoplasmic reticulum (ER) stress pathway. In the present study, BrdU, flow cytometry and western blotting were used to examine cell proliferation, apoptosis and protein expression, respectively. The present study revealed that activin A inhibited human lung adenocarcinoma A549 cell proliferation, induced apoptosis, and upregulated the protein levels of C/EBP homologous protein (CHOP), growth arrest and DNA damageinducible protein 34 (GADD34), cleavedcaspase3 and caspase12. Furthermore, the administration of activin A did not alter the levels of suppressor of mothers against decapentaplegic 3 (Smad3) or phosphorylated (p)Smad3 proteins, whereas, it significantly elevated the levels of ActRIIA and pextracellular signal regulated kinase proteins 1 and 2 (ERK1/2) proteins in A549 cells. The apoptotic effects of activin A on A549 cells were attenuated by the ERK inhibitor FR180204, which also downregulated CHOP and caspase12 protein levels. Additionally, activin A increased intracellular calcium flux in A549 cells, and the calcium ion chelator BAPTA acetoxymethyl ester (BAPTAAM) inhibited activin Ainduced A549 cell apoptosis, whereas the calcium agonist ionomycin significantly increased apoptosis of A549 cells induced by activin A. These findings indicated that the activation of the ER stress pathway resulting in apoptosis of A549 cells triggered by activin A is facilitated by the ActRIIAERK1/2 signaling and calcium signaling. The present findings suggest that the agonists of ERK and calcium signaling exhibit promising clinical therapeutic potential for the induction of apoptosis in lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Células A549 , Cálcio/metabolismo , Caspase 12 , Linhagem Celular Tumoral , Apoptose , Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Estresse do Retículo EndoplasmáticoRESUMO
Mammary fat plays a profound role in the postnatal development of mammary glands. However, the specific types (white, brown, or beige) of adipocytes in mammary fat and their potential regulatory effects on modulating mammary gland development remain poorly understood. This study aimed to investigate the role of the browning of mammary fat on pubertal mammary gland development and explore the underlying mechanisms. Thus, the mammary gland development and the serum lipid profile were evaluated in mice treated with CL316243, a ß3-adrenoceptor agonist, to induce mammary fat browning. In addition, the proliferation of HC11 cells co-cultured with brown adipocytes or treated with the altered serum lipid metabolite was determined. Our results showed that the browning of mammary fat by injection of CL316243 suppressed the pubertal development of mice mammary glands, accompanied by the significant elevation of serum dioleoylphosphocholine (DOPC). In addition, the proliferation of HC11 was repressed when co-cultured with brown adipocytes or treated with DOPC. Furthermore, DOPC suppressed the activation of the PI3K/Akt pathway, while the DOPC-inhibited HC11 proliferation was reversed by SC79, an Akt activator, suggesting the involvement of the PI3K/Akt pathway in the DOPC-inhibited proliferation of HC11. Together, the browning of mammary fat suppressed the development of the pubertal mammary gland, which was associated with the elevated serum DOPC and the inhibition of the PI3K/Akt pathway.
Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Adipócitos Marrons/metabolismo , Lecitinas/farmacologiaRESUMO
Accurately predicting electricity consumption is crucial for reducing power waste and maintaining power system stability. To address the non-linear and seasonal fluctuations of electricity consumption, this paper proposes a seasonal prediction method based on Seasonal and Trend decomposition using Loess (STL) algorithm and gray model by introducing time series decomposition method. The STL decomposition algorithm decomposes fluctuating electricity data into three components: trend, seasonal, and remainder. Then reasonable methods are used to predict components with different data characteristics. The novel model is employed to analyze the quarterly electricity consumption in Zhejiang province of China from 2014Q4 to 2022Q3. The experimental results show that the prediction accuracy of this model is superior to the state-of-the art models; the MAPE and RMSPE values are 1.77% and 2.37%, respectively. Our model that can effectively identify seasonal fluctuations in data sequences provides a new method for predicting seasonal fluctuation data and optimizing seasonal electricity supply schemes.
Assuntos
Algoritmos , Eletricidade , Estações do Ano , Fatores de Tempo , ChinaRESUMO
OBJECTIVES: To investigate sexual behaviours among HIV-discordant heterosexual couples and assess the correlates of condom use at the couple level. DESIGN: Cross-sectional study. SETTING: Seven prefectures along the Yangtze River in the Anhui Province, China. PARTICIPANTS: We included 412 participants aged 18 years or older (206 married HIV-discordant couples). PRIMARY AND SECONDARY OUTCOME MEASURES: In this study, sexual behaviours included marital or extramarital sex in the past 6 months, as well as the frequency of marital sex and condom use (always, sometimes or never) if having marital sex in the past 6 months. We used stepwise ordinal logistic regression modelling to determine the correlates of condom use. RESULTS: In total, 63.1% (130 of 206) of couples had marital sex in the past 6 months, of which 89.2% (116 of 130) used condoms consistently. Couples with more marital duration (OR=1.15; 95% CI: 1.03, 1.28) were more inclined to adhere to condom use, whereas those lacking support and care (OR=0.25; 95% CI: 0.07, 0.94) and being remarried (OR=0.08; 95% CI: 0.02, 0.43) were associated with less condom use. In addition, HIV-positive respondents were more likely to have extramarital sex than HIV-negative respondents (p=0.015). CONCLUSIONS: The extramarital sex of HIV-positive spouses should be considered. Implementation of interventions, such as increasing support and care between spouses to promote marital intimacy and stability, could reduce unprotected sexual behaviour.
Assuntos
Preservativos , Infecções por HIV , Humanos , Estudos Transversais , Comportamento Sexual , ChinaRESUMO
OBJECTIVE: Brown adipose tissue (BAT) plays a crucial role in regulating non-shivering thermogenesis under cold exposure. Proline hydroxylases (PHDs) were found to be involved in adipocyte differentiation and lipid deposition. However, the effects of PHDs on regulatory mechanisms of BAT thermogenesis are not fully understood. METHODS: We detected the expression of PHDs in different adipose tissues by using immunoblotting and real-time PCR. Further, immunoblotting, real-time PCR, and immunostaining were performed to determine the correlation between proline hydroxylase 2 (PHD2) and UCP1 expression. Inhibitor of PHDs and PHD2-sgRNA viruses were used to construct the PHD2-deficiency model in vivo and in vitro to investigate the impacts of PHD2 on BAT thermogenesis. Afterward, the interaction between UCP1 and PHD2 and the hydroxylation modification level of UCP1 were verified by Co-IP assays and immunoblotting. Finally, the effect of specific proline hydroxylation on the expression/activity of UCP1 was further confirmed by site-directed mutation of UCP1 and mass spectrometry analysis. RESULTS: PHD2, but not PHD1 and PHD3, was highly enriched in BAT, colocalized, and positively correlated with UCP1. Inhibition or knockdown of PHD2 significantly suppressed BAT thermogenesis under cold exposure and aggravated obesity of mice fed HFD. Mechanistically, mitochondrial PHD2 bound to UCP1 and regulated the hydroxylation level of UCP1, which was enhanced by thermogenic activation and attenuated by PHD2 knockdown. Furthermore, PHD2-dependent hydroxylation of UCP1 promoted the expression and stability of UCP1 protein. Mutation of the specific prolines (Pro-33, 133, and 232) in UCP1 significantly mitigated the PHD2-elevated UCP1 hydroxylation level and reversed the PHD2-increased UCP1 stability. CONCLUSIONS: This study suggested an important role for PHD2 in BAT thermogenesis regulation by enhancing the hydroxylation of UCP1.