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PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .
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There have been few studies on the role of nanofluids in oil displacement and injection parameters, despite their significant impact on the oil displacement effect. To enhance oil recovery in an ultralow-permeability reservoir, the nanosized oil-displacement agent with nano-SiO2 modified by a silane coupling agent as a main component was selected for the first time in the Changqing oilfield. To assess the performance of the nanofluid, various factors such as particle size, contact angle, interfacial tension, and emulsion stability were taken into consideration. The oil displacement effect of nanofluids was evaluated by a microscopic model and ultralow-permeability core displacement experiment, and its optimal injection parameters were determined. The average particle size of the nano-oil displacement agent is 22-30 nm. It can change the wetting condition of the rock from oil-wet to water-wet and reduce the oil-water interfacial tension. Even at 80 °C, the emulsion formed by the agent remained stable. The oil displacement experiment shows that the nano-oil displacement agent whose injection pressure increases can displace the residual oil trapped in small pores that cannot be affected by conventional water flooding. The injection mode of "nanoflooding agent drive + water drive + nanoflooding agent drive", injection rate of 0.1 mL/min, injection concentration of 0.5%, and injection volume of 0.5 PV (0.25 PV per segment), which can effectively guide the injection of the oil displacement agent, achieve the best oil displacement effect.
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Patients with Parkinson's disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, Padjusted = 0.011; WM: 4.87 ± 7.88, Padjusted = 0.049) and controls (GM: -0.58 ± 7.04, Padjusted = 0.004; WM: 0.88 ± 7.45, Padjusted = 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (Padjusted = 0.011) and MoCA (Padjusted = 0.013) and positively correlated with UPDRS Part II (Padjusted = 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (Padjusted = 0.003 and Padjusted < 0.001). Also, altered brain regions in PD-CI were identified and significantly correlated with brain age measures, implicating the neuroanatomical underpinning of neurodegeneration in PD-CI. Moreover, the brain age metrics can improve the classification between PD-CI and PD-NCI. The findings suggest that patients with PD-CI had advanced brain aging that was associated with poor cognitive functions. The identified neuroimaging features and brain age measures can serve as potential biomarkers of PD-CI.
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A large number of studies have explored the separate roles of information and trust in consumer choices of organic food, but little attention has been paid to exploring the interactive effects of information and trust. Here, for the first time to our knowledge, we explored the joint effects of information and consumers' trust in shaping consumer preferences for organic food. A hypothetical choice experiment was employed to elicit consumer preferences for organic food, and a between-subject design approach was used to explore the effects of information. Our results from a sample of 2382 Chinese consumers indicated that consumers are willing to pay extra price for organic rice compared to the conventional rice. Notably, individuals with a high level of trust exhibited a significantly higher willingness to pay for organic rice than those with lower trust levels. Furthermore, the introduction of information leads to a substantial 40% increase in consumers' willingness to pay for organic rice, with an even more significant 50% increase observed among high-trust consumers. These results highlight the augmenting role of trust in amplifying the effects of information. Consequently, effective strategies should encompass both the provision of information and the cultivation of trust concurrently to promote consumer choices of organic food.
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Alimentos Orgânicos , Confiança , Humanos , China , Comportamento do ConsumidorRESUMO
ARHGAP35, which encodes p190A RhoGAP (p190A), is a major cancer gene. p190A is a tumor suppressor that activates the Hippo pathway. p190A was originally cloned via direct binding to p120 RasGAP (RasGAP). Here, we determine that interaction of p190A with the tight-junction-associated protein ZO-2 is dependent on RasGAP. We establish that both RasGAP and ZO-2 are necessary for p190A to activate large tumor-suppressor (LATS) kinases, elicit mesenchymal-to-epithelial transition, promote contact inhibition of cell proliferation, and suppress tumorigenesis. Moreover, RasGAP and ZO-2 are required for transcriptional modulation by p190A. Finally, we demonstrate that low ARHGAP35 expression is associated with shorter survival in patients with high, but not low, transcript levels of TJP2 encoding ZO-2. Hence, we define a tumor-suppressor interactome of p190A that includes ZO-2, an established constituent of the Hippo pathway, and RasGAP, which, despite strong association with Ras signaling, is essential for p190A to activate LATS kinases.
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Proteínas Ativadoras de GTPase , Via de Sinalização Hippo , Humanos , Proliferação de Células , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Transdução de SinaisRESUMO
Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix in the myocardium with cardiac fibroblast activation, leading to chronic cardiac remodeling and dysfunction. However, little is known about metabolic alterations in fibroblasts during cardiac fibrosis, and there is a lack of pharmaceutical treatments that target metabolic dysregulation. Here, we provided evidence that fatty acid ß-oxidation (FAO) dysregulation contributes to fibroblast activation and cardiac fibrosis. With transcriptome, metabolome, and functional assays, we demonstrated that FAO was downregulated during fibroblast activation and cardiac fibrosis, and that perturbation of FAO reversely affected the fibroblast-to-myofibroblast transition. The decrease in FAO may be attributed to reduced long-chain fatty acid (LCFA) uptake. Voltage-dependent anion channel 1 (VDAC1), the main gatekeeper of the outer mitochondrial membrane (OMM), serves as the transporter of LCFA into the mitochondria for further utilization and has been shown to be decreased in myofibroblasts. In vitro, the addition of exogenous VDAC1 was shown to ameliorate cardiac fibroblast activation initiated by transforming growth factor beta 1 (TGF-ß1) stimuli, and silencing of VDAC1 displayed the opposite effect. A mechanistic study revealed that VDAC1 exerts a protective effect by regulating LCFA uptake into the mitochondria, which is impaired by an inhibitor of carnitine palmitoyltransferase 1A. In vivo, AAV9-mediated overexpression of VDAC1 in myofibroblasts significantly alleviated transverse aortic constriction (TAC)-induced cardiac fibrosis and rescued cardiac function in mice. Finally, we treated mice with the VDAC1-derived R-Tf-D-LP4 peptide, and the results showed that R-Tf-D-LP4 prevented TAC-induced cardiac fibrosis and dysfunction in mice. In conclusion, this study provides evidence that VDAC1 maintains FAO metabolism in cardiac fibroblasts to repress fibroblast activation and cardiac fibrosis and suggests that the VDAC1 peptide is a promising drug for rescuing fibroblast metabolism and repressing cardiac fibrosis.
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Fibroblastos , Canal de Ânion 1 Dependente de Voltagem , Animais , Camundongos , Ácidos Graxos/metabolismo , Fibroblastos/metabolismo , Fibrose , Peptídeos/metabolismo , Canal de Ânion 1 Dependente de Voltagem/genética , Canal de Ânion 1 Dependente de Voltagem/metabolismoRESUMO
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.
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Núcleo Celular , Oncogenes , Humanos , Animais , Camundongos , Ativação Transcricional , Proteínas Correpressoras , Modelos Animais de Doenças , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Fatores de Transcrição , Proteínas Supressoras de TumorRESUMO
Bile acids (BAs), key regulators in the metabolic network, are not only involved in lipid digestion and absorption but also serve as potential therapeutic targets for metabolic disorders. Studies have shown that cardiac dysfunction is associated with abnormal BA metabolic pathways. As ligands for several nuclear receptors and membrane receptors, BAs systematically regulate the homeostasis of metabolism and participate in cardiovascular diseases (CVDs), such as myocardial infarction, diabetic cardiomyopathy, atherosclerosis, arrhythmia, and heart failure. However, the molecular mechanism by which BAs trigger CVDs remains controversial. Therefore, the regulation of BA signal transduction by modulating the synthesis and composition of BAs is an interesting and novel direction for potential therapies for CVDs. Here, we mainly summarized the metabolism of BAs and their role in cardiomyocytes and noncardiomyocytes in CVDs. Moreover, we comprehensively discussed the clinical prospects of BAs in CVDs and analyzed the clinical diagnostic and application value of BAs. The latest development prospects of BAs in the field of new drug development are also prospected. We aimed to elucidate the underlying mechanism of BAs treatment in CVDs, and the relationship between BAs and CVDs may provide new avenues for the prevention and treatment of these diseases.
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Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug Administration (FDA) approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.
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Linfoma de Células T , Transdução de Sinais , Humanos , Receptores de Antígenos de Linfócitos T/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linfócitos T , Linfoma de Células T/tratamento farmacológicoRESUMO
Cardiac fibrosis is associated with an adverse prognosis in cardiovascular disease that results in a decreased cardiac compliance and, ultimately, heart failure. Recent studies have identified the role of long noncoding RNA (lncRNA) in cardiac fibrosis. However, the functions of many lncRNAs in cardiac fibrosis remain to be characterized. Through a whole-transcriptome sequencing and bioinformatics analysis on a mouse model of pressure overload-induced cardiac fibrosis, we screened a key lncRNA termed thrombospondin 1 antisense 1 (THBS1-AS1), which was positively associated with cardiac fibrosis. In vitro functional studies demonstrated that the silencing of THBS1-AS1 ameliorated TGF-ß1 effects on cardiac fibroblast (CF) activation, and the overexpression of THBS1-AS1 displayed the opposite effect. A mechanistic study revealed that THBS1-AS1 could sponge miR-221/222 to regulate the expression of TGFBR1. Moreover, under TGF-ß1 stimulation, the forced expression of miR-221/222 or the knockdown TGFBR1 significantly reversed the THBS1-AS1 overexpression induced by further CF activation. In vivo, specific knockdown of THBS1-AS1 in activated CFs significantly alleviated transverse aorta constriction-induced (TAC-induced) cardiac fibrosis in mice. Finally, we demonstrated that the human THBS1-AS1 can also affect the activation of CFs by regulating TGFBR1. In conclusion, this study reveals that lncRNA THBS1-AS1 is a potentially novel regulator of cardiac fibrosis and may serve as a target for the treatment of cardiac fibrosis.
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Cardiomiopatias , MicroRNAs , RNA Longo não Codificante , Humanos , Camundongos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , MicroRNAs/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Trombospondina 1/genética , Trombospondina 1/metabolismo , Fibrose , Cardiomiopatias/metabolismo , Fibroblastos/metabolismoRESUMO
Cardiac fibrosis is a pathological process underlying myocardial remodeling and is characterized by excessive deposition of the myocardial extracellular matrix. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of various biological processes. In this study, we investigated the role of a novel lncRNA, Gm41724, in cardiac fibrosis induced by pressure overload. High-throughput whole transcriptome sequencing analysis was performed to detect differentially expressed lncRNAs in cardiac fibroblasts (CFs) with or without TGF-ß1 treatment. Differential expression analysis and gene set enrichment analysis identified Gm41724 as a potential molecule targeting fibrosis. Gm41724 positively regulated the activation of CFs induced by TGF-ß1 and pressure overload. Knocking down Gm41724 could inhibit the differentiation of CFs into myofibroblasts and alleviate cardiac fibrosis induced by pressure overload. Mechanistically, comprehensive identification of RNA-binding proteins by mass spectrometry (CHIRP-MS) and RNA immunoprecipitation (RIP) assay combined with other methods of molecular biological revealed the important role of Gm41724 binding to lamina-associated polypeptide 2α (lap2α) for the activation of CFs. Further mechanistic studies indicated that the regulator of G protein signaling 4 (Rgs4), as the downstream effector of Gm41724/lap2α, regulated CFs activation. Our results implicated the involvement of Gm41724 in cardiac fibrosis induced by pressure overload and it is expected to be a promising target for anti-fibrotic therapy.
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Cardiomiopatias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Cardiomiopatias/metabolismo , Miocárdio/patologia , Fibrose , Fibroblastos/metabolismoRESUMO
Cardiac hypertrophy initially serves as an adaptive response to physiological and pathological stimuli. Sustained hypertrophy progress to pathological cardiac hypertrophy, cardiac fibrosis and ultimately lead to heart failure, one of the leading medical causes of mortality worldwide. Intervention of pathological cardiac hypertrophy can effectively reduce the occurrence of heart failure. Abundant factors, such as adrenergic, angiotensin, and endothelin (ET-1) receptors, have been shown to participate in the regulation of pathological cardiac hypertrophy. Recently, an increasing number of studies have indicated that circRNA and circRNA-miRNA-mRNA network regulation is indispensable for the posttranscriptional regulation of mRNA in cardiac hypertrophy. In our study, the morphological, cardiac function and pathological changes during cardiac hypertrophy were investigated. RNA sequencing identified 93 circRNAs that were differentially expressed in the TAC_2w group, and 55 circRNAs in the TAC_4w group compared with the sham group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified several significant pathways, including hypertrophic cardiomyopathy, extracellular matrix (ECM)-receptor interaction and focal adhesion. Coexpression analyses were performed for differentially expressed circRNAs and differentially expressed mRNAs. Based on gene set enrichment analysis (GSEA), 8 circRNAs (mmu-Nfkb1_0001, mmu-Smad4_0007, mmu-Hecw2_0009, mmu-Itgbl1_0002, mmu-Lrrc2_0005, mmu-Cpeb3_0007, mmu-Ryr2_0040, and mmu-Rtn4_0001) involved in cardiac hypertrophy and cardiac fibrosis were identified. We validated some key circRNAs by qPCR. The crucial coexpression of circRNA-mRNA and its interaction with miRNA showed the possible mechanism of circRNAs in the process of cardiac dysfunction. Our results may provide promising targets for the treatment of pathological cardiac hypertrophy and fibrosis.
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Earlier studies have noted potential adverse impacts of land-related emissions mitigation strategies on food security, particularly due to food price increases-but without distinguishing these strategies' individual effects under different conditions. Using six global agroeconomic models, we show the extent to which three factors-non-CO2 emissions reduction, bioenergy production and afforestation-may change food security and agricultural market conditions under 2 °C climate-stabilization scenarios. Results show that afforestation (often simulated in the models by imposing carbon prices on land carbon stocks) could have a large impact on food security relative to non-CO2 emissions policies (generally implemented as emissions taxes). Respectively, these measures put an additional 41.9 million and 26.7 million people at risk of hunger in 2050 compared with the current trend scenario baseline. This highlights the need for better coordination in emissions reduction and agricultural market management policies as well as better representation of land use and associated greenhouse gas emissions in modelling.
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Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2-mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.
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Resistencia a Medicamentos Antineoplásicos , Fator de Transcrição Ikaros , Fatores Imunológicos/farmacologia , Linfoma de Células T , Mieloma Múltiplo , Ubiquitina-Proteína Ligases , Humanos , Fator de Transcrição Ikaros/metabolismo , Lenalidomida/farmacologia , Linfoma de Células T/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
The glycocalyx is a complex polysaccharide-protein layer lining the lumen of vascular endothelial cells. Changes in the structure and function of the glycocalyx promote an inflammatory response in blood vessels and play an important role in the pathogenesis of many vascular diseases (e.g., diabetes, atherosclerosis, and sepsis). Vascular endothelial dysfunction is a hallmark of inflammation-related diseases. Endothelial dysfunction can lead to tissue swelling, chronic inflammation, and thrombosis. Therefore, elimination of endothelial inflammation could be a potential target for the treatment of vascular diseases. This review summarizes the key role of the glycocalyx in the inflammatory process and the possible mechanism by which it alleviates this process by interrupting the cycle of endothelial dysfunction and inflammation. Especially, we highlight the roles of different components of the glycocalyx in modulating the inflammatory process, including components that regulate leukocyte rolling, L-selectin binding, inflammasome activation and the signaling interactions between the glycocalyx components and the vascular cells. We discuss how the glycocalyx interferes with the development of inflammation and the importance of preventing glycocalyx impairment. Finally, drawing on current understanding of the role of the glycocalyx in inflammation, we consider a potential strategy for the treatment of vascular diseases.
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PURPOSE: To develop microchannel-based preparation of curcumin (Cur)-loaded hybrid nanoparticles using enzyme-targeted peptides and star-shaped polycyclic lipids as carriers, and to accomplish a desirable targeted drug delivery via these nanoparticles, which could improve the bioavailability and antitumor effects of Cur. METHODS: The amphiphilic tri-chaintricarballylic acid-poly (ε-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) and the enzyme-targeted tetra-chain pentaerythritol-poly (ε-caprolactone)-polypeptide (PET-CL-P) were synthesized. The Cur-loaded enzyme-targeted hybrid nano-delivery systems (Cur-P-NPs) were prepared by using the microfluidic continuous granulation technology. The physicochemical properties, release behavior in vitro, and stability of these Cur-P-NPs were investigated. Their cytotoxicity, cellular uptake, anti-proliferative efficacy in vitro, biodistribution, and antitumor effects in vivo were also studied. RESULTS: The particle size of the prepared Cur-P-NPs was 146.1 ± 1.940 nm, polydispersity index was 0.175 ± 0.014, zeta potential was 10.1 ± 0.300 mV, encapsulation rate was 74.66 ± 0.671%, and drug loading capacity was 5.38 ± 0.316%. The stability of Cur-P-NPs was adequate, and the in vitro release rate increased with the decrease of the environmental pH. Seven days post incubation, the cumulative release values of Cur were 52.78%, 67.39%, and 98.12% at pH 7.4, pH 6.8 and pH 5.0, respectively. Cur-P-NPs exhibited better cell entry and antiproliferation efficacy against U251 cells than the Cur-solution and Cur-NPs and were safe for use. Cur-P-NPs specifically targeted tumor tissues and inhibited their growth (78.63% tumor growth inhibition rate) with low toxic effects on normal tissues. CONCLUSION: The enzyme-targeted hybrid nanoparticles prepared in the study clearly have the tumor-targeting ability. Cur-P-NPs can effectively improve the bioavailability of Cur and have potential applications in drug delivery and tumor management.
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Curcumina/química , Curcumina/farmacologia , Dispositivos Lab-On-A-Chip , Nanopartículas/química , Nanotecnologia/instrumentação , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Caproatos/química , Linhagem Celular Tumoral , Curcumina/farmacocinética , Portadores de Fármacos/química , Humanos , Lactonas/química , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Distribuição TecidualRESUMO
Long non-coding RNA (lncRNA) Dnm3os plays a critical role in peritendinous fibrosis and pulmonary fibrosis, but its role in the process of cardiac fibrosis is still unclear. Therefore, we carried out study by using the myocardial fibrotic tissues obtained by thoracic aortic constriction (TAC) in an early study of our group, and the in vitro cardiac fibroblast activation model induced by transforming growth factor-ß1 (TGF-ß1). Quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, and collagen gel contraction test were used to identify the changes of activation phenotype and the expression of Dnm3os in cardiac fibroblasts. Small interfering RNA was used to silence Dnm3os to explore its role in the activation of cardiac fibroblasts. The results showed that the expression of Dnm3os was increased significantly in myocardial fibrotic tissues and in the activated cardiac fibroblasts. And the activation of cardiac fibroblasts could be alleviated by Dnm3os silencing. Furthermore, the TGF-ß1/Smad2/3 pathway was activated during the process of cardiac fibroblasts activation, while was inhibited after silencing Dnm3os. The results suggest that Dnm3os silencing may affect the process of cardiac fibroblast activation by inhibiting TGF-ß1/Smad2/3 signal pathway. Therefore, interfering with the expression of lncRNA Dnm3os may be a potential target for the treatment of cardiac fibrosis.
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RNA Longo não Codificante , Fibroblastos , Fibrose , Humanos , Miocárdio/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta1RESUMO
Cell proliferation is an important cellular process for physiological tissue homeostasis and remodeling. The mechanisms of cell proliferation in response to pathological stresses are not fully understood. Mitochondria are highly dynamic organelles whose shape, number, and biological functions are modulated by mitochondrial dynamics, including fusion and fission. Mitofusin-2 (Mfn-2) is an essential GTPase-related mitochondrial dynamics protein for maintaining mitochondrial network and bioenergetics. A growing body of evidence indicates that Mfn-2 has a potential role in regulating cell proliferation in various cell types. Here we review these new functions of Mfn-2, highlighting its crucial role in several signaling pathways during the process of pathological cell proliferation. We conclude that Mfn-2 could be a new mediator of pathological cell proliferation and a potential therapeutic target.