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Overweight and obesity affect almost 2 billion adults worldwide, and food restriction (FR) is commonly used to reduce body fat. Whether refeeding (Re) after FR at different ages and to different degrees leads to overweight and its possible mechanisms are uncertain. In this study, adult and young mice were both restricted to 15% and 40% of their casual food intake, and then were fed 60% high-fat chow (FR15%-Re, FR40%-Re), whereas the control groups(CON) consumed high-fat or normal food throughout, respectively. The results of the study suggest that mild FR-heavy feeding may lead to more significant abnormal fat accumulation, liver damage, and increased recruitment of intestinal inflammatory factors and immune cells in mice of different ages and involves multiple types of alterations in the gut microbiota. Further fecal transplantation experiments as well as serum and liver enzyme-linked immunosorbent assay experiments preliminarily suggest that the link between lipid metabolism and inflammatory responses and the gut microbiota may be related to the regulation of the gut and live by Lipopolysaccharides(LPS) and Peroxisome Proliferator-Activated Receptor-Alpha(PPAR-α). In addition, our study may also serve as a reference for studying obesity prevention and treatment programs at different ages.
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High basal autophagy and enhanced mitochondrial fission in triple-negative breast cancer (TNBC) cells support cell migration and promote plasticity of cancer cell metabolism. Here, we suggest a novel combination therapy approach for the treatment of TNBC that targets Drp1-mediated mitochondrial fission and autophagy pathways. Hydrogen sulfide (H2S) mediates a myriad of biological processes, including autophagy and mitochondrial function. In this study, we demonstrated that 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), one of the most widely utilized sustained-release H2S donors, effectively suppresses metastasis of TNBC cells in the absence of proliferation inhibition in vitro and in vivo. ADT-OH treatment ameliorated autophagy flux by suppressing autophagosome formation and induced mitochondrial elongation through decreasing expression of dynamin-related protein 1 (Drp1) and increasing expression of mitochondrial fusion protein (Mfn2). At the same time, ADT-OH downregulated mitophagy flux and inhibited mitochondrial function, eventually leading to the inhibition of migration and invasion in TNBC cells. In vivo, intraperitoneal administration of ADT-OH revealed a potent anti-metastatic activity in three different animal models, the MDA-MB-231 orthotopic xenograft model, the 4T1-Luci orthotopic model and the 4T1-Luci tail vein metastasis model. However, ADT-OH has an extremely low water solubility, which is a significant barrier to its effectiveness. Thus, we demonstrated that the solubility of ADT-OH in water can be improved significantly by absorption with hydroxypropyl-ß-cyclodextrin (CD). Remarkably, the obtained CD-ADT-OH demonstrated superior anti-cancer effect to ADT-OH in vivo. Altogether, this study describes a novel regulator of mammalian mitochondrial fission and autophagy, with potential utility as an experimental therapeutic agent for metastatic TNBC.
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Autofagia , Dinâmica Mitocondrial , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Humanos , Animais , Autofagia/efeitos dos fármacos , Feminino , Linhagem Celular Tumoral , Camundongos , Movimento Celular/efeitos dos fármacos , Camundongos Nus , Tionas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Metástase Neoplásica , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Dinaminas/metabolismo , Tiofenos/farmacologiaRESUMO
BACKGROUND: Neutrophil extracellular traps (NETs), antibacterial weapons of neutrophils (NEs), have been found to play a crucial role in cancer metastasis in recent years. More and more cancer research is focusing on anti-NETs. However, almost all anti-NETs treatments have limitations such as large side effects and limited efficacy. Therefore, exploring new anti-NETs therapeutic strategies is a long-term goal. RESULTS: The transmembrane protein coiled-coil domain containing 25 (CCDC25) on tumor cell membranes can bind NETs-DNA with high specificity and affinity, enabling tumor cells to sense NETs and thus promote distant metastasis. We transformed shCCDC25 into VNP20009 (VNP), an oncolytic bacterium, to generate VNP-shCCDC25 and performed preclinical evaluation of the inhibitory effect of shCCDC25 on cancer metastasis in B16F10 lung metastasis and 4T1 orthotopic lung metastasis models. VNP-shCCDC25 effectively blocked the downstream prometastatic signaling pathway of CCDC25 at tumor sites and reduced the formation of NETs while recruiting more neutrophils and macrophages to the tumor core, ultimately leading to excellent metastasis inhibition in the two lung metastasis models. CONCLUSION: This study is a pioneer in focusing on the effect of anti-NET treatment on CCDC25. shCCDC25 is effectively delivered to tumor sites via the help of oncolytic bacteria and has broad application in the inhibition of cancer metastasis via anti-NETs.
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Armadilhas Extracelulares , Neoplasias Pulmonares , Ácidos Nucleicos , Humanos , Armadilhas Extracelulares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neutrófilos/metabolismo , Ácidos Nucleicos/uso terapêuticoRESUMO
Ferroptosis is iron-dependent and regulates necrosis caused by lipid peroxidation and mitochondrial damage. Recent evidence has revealed an emerging role for ferroptosis in the pathophysiology of acute kidney injury (AKI). Sulfide:quinone oxidoreductase (SQOR) is a mitochondrial inner membrane protein highly expressed in the renal cortex. However, the effects of SQOR on ferroptosis and AKI have not been elucidated. In this study, we evaluated the effects of SQOR in several AKI models. We observed a rapid decrease in SQOR expression after cisplatin stimulation in both in vivo and in vitro models. SQOR-deletion mice exhibit exacerbated kidney impairment and ferroptosis in renal tubular epithelial cells following cisplatin injury. Additionally, our results showed that the overexpression of SQOR or ADT-OH (the slow-releasing H2S donor) preserved renal function in the three AKI mouse models. These effects were evidenced by lower levels of serum creatinine (SCr), blood urea nitrogen (BUN), renal neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (KIM-1). Importantly, SQOR knockout significantly aggravates cisplatin-induced ferroptosis by promoting mitochondrial dysfunction in renal tubular epithelial cells (RTECs). Moreover, online database analysis combined with our study revealed that SYVN1, an upregulated E3 ubiquitin ligase, may mediate the ubiquitin-mediated degradation of SQOR in AKI. Consequently, our results suggest that SYVN1-mediated ubiquitination degradation of SQOR may induce mitochondrial dysfunction in RTECs, exacerbating ferroptosis and thereby promoting the occurrence and development of AKI. Hence, targeting the SYVN1-SQOR axis could be a potential therapeutic strategy for AKI treatment.
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Injúria Renal Aguda , Ferroptose , Doenças Mitocondriais , Camundongos , Animais , Cisplatino/efeitos adversos , Injúria Renal Aguda/etiologia , Oxirredutases , Quinonas , SulfetosRESUMO
BACKGROUND: Myeloid leukemia is associated with reduced serum zinc and increased intracellular zinc. Our previous studies found that zinc depletion by TPEN induced apoptosis with PML-RARα oncoprotein degradation in acute promyelocytic NB4 cells. The effect of zinc homeostasis on intracellular signaling pathways in myeloid leukemia cells remains unclear. OBJECTIVE: This study examined how zinc homeostasis affected MAPK and Akt/mTOR pathways in NB4 cells. METHODS: We used western blotting to detect the activation of p38 MAPK, JNK, ERK1/2, and Akt/mTOR pathways in NB4 cells stimulated with the zinc chelator TPEN. Whether the effects of TPEN on these pathways could be reversed by zinc or the nitric oxide donor sodium nitroprusside (SNP) was further explored by western blotting. We used Zinpyr-1 staining to assess the role of SNP on labile zinc levels in NB4 cells treated with TPEN. In additional, we evaluated expressional correlations between the zinc-binding protein Metallothionein-2A (MT2A) and genes related to MAPKs and Akt/mTOR pathways in acute myeloid leukemia (AML) based on the TCGA database. RESULTS: Zinc depletion by TPEN activated p38 and JNK phosphorylation in NB4 cells, whereas ERK1/2 phosphorylation was increased first and then decreased. The protein expression levels of Akt and mTOR were downregulated by TPEN. The nitric oxide donor SNP promotes zinc release in NB4 cells under zinc depletion conditions. We further found that the effects of zinc depletion on MAPK and Akt/mTOR pathways in NB4 cells can be reversed by exogenous zinc supplementation or treatment with the nitric oxide donor SNP. By bioinformatics analyses based on the TCGA database, we demonstrated that MT2A expression was negatively correlated with the expression of JNK, and was positively correlated with the expression of ERK1 and Akt in AML. CONCLUSION: Our findings indicate that zinc plays a critical role in leukemia cells and help understanding how zinc depletion induces apoptosis.
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Leucemia Mieloide , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doadores de Óxido Nítrico/farmacologia , Fosforilação , Zinco/farmacologia , Zinco/metabolismo , Apoptose , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Colorectal cancer is one of the most prevalent cancers in the world, but the research on its prevention, early diagnosis and treatment is still a major challenge in clinical oncology. Thus, there is a pressing requirement to find effective strategies to improve the survival of colon cancer patients. METHODS: Celecoxib has been accounted to be an effective antitumor drug, but may exhibit significant side effects. In recent studies, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), one of the most commonly used reagents for the synthesis of sustained-release H2 S donors, has also been reported to inhibit cancer progression by affecting processes such as cell cycle, angiogenesis, and apoptosis. Therefore, we evaluated the therapeutic effect of the combination of ADT-OH and celecoxib on colorectal cancer through in vitro and in vivo, hoping to achieve better therapeutic effect and reduce the effect of celecoxib on gastric injury through exogenous administration of H2 S. RESULTS: Our results demonstrated that ADT-OH combined with celecoxib synergistically inhibited the proliferation and migration ability of human colorectal cancer HCT116 cells, altered cell cycle and cytoskeleton, increased intracellular reactive oxygen species (ROS), and promoted cell apoptosis. Noteworthy, in vivo studies also indicated the excellent antitumor therapeutic effect of the combination therapy without apparent toxicity. CONCLUSIONS: In general, our results provide a reasonable combination strategy of low-dose ADT-OH and celecoxib in the preclinical application of colorectal cancer.
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Neoplasias do Colo , Tionas , Humanos , Celecoxib/farmacologia , Celecoxib/uso terapêutico , Tionas/farmacologia , Tionas/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Apoptose , Proliferação de Células , Linhagem Celular TumoralRESUMO
Zinc homeostasis is regulated by the SLC39A/ZIP, SLC30A/ZnT, and metallothionein (MT) protein families. The association of zinc homeostasis with acute myeloid leukemia (AML) is unclear. We previously demonstrated that zinc depletion by TPEN triggers apoptosis in NB4 AML cells with the degradation of PML-RARα oncoprotein, suggesting that zinc homeostasis may be associated with AML. The primary aim of this study was to explore the expression pattern and prognostic roles of zinc homeostasis-related genes in AML. Bioinformatics analyses were performed using integrated datasets from the TCGA and GTEx projects. The GEPIA tool was used to analyze the differential expression of zinc homeostasis-related genes. Correlations between zinc homeostasis-related genes were assessed with Spearman's correlation coefficient. OncoLnc was used to evaluate the prognostic roles of zinc homeostasis-related genes with Kaplan-Meier and Cox regression models. In both NB4 and U937 cells, the transcriptional regulation of zinc homeostasis-related genes by zinc depletion was detected through qPCR. We found that multiple ZIPs, ZnTs, and MTs were differentially expressed and correlated in AML tumors. In AML patients, higher expression of ZIP4 and lower expression of ZnT5 and ZnT7 predicted poorer survival. We further found that zinc depletion by TPEN upregulated ZIP7, ZIP9, ZIP10, ZIP13, and ZnT7 and downregulated ZIP14, ZnT1, ZnT6, and most of the positively expressed MTs in both NB4 and U937 AML cells. Our findings suggest high expression of ZIP4 and low expression of ZnT5 and ZnT7 as potential risk factors for the prognosis of AML. Zinc homeostasis may be a potential therapeutic target for AML, deserving further exploration.
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Proteínas de Transporte de Cátions , Leucemia Mieloide Aguda , Humanos , Prognóstico , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Zinco/metabolismo , Retículo Endoplasmático/metabolismo , Leucemia Mieloide Aguda/genética , Homeostase/genéticaRESUMO
Lithium, a trace element important for fetal health and development, is considered a metal drug with a well-established clinical regime, economical production process, and a mature storage system. Several studies have shown that lithium affects tumor development by regulating inositol monophosphate (IMPase) and glycogen synthase kinase-3 (GSK-3). Lithium can also promote proliferation and programmed cell death (PCD) in tumor cells through a number of new targets, such as the nuclear receptor NR4A1 and Hedgehog-Gli. Lithium may increase cancer treatment efficacy while reducing side effects, suggesting that it can be used as an adjunctive therapy. In this review, we summarize the effects of lithium on tumor progression and discuss the underlying mechanisms. Additionally, we discuss lithium's limitations in antitumor clinical applications, including its narrow therapeutic window and potential pro-cancer effects on the tumor immune system.
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The attenuated Salmonella typhimurium VNP20009, enriched in tumors, is known to have antitumor effects and recruit macrophages. Little is known, however, about whether VNP will lead to specific changes in macrophages, e.g., cell temperature. Here, using a real-time wireless multicell thermometry system, we reported for the first time that VNP20009 increases the macrophage temperature by 0.2 °C. Nigericin, recognized as an inducer of pyroptosis, was found to induce macrophage warming. Moreover, the ΔsipD-VNP20009 strain failed to induce macrophage pyroptosis and simultaneously failed to warm macrophages, and the Gsdmd-/- macrophages that were unable to achieve pyroptosis were no longer warmed following VNP20009 induction. These results suggested that the occurrence of macrophage pyroptosis is the key to VNP20009-mediated cell warming. With the aid of a single-cell thermometry system, it was further confirmed that cell warming occurred in pyroptosis-like macrophages. Cellular warming was not detected after the induction of pyroptosis in macrophages with loss of mitochondrial biological function, suggesting a critical role of mitochondria in warming. Moreover, we found that VNP20009 caused local tumor temperature increases. The local tumor warming induced by VNP20009 was significantly reduced after macrophage clearance. Notably, this temperature increase contributed to M1-type polarization. These findings expanded our knowledge of the cellular biological changes induced by the strain on macrophages, as well as the biochemical phenomena accompanying pyroptosis, and provide a reference for the study of biochemical signals transduced to biothermal signals with a combined cell-level temperature detector.
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Salmonella typhimurium , Termometria , Piroptose , Nigericina , Macrófagos , FenótipoRESUMO
Acute lymphoblastic leukemia (ALL) is a common and life-threatening hematologic malignancy, its occurrence and progression are closely related to immune/stromal cell infiltration in the bone marrow (BM) microenvironment. However, no studies have described an immune/stromal cell infiltration-related gene (ISCIRG)-based prognostic signature for ALL. A total of 444 patients involving 437 bulk and 7 single-cell RNA-seq datasets were included in this study. Eligible datasets were searched and reviewed from the database of TCGA, TARGET project and GEO. Then an integrated bioinformatics analysis was performed to select optimal prognosis-related genes from ISCIRGs, construct a nomogram model for predicting prognosis, and assess the predictive power. After LASSO and multivariate Cox regression analyses, a seven ISCIRGs-based signature was proved to be able to significantly stratify patients into high- and low-risk groups in terms of OS. The seven genes were confirmed that directly related to the composition and status of immune/stromal cells in BM microenvironment by analyzing bulk and single-cell RNA-seq datasets. The calibration plot showed that the predicted results of the nomogram were consistent with the actual observation results of training/validation cohort. This study offers a reference for future research regarding the role of ISCIRGs in ALL and the clinical care of patients.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Células Estromais , Estudos de Coortes , Humanos , Nomogramas , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Microambiente Tumoral/genéticaRESUMO
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of RNA-binding proteins with important roles in multiple aspects of nucleic acid metabolism, including the packaging of nascent transcripts, alternative splicing, transactivation of gene expression, and regulation of protein translation. As a core component of the hnRNP complex in mammalian cells, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNP A2B1) participates in and coordinates various molecular events. Given its regulatory role in inflammation and cancer progression, hnRNP A2B1 has become a novel player in immune response, inflammation, and cancer development. Concomitant with these new roles, a surprising number of mechanisms deemed to regulate hnRNP A2B1 functions have been identified, including post-translational modifications, changes in subcellular localization, direct interactions with multiple DNAs, RNAs, and proteins or the formation of complexes with them, which have gradually made hnRNP A2B1 a molecular target for multiple drugs. In light of the rising interest in the intersection between cancer and inflammation, this review will focus on recent knowledge of the biological roles of hnRNP A2B1 in cancer, immune response, and inflammation.
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Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B , Neoplasias , Animais , Humanos , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/química , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , RNA/metabolismo , Neoplasias/genética , Inflamação/genética , Mamíferos/genéticaRESUMO
Bifidobacterium has been widely administrated orally as probiotics to prevent pathogen colonization and modulate the gut microbiome balance. Endostatin is an endogenous inhibitor of angiogenesis and has been shown to inhibit tumor growth, invasion, and metastasis. At present, the combination of endostatin and chemotherapeutic drugs has been regarded as a promising antitumor treatment strategy. In this study, we selected a safe strain of Bifidobacterium longum as a delivery system to transport endostatin to the gastrointestinal tract and explored their combined effect on inflammatory bowel disease (IBD) and colitis-associated cancer. The results indicated that B. longum-Endo relieved dextran sulfate sodium-induced body weight loss, diarrhea, colon shortening, and epithelium damage. Long-term oral administration of B. longum-Endo significantly decreased tumor formation rate, tumor number, and tumor size. Moreover, the effect of B. longum-Endo on gut microbiota dysbiosis was also confirmed by 16S rRNA sequencing analysis. The levels of potentially beneficial bacteria, such as Lactobacillus, Bifidobacterium, Allobaculum, and Parabateroides, were increased in the B. longum-Endo group compared to the model and B. longum groups. Meanwhile, levels of potentially pathogenic bacteria including Desulfovibrio, Helicobacter, and Enterorhabdus were decreased. Taken together, these results suggested that oral administration of recombinant B. longum-Endo strain may be a promising therapeutic strategy for IBD and colitis-associated cancer.
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Hydrogen sulfide (H2S) is widely recognized as the third endogenous gas signaling molecule and may play a key role in cancer biological processes. ADT-OH (5-(4-hydroxyphenyl)-3H-1,2-dithiocyclopentene-3-thione) is one of the most widely used organic donors for the slow release of H2S and considered to be a potential anticancer compound. In this study, we investigated the antimetastatic effects of ADT-OH in highly metastatic melanoma cells. A tail-vein-metastasis model was established by injecting B16F10 and A375 cells into the tail veins of mice, whereas a mouse footpad-injection model was established by injecting B16F10 cells into mouse footpads. We showed that administration of ADT-OH significantly inhibited the migration and invasion of melanoma cells in the three different animal models. We further showed that ADT-OH dose-dependently inhibited the migration and invasion of B16F10, B16F1 and A375 melanoma cells as evaluated by wound healing and Transwell assays in vitro. LC-MS/MS and bioinformatics analyses revealed that ADT-OH treatment inhibited the EMT process in B16F10 and A375 cells by reducing the expression of FAK and the downstream response protein Paxillin. Overexpression of FAK reversed the inhibitory effects of ADT-OH on melanoma cell migration. Moreover, after ADT-OH treatment, melanoma cells showed abnormal expression of the H2S-producing enzymes CSE/CBS and the AKT signaling pathways. In addition, ADT-OH significantly suppressed the proliferation of melanoma cells. Collectively, these results demonstrate that ADT-OH inhibits the EMT process in melanoma cells by suppressing the CSE/CBS and FAK signaling pathways, thereby exerting its antimetastatic activity. ADT-OH may be used as an antimetastatic agent in the future.
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Melanoma , Tionas , Animais , Linhagem Celular Tumoral , Movimento Celular , Cromatografia Líquida , Quinase 1 de Adesão Focal/metabolismo , Melanoma/tratamento farmacológico , Camundongos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Paxilina , Transdução de Sinais , Neoplasias Cutâneas , Espectrometria de Massas em Tandem , Melanoma Maligno CutâneoRESUMO
Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family, which uncouples oxidative phosphorylation from ATP synthesis by facilitating proton leak across the mitochondrial inner membrane. UCP2 has been reported to modulate inflammation. In this study we investigated whether and how UCP2 modulated neuroinflammation through microglia/macrophages following ICH in vitro and in vivo. We used an in vitro neuroinflammation model in murine BV2 microglia to mimic microglial activation following ICH. ICH in vivo model was established in mice through collagenase infusion into the left striatum. ICH mice were treated with anetholetrithione (ADT, 50 mg· kg-1 ·d-1, ip) or the classical protonophoric uncoupler FCCP (injected into hemorrhagic striatum). We showed that the expression and mitochondrial location of microglial UCP2 were not changed in both in vitro and in vivo ICH models. Knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ICH models, suggesting that endogenous UCP2 inhibited neuroinflammation and therefore played a protective role following ICH. ADT enhanced mitochondrial ROS production thus inducing mitochondrial uncoupling and activating UCP2 in microglia. ADT robustly suppressed neuroinflammation, attenuated brain edema and improved neurological deficits following ICH, and these effects were countered by striatal knockdown of UCP2. ADT enhanced AMP-activated protein kinase (AMPK) activation in the hemorrhagic brain, which was abrogated by striatal knockdown of UCP2. Moreover, striatal knockdown of AMPK abolished the suppression of neuroinflammation by ADT following ICH. On the other hand, FCCP-induced mitochondrial uncoupling was independent of UCP2 in microglia; and striatal knockdown of UCP2 did not abrogate the suppression of neuroinflammation by FCCP in ICH mice. In conclusion, the uncoupling activity is essential for suppression of neuroinflammation by UCP2. We prove for the first time the concept that activators of endogenous UCP2 such as anetholetrithione are a new class of uncouplers with translational significance.
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Anetol Tritiona , Anetol Tritiona/metabolismo , Anetol Tritiona/farmacologia , Animais , Hemorragia Cerebral/tratamento farmacológico , Camundongos , Microglia , Doenças Neuroinflamatórias , Proteína Desacopladora 2/metabolismoRESUMO
Adenylate kinase 2 (AK2) is a wide-spread and highly conserved protein kinase whose main function is to catalyze the exchange of nucleotide phosphate groups. In this study, we showed that AK2 regulated tumor cell metastasis in lung adenocarcinoma. Positive expression of AK2 is related to lung adenocarcinoma progression and poor survival of patients. Knockdown or knockout of AK2 inhibited, while overexpression of AK2 promoted, human lung adenocarcinoma cell migration and invasion ability. Differential proteomics results showed that AK2 might be closely related to epithelial-mesenchymal transition (EMT). Further research indicated that AK2 regulated EMT occurrence through the Smad-dependent classical signaling pathways as measured by western blot and qPCR assays. Additionally, in vivo experiments showed that AK2-knockout in human lung tumor cells reduced their EMT-like features and formed fewer metastatic nodules both in liver and in lung tissues. In conclusion, we uncover a cancer metastasis-promoting role for AK2 and provide a rationale for targeting AK2 as a potential therapeutic approach for lung cancer.
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PURPOSE: Infliximab (INX) has been approved for treating Crohn disease (CD) for many years, showing promis-ing efficacy in the clinic. However, the efficacy of the drug and the prognosis of CD vary significantly with dif-ferent locations of disease pathology. This study evaluated the efficacy of INX and prognosis in CD in different locations of disease pathology using systematic meta-analysis. METHODS: We used "Infliximab OR Remicade OR Avakine OR Inflectra OR Renflexis OR Remsima OR IgG1k monoclonal antibody" AND "Crohn's disease OR IBD OR inflammatory bowel disease" as search strategies for searching in PubMed, Wanfang and Embase. A systematic meta-analysis for overall proportions was used to analyze the data. RESULTS: Twelve studies involving 1,978 patients were included. The results confirmed that treatment with INX led to high clinical remission rates (82%, 95% CI: 64%-92%) and low relapse rates (4%, 95% CI: 2%-9%) in patients with CD. Our results also indicated that use of INX in patients with colon only (L2) CD led to lower clinical remission rates, and use of INX in patients with ileum and colon (L3) CD led to higher relapse rates. CONCLUSION: Our findings show different remission rates depending on location of the disease and may be useful for clinicians' choice of therapeutics.
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Doença de Crohn , Doença de Crohn/tratamento farmacológico , Humanos , Infliximab/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Zinc homeostasis is regulated by SLC39A/ZIP, SLC30A/ZnT, and metallothionein (MT) families in human cells. Zinc dyshomeostasis may affect or be affected by the abnormal behavior of cancer cells. Although decreased serum zinc levels are observed in patients with pancreatic adenocarcinoma (PAAD), limited information is available regarding the expression pattern and prognostic roles of zinc homeostasis-related genes in PAAD. OBJECTIVES: The primary objective of this study was to explore the expression pattern and prognostic roles of zinc homeostasis-related genes in PAAD. METHODS: The expression pattern of 35 known zinc homeostasis-related genes in PAAD was systemically explored based on RNA-sequencing data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) projects. The association between the expression levels of zinc homeostasis-related genes and survival of PAAD patients was evaluated using the Kaplan-Meier method and the log-rank test. Expressional correlation between zinc homeostasis-related genes with potential prognostic value in PAAD and normal pancreatic controls was evaluated using Pearson's correlation analysis. Functional enrichment analyses were performed to elucidate possible mechanisms for the potential prognostic and therapeutic roles of these zinc homeostasis-related genes in PAAD. Effects of ZIP11, ZnT1, or ZnT6 knockdown on the proliferation and the migration of Capan-1 pancreatic cancer cells were assessed by the CCK-8 assay and the wound healing assay respectively. RESULTS: We demonstrated that the expression levels of ZIP1, ZIP3, ZIP4, ZIP6, ZIP7, ZIP9, ZIP10, ZIP11, ZIP13, ZnT1, ZnT5, ZnT6, ZnT7, and ZnT9 were increased, whereas the expression levels of ZIP5, ZIP14, ZnT2, MT1â¯G, MT1H, and MT1X were decreased in PAAD tumors compared with normal pancreatic controls. Among these differentially-expressed genes related to zinc homeostasis, higher expression of ZIP4, ZIP11, ZnT1 or ZnT6 predicted poorer prognosis with the possible involvement of several cancer-related processes and pathways in PAAD patients. We further demonstrated that knockdown of ZIP11 attenuated Capan-1 cell proliferation with decreased activation of ERK1/2 pathway; knockdown of ZnT1 attenuated Capan-1 cell proliferation with decreased activation of ERK1/2, p38 MAPK, NF-kB, and mTOR pathways; knockdown of ZnT6 attenuated Capan-1 cell proliferation with decreased activation of ERK1/2, p38 MAPK, and NF-kB pathways. CONCLUSIONS: Higher expression of the zinc transporter ZIP4, ZIP11, ZnT1 or ZnT6 predicted poorer prognosis in patients with PAAD. These findings provide new clues for understanding the complex relationship between zinc homeostasis and pancreatic cancer.
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Proteínas de Transporte de Cátions/genética , Neoplasias Pancreáticas/genética , Perfilação da Expressão Gênica , Humanos , Neoplasias Pancreáticas/diagnóstico , Prognóstico , RNA Mensageiro/genética , RNA-Seq , Células Tumorais CultivadasRESUMO
Inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, is a complex disease involving genetic, immune, and microbiological factors. A variety of animal models of IBD have been developed to study the pathogenesis of human IBD, but there is no model that can fully represent the complexity of IBD. In this study, we established two acute enteritis models by oral 3% DSS or intraperitoneal injection of anti-CD3 antibody, and two chronic enteritis models by feeding 3 cycles of 1.5% DSS or 3 months of the high-fat diet, respectively, and then examined the clinical parameters, histological changes, and cytokine expression profiles after the successful establishment of the models. Our results indicated that in 3% DSS-induced acute enteritis, the colorectal injury was significantly higher than that of the small intestine, while in anti-CD3 antibody-induced acute enteritis, the small intestine injury was significantly higher than that of colorectal damage. Besides, in the 1.5% DSS-induced chronic enteritis, the damage was mainly concentrated in the colorectal, while the damage caused by long-term HFD-induced chronic enteritis was more focused on the small intestine. Therefore, our work provides a reference for selecting appropriate models when conducting research on factors related to the pathogenesis of IBD or evaluating the potential diagnosis and treatment possibilities of pharmaceuticals.