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1.
Front Immunol ; 15: 1322125, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38440735

RESUMO

Introduction: One rare type of autoimmune disease is called neuromyelitis optica spectrum disorder (NMOSD) and the peripheral immune characteristics of NMOSD remain unclear. Methods: Here, single-cell RNA sequencing (scRNA-seq) is used to characterize peripheral blood mononuclear cells from individuals with NMOSD. Results: The differentiation and activation of lymphocytes, expansion of myeloid cells, and an excessive inflammatory response in innate immunity are observed. Flow cytometry analyses confirm a significant increase in the percentage of plasma cells among B cells in NMOSD. NMOSD patients exhibit an elevated percentage of CD8+ T cells within the T cell population. Oligoclonal expansions of B cell receptors are observed after therapy. Additionally, individuals with NMOSD exhibit elevated expression of CXCL8, IL7, IL18, TNFSF13, IFNG, and NLRP3. Discussion: Peripheral immune response high-dimensional single-cell profiling identifies immune cell subsets specific to a certain disease and identifies possible new targets for NMOSD.


Assuntos
Doenças Autoimunes , Neuromielite Óptica , Humanos , Leucócitos Mononucleares , Neuromielite Óptica/genética , Processos de Crescimento Celular , Análise de Sequência de RNA
2.
Phys Rev Lett ; 132(9): 098403, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38489620

RESUMO

Cells employ control strategies to maintain a stable size. Dividing at a target size (the "sizer" strategy) is thought to produce the tightest size distribution. However, this result follows from phenomenological models that ignore the molecular mechanisms required to implement the strategy. Here we investigate a simple mechanistic model for exponentially growing cells whose division is triggered at a molecular abundance threshold. We find that size noise inherits the molecular noise and is consequently minimized not by the sizer but by the "adder" strategy, where a cell divides after adding a target amount to its birth size. We derive a lower bound on size noise that agrees with publicly available data from six microfluidic studies on Escherichia coli bacteria.


Assuntos
Escherichia coli , Modelos Biológicos , Processos de Crescimento Celular , Escherichia coli/genética , Microfluídica , Tamanho Celular
3.
Cell Rep ; 43(2): 113782, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38358892

RESUMO

Oocytes are arrested in prophase I. In vertebrates, meiotic resumption is triggered by hormonal stimulation that results in cAMP-dependent protein kinase (PKA) downregulation leading to Cdk1 activation. Yet the pathways connecting PKA to Cdk1 remain unclear. Here, we identify molecular events triggered by PKA downregulation occurring upstream of Cdk1 activation. We describe a two-step regulation controlling cyclin B1 and Mos accumulation, which depends on both translation and stabilization. Cyclin B1 accumulation is triggered by PKA inhibition upstream of Cdk1 activation, while its translation requires Cdk1 activity. Conversely, Mos translation initiates in response to the hormone, but the protein accumulates only downstream of Cdk1. Furthermore, two successive translation waves take place, the first controlled by PKA inhibition and the second by Cdk1 activation. Notably, Arpp19, an essential PKA effector, does not regulate the early PKA-dependent events. This study elucidates how PKA downregulation orchestrates multiple pathways that converge toward Cdk1 activation and induce the oocyte G2/M transition.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico , Oócitos , Animais , Ciclina B1 , Regulação para Baixo , Processos de Crescimento Celular
4.
Int J Mol Sci ; 24(17)2023 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-37686196

RESUMO

Three Special Issues, so far, have been dedicated to overall MSC prospective biology, from cell regulation to tissue regeneration [...].


Assuntos
Estudos Prospectivos , Processos de Crescimento Celular
5.
Cell Rep ; 42(8): 112994, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37611586

RESUMO

SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor ß (TGF-ß)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD.


Assuntos
Doença de Alzheimer , Clusterina , Humanos , Clusterina/genética , Doença de Alzheimer/genética , Neurônios , Processos de Crescimento Celular , Apolipoproteínas E/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras
6.
J Biol Chem ; 299(7): 104908, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37307919

RESUMO

Whereas it is known that p53 broadly regulates cell metabolism, the specific activities that mediate this regulation remain partially understood. Here, we identified carnitine o-octanoyltransferase (CROT) as a p53 transactivation target that is upregulated by cellular stresses in a p53-dependent manner. CROT is a peroxisomal enzyme catalyzing very long-chain fatty acids conversion to medium chain fatty acids that can be absorbed by mitochondria during ß-oxidation. p53 induces CROT transcription through binding to consensus response elements in the 5'-UTR of CROT mRNA. Overexpression of WT but not enzymatically inactive mutant CROT promotes mitochondrial oxidative respiration, while downregulation of CROT inhibits mitochondrial oxidative respiration. Nutrient depletion induces p53-dependent CROT expression that facilitates cell growth and survival; in contrast, cells deficient in CROT have blunted cell growth and reduced survival during nutrient depletion. Together, these data are consistent with a model where p53-regulated CROT expression allows cells to be more efficiently utilizing stored very long-chain fatty acids to survive nutrient depletion stresses.


Assuntos
Carnitina Aciltransferases , Sobrevivência Celular , Nutrientes , Proteína Supressora de Tumor p53 , Regiões 5' não Traduzidas/genética , Carnitina/metabolismo , Carnitina Aciltransferases/genética , Carnitina Aciltransferases/metabolismo , Processos de Crescimento Celular , Respiração Celular , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Mutação , Nutrientes/deficiência , Nutrientes/metabolismo , Oxirredução , Peroxissomos/enzimologia , Elementos de Resposta/genética , Estresse Fisiológico , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismo
7.
J Ethnopharmacol ; 315: 116644, 2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37196814

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zhuidu Formula (ZDF) is composed of triptolide, cinobufagin and paclitaxel, which are the active ingredients of Tripterygium wilfordii Hook. F, dried toad skin and Taxus wallichiana var. chinensis (Pilg) Florin, respectively. Modern pharmacological studies show that triptolide, cinobufagin, and paclitaxel are well-known natural compounds that exert anti-tumor effects by interfering with DNA synthesis, inducing tumor cell apoptosis, and inhibiting the dynamic balance of the tubulin. However, the mechanism by which the three compounds inhibit triple-negative breast cancer (TNBC) metastasis is unknown. OBJECTIVE: The objective of this investigation was to examine the inhibitory essences of ZDF on the metastasis of TNBC and elucidate its potential mechanism. MATERIALS AND METHODS: Cell viability of triptolide (TPL), cinobufagin (CBF), and paclitaxel (PTX) on MDA-MB-231 cells was assessed employing a CCK-8 assay. The drug interactions of the three drugs on MDA-MB-231 cells were determined in vitro utilizing the Chou-Talalay method. MDA-MB-231 cells were identified for migration, invasion and adhesion in vitro through the implementation of the scratch assay, transwell assay and adhesion assay, respectively. The formation of cytoskeleton protein F-actin was detected by immunofluorescence assay. The expressions of MMP-2 and MMP-9 in the supernatant of the cells were determined by ELISA analysis. The Western blot and RT-qPCR were employed to explore the protein expressions associated with the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. The anti-tumor efficacy of ZDF in vivo and its preliminary mechanism were investigated in the mouse 4T1 TNBC model. RESULTS: The results demonstrated that ZDF could significantly reduce the viability of the MDA-MB-231 cell, and the combination index (CI) values of actual compatibility experimental points were all less than 1, demonstrating a favorable synergistic compatibility relationship. It was found that ZDF reduces RhoA/ROCK and CDC42/MRCK dual signaling pathways, which are responsible for MDA-MB-231cell migration, invasion, and adhesion. Additionally, there has been a significant reduction in the manifestation of cytoskeleton-related proteins. Furthermore, the expression levels of RhoA, CDC42, ROCK2, and MRCKß mRNA and protein were down-regulated. ZDF significantly decreased the protein expressions of vimentin, cytokeratin-8, Arp2 and N-WASP, and inhibited actin polymerization and actomyosin contraction. Furthermore, MMP-2 and MMP-9 levels in the high-dose ZDF group were decreased by 30% and 26%, respectively. ZDF significantly reduced the tumor volume and protein expressions of ROCK2 and MRCKß in tumor tissues without eliciting any perceptible alterations in the physical mass of the mice, and the reduction was more pronounced than that of the BDP5290 treated group. CONCLUSION: The current investigation demonstrates that ZDF exhibits a proficient inhibitory impact on TNBC metastasis by regulating cytoskeletal proteins through the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. Furthermore, the findings indicate that ZDF has significant anti-tumorigenic and anti-metastatic characteristics in breast cancer animal models.


Assuntos
Medicina Tradicional Chinesa , Miotonina Proteína Quinase , Invasividade Neoplásica , Paclitaxel , Transdução de Sinais , Neoplasias de Mama Triplo Negativas , Quinases Associadas a rho , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Miotonina Proteína Quinase/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Etnofarmacologia , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Células MDA-MB-231 , Adesão Celular/efeitos dos fármacos , Humanos , Animais , Camundongos , Metástase Neoplásica/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Sinergismo Farmacológico , Metaloproteinases da Matriz/metabolismo , Actinas/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos
8.
J Biol Chem ; 299(1): 102788, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36509146

RESUMO

Mechanistic target of rapamycin (mTOR) is a protein kinase that integrates multiple inputs to regulate anabolic cellular processes. For example, mTOR complex 1 (mTORC1) has key functions in growth control, autophagy, and metabolism. However, much less is known about the signaling components that act downstream of mTORC1 to regulate cellular morphogenesis. Here, we show that the RNA-binding protein Unkempt, a key regulator of cellular morphogenesis, is a novel substrate of mTORC1. We show that Unkempt phosphorylation is regulated by nutrient levels and growth factors via mTORC1. To analyze Unkempt phosphorylation, we immunoprecipitated Unkempt from cells in the presence or the absence of the mTORC1 inhibitor rapamycin and used mass spectrometry to identify mTORC1-dependent phosphorylated residues. This analysis showed that mTORC1-dependent phosphorylation is concentrated in a serine-rich intrinsically disordered region in the C-terminal half of Unkempt. We also found that Unkempt physically interacts with and is directly phosphorylated by mTORC1 through binding to the regulatory-associated protein of mTOR, Raptor. Furthermore, analysis in the developing brain of mice lacking TSC1 expression showed that phosphorylation of Unkempt is mTORC1 dependent in vivo. Finally, mutation analysis of key serine/threonine residues in the serine-rich region indicates that phosphorylation inhibits the ability of Unkempt to induce a bipolar morphology. Phosphorylation within this serine-rich region thus profoundly affects the ability of Unkempt to regulate cellular morphogenesis. Taken together, our findings reveal a novel molecular link between mTORC1 signaling and cellular morphogenesis.


Assuntos
Proteínas de Transporte , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteína Regulatória Associada a mTOR , Serina-Treonina Quinases TOR , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Morfogênese , Fosforilação , Serina/metabolismo , Sirolimo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Processos de Crescimento Celular , Proteínas de Transporte/metabolismo
9.
Front Immunol ; 13: 1061959, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569860

RESUMO

NK cells are innate lymphocytes involved in a large variety of contexts and are crucial in the immunity to intracellular pathogens as well as cancer due to their ability to kill infected or malignant cells. Thus, they harbor a strong potential for clinical and therapeutic use. NK cells do not require antigen exposure to get activated; their functional response is rather based on a balance between inhibitory/activating signals and on the diversity of germline-encoded receptors they express. In order to reach optimal functional status, NK cells go through a step-wise development in the bone marrow before their egress, and dissemination into peripheral organs via the circulation. In this review, we summarize bone marrow NK cell developmental stages and list key factors involved in their differentiation before presenting newly discovered and emerging factors that regulate NK cell central and peripheral maturation. Lastly, we focus on the impact inflammatory contexts themselves can have on NK cell development and functional maturation.


Assuntos
Células Matadoras Naturais , Diferenciação Celular , Processos de Crescimento Celular
10.
Front Immunol ; 13: 1075675, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36544777

RESUMO

Introduction: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a rare autoimmune disease, and the peripheral immune characteristics associated with anti-NMDARE antibodies remain unclear. Methods: Herein, we characterized peripheral blood mononuclear cells from patients with anti-NMDARE and healthy individuals by single-cell RNA sequencing (scRNA-seq). Results: The transcriptional profiles of 129,217 cells were assessed, and 21 major cell clusters were identified. B-cell activation and differentiation, plasma cell expansion, and excessive inflammatory responses in innate immunity were all identified. Patients with anti-NMDARE showed higher expression levels of CXCL8, IL1B, IL6, TNF, TNFSF13, TNFSF13B, and NLRP3. We observed that anti-NMDARE patients in the acute phase expressed high levels of DC_CCR7 in human myeloid cells. Moreover, we observed that anti-NMDARE effects include oligoclonal expansions in response to immunizing agents. Strong humoral immunity and positive regulation of lymphocyte activation were observed in acute stage anti-NMDARE patients. Discussion: This high-dimensional single-cell profiling of the peripheral immune microenvironment suggests that potential mechanisms are involved in the pathogenesis and recovery of anti-NMDAREs.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Humanos , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Leucócitos Mononucleares , Transcriptoma , Processos de Crescimento Celular , Imunidade Humoral , Microambiente Tumoral
11.
Mol Med Rep ; 26(2)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35775372

RESUMO

Under aerobic conditions, the preferential use of anaerobic glycolysis by tumour cells leads to a high level of lactate accumulation in tumour microenvironment. Lactate acts not only as a cellular energy source but also as a signalling molecule that regulates cancer cell growth, metastasis and metabolism. It has been reported that a G­protein­coupled receptor for lactate named hydroxycarboxylic acid receptor 1 (HCAR1) is highly expressed in numerous types of cancer, but the detailed mechanism remains unclear. In the present study, it was reported that HCAR1 is highly expressed in breast cancer cells. Genetic deletion of HCAR1 in MCF7 cells leads to reduced cell proliferation and migration. Moreover, it was observed that knockout (KO) of HCAR1 attenuated the expression and activity of phosphofructokinase and hexokinase, key rate­limiting enzymes in glycolysis. Using an extracellular flux analyzer, it was showed that KO of HCAR1 promoted a metabolic shift towards a decreased glycolysis state, as evidenced by a decreased extracellular acidification rate and increased oxygen consumption rate in MCF7 cells. Taken together, our results suggested that lactate acts through HCAR1 as a metabolic regulator in breast cancer cells that may be therapeutically exploited.


Assuntos
Neoplasias da Mama , Receptores Acoplados a Proteínas G , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Metabolismo Energético , Feminino , Glicólise , Humanos , Ácido Láctico/metabolismo , Células MCF-7 , Metástase Neoplásica , Receptores Acoplados a Proteínas G/metabolismo , Microambiente Tumoral
12.
Int J Mol Sci ; 23(13)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35806446

RESUMO

It has been proven that tumour growth and progression are regulated by a variety of mediators released during the inflammatory process preceding the tumour appearance, but the role of inflammation in the development of bladder cancer is ambiguous. This study was designed around the hypothesis that sphingosine-1-phosphate (S1P), as a regulator of several cellular processes important in both inflammation and cancer development, may exert some of the pro-tumorigenic effects indirectly due to its ability to regulate the expression of human cathelicidin (hCAP-18). LL-37 peptide released from hCAP-18 is involved in the development of various types of cancer in humans, especially those associated with infections. Using immunohistological staining, we showed high expression of hCAP-18/LL-37 and sphingosine kinase 1 (the enzyme that forms S1P from sphingosine) in human bladder cancer cells. In a cell culture model, S1P was able to stimulate the expression and release of hCAP-18/LL-37 from human bladder cells, and the addition of LL-37 peptide dose-dependently increased their proliferation. Additionally, the effect of S1P on LL-37 release was inhibited in the presence of FTY720P, a synthetic immunosuppressant that blocks S1P receptors. Together, this study presents the possibility of paracrine relation in which LL-37 production following cell stimulation by S1P promotes the development and growth of bladder cancer.


Assuntos
Peptídeos Catiônicos Antimicrobianos , Lisofosfolipídeos , Esfingosina , Neoplasias da Bexiga Urinária , Peptídeos Catiônicos Antimicrobianos/metabolismo , Processos de Crescimento Celular/fisiologia , Humanos , Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Catelicidinas
13.
Bull Exp Biol Med ; 173(2): 240-245, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35737152

RESUMO

This study aims to understand the molecular basis of manganese superoxide dismutase (MnSOD) impacts on breast cancer cell growth. Modulation of the level of MnSOD by genetic engineering led significant changes in the expression of angiopoietin-like protein 4 (ANGPTL4) and activity of peroxisome proliferator-activated receptor α (PPARα) in MCF7 cells. PPARα agonist increased ANGPTL4 expression inhibited by MnSOD. Proliferation of MCF7 cells was inhibited by MnSOD, however, ANGPTL4 transduction into MCF7 cells with MnSOD overexpression significantly stimulated cell proliferation. MnSOD induced G0/G1 cell cycle arrest, nevertheless, ANGPTL4 transduction significantly reduced the percentage of cells in G0/G1 phase overexpressing MnSOD. In conclusion, MnSOD suppressed the expression of ANGPTL4 in breast cancer cells via the PPARα signaling pathway, and ANGPTL4 was involved in MnSOD-mediated proliferation inhibition and cell cycle arrest.


Assuntos
Angiopoietina-1 , Neoplasias da Mama , Superóxido Dismutase , Angiopoietina-1/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Processos de Crescimento Celular , Feminino , Humanos , PPAR alfa/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo
14.
Biochem Biophys Res Commun ; 608: 52-58, 2022 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-35390672

RESUMO

Sialylation, the final stage of post-translational modification of proteins, is achieved in the Golgi apparatus and is related to the malignant phenotype of cancer. Disialylation of ganglioside (GD3) by St8sia1 and polysialylation by St8sia2 and 4 have been shown to be related to malignant phenotypes; however, di/oligosialylation by St8sia6 is still unknown. In this study, we analyzed the malignant phenotype of St8sia6 and found that upregulation of St8sia6 in melanoma B16 cells increased anchorage-independent cell growth, which was not due to sialic acid cleavage by a sialidase. Moreover, unlike other sialyltransferases, St8sia6 localized to the endoplasmic reticulum (ER). We found that the localization to the Golgi apparatus could be regulated by swapping experiments using St8sia2; however, the malignant phenotype did not change. These data demonstrate that the enhancement of anchorage-independent cell growth by St8sia6 is not due to its localization of ER, but is due to the expression of the protein itself.


Assuntos
Retículo Endoplasmático , Neoplasias , Sialiltransferases , Processos de Crescimento Celular , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/metabolismo , Gangliosídeos/metabolismo , Complexo de Golgi/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Sialiltransferases/metabolismo
15.
Aging (Albany NY) ; 14(3): 1068-1086, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35158337

RESUMO

Radiation therapy is a commonly used treatment modality for cancer. Although effective in providing local tumor control, radiation causes oxidative stress, inflammation, immunomodulatory and mitogenic cytokine production, extracellular matrix production, and premature senescence in lung parenchyma. The senescence associated secretory phenotype (SASP) can promote inflammation and stimulate alterations in the surrounding tissue. Therefore, we hypothesized that radiation-induced senescent parenchymal cells in irradiated lung would enhance tumor growth. Using a murine syngeneic tumor model of melanoma and non-small cell lung cancer lung metastasis, we demonstrate that radiation causes a significant increase in markers of premature senescence in lung parenchyma within 4 to 8 weeks. Further, injection of B16F0 (melanoma) or Lewis Lung carcinoma (epidermoid lung cancer) cells at these time points after radiation results in an increase in the number and size of pulmonary tumor nodules relative to unirradiated mice. Treatment of irradiated mice with a senolytic agent (ABT-737) or agents that prevent senescence (rapamycin, INK-128) was sufficient to reduce radiation-induced lung parenchymal senescence and to mitigate radiation-enhanced tumor growth. These agents abrogated radiation-induced expression of 12-Lipoxygenase (12-LOX), a molecule implicated in several deleterious effects of senescence. Deficiency of 12-LOX prevented radiation-enhanced tumor growth. Together, these data demonstrate the pro-tumorigenic role of radiation-induced senescence, introduces the dual TORC inhibitor INK-128 as an effective agent for prevention of radiation-induced normal tissue senescence, and identifies senescence-associated 12-LOX activity as an important component of the pro-tumorigenic irradiated tissue microenvironment. These studies suggest that combining senotherapeutic agents with radiotherapy may decrease post-therapy tumor growth.


Assuntos
Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Melanoma Experimental , Animais , Araquidonato 12-Lipoxigenase/farmacologia , Carcinoma Pulmonar de Lewis/enzimologia , Carcinoma Pulmonar de Lewis/patologia , Processos de Crescimento Celular , Senescência Celular , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos , Microambiente Tumoral
16.
BMC Cancer ; 22(1): 105, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35078427

RESUMO

BACKGROUND: Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state. METHODS: To unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with a specific focus on AMPK, mTORC, and their modulators. Specifically, we constructed an ordinary differential equation-based mechanistic model of AMPK-mTORC signaling, and parametrized the model based on existing experimental data. RESULTS: Model simulations were conducted to yield the following predictions: (i) increasing AMPK activity has opposite effects on mTORC depending on the nutrient availability; (ii) indirect inhibition of AMPK activity through inhibition of sirtuin 1 (SIRT1) only has an effect on mTORC activity under conditions of low nutrient availability; (iii) the balance between cell proliferation and survival exhibits an intricate dependence on DEP domain-containing mTOR-interacting protein (DEPTOR) abundance and AMPK activity; (iv) simultaneous direct inhibition of mTORC2 and activation of AMPK is a potential strategy for suppressing both cell survival and proliferation. CONCLUSIONS: Taken together, model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Carcinogênese/metabolismo , Neoplasias/enzimologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Processos de Crescimento Celular , Proliferação de Células , Simulação por Computador , Metabolismo Energético , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
17.
BMC Cancer ; 22(1): 100, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35073851

RESUMO

BACKGROUND: Platinum chemoresistance results in high-grade serous ovarian cancer (HGSOC) disease recurrence. Recent treatment advances using checkpoint inhibitor immunotherapy has not benefited platinum-resistant HGSOC. In ovarian cancer, DNA methyltransferase inhibitors (DNMTi) block methylation and allow expression of silenced genes, primarily affecting immune reactivation pathways. We aimed to determine the epigenome and transcriptome response to sequential treatment with DNMTi and carboplatin in HGSOC. METHODS: In vitro studies with azacitidine or carboplatin alone and in sequential combination. Response was determined by cell growth, death and apoptosis. Genome-wide DNA methylation levels and transcript expression were compared between untreated and azacitidine and carboplatin sequential treatment. RESULTS: Sequential azacitidine and carboplatin significantly slowed cell growth in 50% of cell lines compared to carboplatin alone. The combination resulted in significantly higher cell death in 25% of cell lines, and significantly higher cell apoptosis in 37.5% of cell lines, than carboplatin alone. Pathway analysis of upregulated transcripts showed that the majority of changes were in immune-related pathways, including those regulating response to checkpoint inhibitors. CONCLUSIONS: Sequential azacitidine and carboplatin treatment slows cell growth, and demethylate and upregulate pathways involved in immune response, suggesting that this combination may be used to increase HGSOC response to immune checkpoint inhibitors in platinum-resistant patients who have exhausted all currently-approved avenues of treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Azacitidina/administração & dosagem , Carboplatina/administração & dosagem , Imunidade/efeitos dos fármacos , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/imunologia , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
18.
Cancer Control ; 29: 10732748211068963, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35043700

RESUMO

The possible role of the naturally occurring deuterium in the regulation of cell division was first described in the 1990s. To investigate the mechanism of influence of deuterium (D) on cell growth, expression of 236 cancer-related and 536 kinase genes were tested in deuterium-depleted (40 and 80 ppm) and deuterium-enriched (300 ppm) media compared to natural D level (150 ppm). Among genes with expression changes exceeding 30% and copy numbers over 30 (124 and 135 genes, respectively) 97.3% of them was upregulated at 300 ppm D-concentration. In mice exposed to chemical carcinogen, one-year survival data showed that deuterium-depleted water (DDW) with 30 ppm D as drinking water prevented tumor development. One quarter of the treated male mice survived 344 days, the females 334 days, while one quarter of the control mice survived only 188 and 156 days, respectively. In our human retrospective study 204 previously treated cancer patients with disease in remission, who consumed DDW, were followed. Cumulative follow-up time was 1024 years, and average follow-up time per patient, 5 years (median: 3.6 years). One hundred and fifty-six patients out of 204 (77.9%) did not relapse during their 803 years cumulative follow-up time. Median survival time (MST) was not calculable due to the extremely low death rate (11 cancer-related deaths, 5.4% of the study population). Importantly, 8 out of 11 deaths occurred several years after stopping DDW consumption, confirming that regular consumption of DDW can prevent recurrence of cancer. These findings point to the likely mechanism in which consumption of DDW keeps D-concentration below natural levels, preventing the D/H ratio from increasing to the threshold required for cell division. This in turn can serve as a key to reduce the relapse rate of cancer patients and/or to reduce cancer incidence in healthy populations.


Assuntos
Deutério/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Recidiva Local de Neoplasia/genética , Neoplasias/genética , Água/administração & dosagem , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Variações do Número de Cópias de DNA/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia/prevenção & controle , Estudos Retrospectivos , Água/química
19.
Immunol Lett ; 241: 35-48, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34890699

RESUMO

Cancer is known to have systemic impact by targeting various organs that ultimately compromises the overall physiology of the host. Several reports have demonstrated the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, their role in mediating systemic effects during cancer progression has not been deciphered so far. Therefore, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern their systemic role, we evaluated neutrophil count and function at different stages of tumor growth in Dalton's Lymphoma mice model. Notably, our results displayed a gradual increase in Ly6G+ neutrophils in peripheral blood and their infiltration in vital organs including liver, lungs, spleen, kidney, lymph nodes and peritoneum of tumor bearing host. We showed remarkable alterations in histoarchitecture and serum enzyme levels that aggravated with tumor progression. We next examined neutrophil function by assessing its granular cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), and matrix metalloproteinases (MMP-8 and MMP-9). Interestingly, blood neutrophils of tumor bearing mice exhibited a marked change in morphology with gradual increase in NE and MPO expression with tumor growth. In addition, we observed upregulated expression of NE, MPO, MMP-8 and MMP-9 in the vital organs of tumor bearing host. Taken together, our results demonstrate heightened infiltration and function of neutrophils in vital organs of tumor bearing host which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.


Assuntos
Elastase de Leucócito/metabolismo , Linfoma/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Neutrófilos/fisiologia , Peroxidase/metabolismo , Animais , Processos de Crescimento Celular , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais , Ativação de Neutrófilo
20.
Explore (NY) ; 18(2): 205-209, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33341371

RESUMO

OBJECTIVE: Mitochondria are considered a portal to receive, process and integrate external energy and information to maintain cellular homeostasis. We examined the effect of Chinese texts with positive and negative meaning on the growth and mitochondrial functions using a mouse kidney collecting duct cell line called M1 cells. METHODS: To avoid skewing the results due to differential handling of the cells or analyzing the results, we conducted experiments by keeping the texts and blanks covered in brown opaque envelopes, exposed the cells to randomly selected envelopes and examined the differences over time. All operators involved in the experiments did not know the contents of the envelopes until the end of the experiments, and all data are expressed relative to the controls. RESULTS: Cell growth rate was not affected for the group treated with positive information but was significantly reduced by 18% when treated with negative information. At the biochemical level, positive texts significantly increased whole cell adenosine triphosphate (ATP) and glutathione (GSH) by 22% and 21% respectively. CONCLUSIONS: This study for the first time demonstrated the effect of written words on specific biochemical measures in cultured mammalian cells.


Assuntos
Atitude , Viés , Processos de Crescimento Celular , Mitocôndrias , Trifosfato de Adenosina/análise , Trifosfato de Adenosina/metabolismo , Animais , Povo Asiático , Pesquisa Biomédica , Processos de Crescimento Celular/fisiologia , Linhagem Celular , Glutationa/análise , Glutationa/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Redação
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