RESUMO
Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.
Assuntos
Glutamina/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias/metabolismo , Sirtuínas/metabolismo , Fatores Ativadores da Transcrição/metabolismo , Animais , Proliferação de Células , Embrião de Mamíferos/citologia , Metabolismo Energético , Glutamato Desidrogenase/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos , Transplante de Neoplasias , Neoplasias/patologia , Serina-Treonina Quinases TOR/metabolismo , Transcrição Gênica , Transplante Heterólogo , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , UbiquitinaçãoRESUMO
A spectral image analysis has the potential to replace traditional approaches for assessing plant responses to different types of stresses, including herbicides, through non-destructive and high-throughput screening (HTS). Therefore, this study was conducted to develop a rapid bioassay method using a multi-well plate and spectral image analysis for the diagnosis of herbicide activity and modes of action. Crabgrass (Digitaria ciliaris), as a model weed, was cultivated in multi-well plates and subsequently treated with six herbicides (paraquat, tiafenacil, penoxsulam, isoxaflutole, glufosinate, and glyphosate) with different modes of action when the crabgrass reached the 1-leaf stage, using only a quarter of the recommended dose. To detect the plant's response to herbicides, plant spectral images were acquired after herbicide treatment using RGB, infrared (IR) thermal, and chlorophyll fluorescence (CF) sensors and analyzed for diagnosing herbicide efficacy and modes of action. A principal component analysis (PCA), using all spectral data, successfully distinguished herbicides and clustered depending on their modes of action. The performed experiments showed that the multi-well plate assay combined with a spectral image analysis can be successfully applied for herbicide bioassays. In addition, the use of spectral image sensors, especially CF images, would facilitate HTS by enabling the rapid observation of herbicide responses at as early as 3 h after herbicide treatment.
Assuntos
Herbicidas , Herbicidas/farmacologia , Plantas , Glifosato , Bioensaio , Plantas DaninhasRESUMO
Patients suffering from Parkinson's disease suffer from voice impairment. In this study, we introduce models to classify normal and Parkinson's patients using their speech. We used an AST (audio spectrogram transformer), a transformer-based speech classification model that has recently outperformed CNN-based models in many fields, and a CNN-based PSLA (pretraining, sampling, labeling, and aggregation), a high-performance model in the existing speech classification field, for the study. This study compares and analyzes the models from both quantitative and qualitative perspectives. First, qualitatively, PSLA outperformed AST by more than 4% in accuracy, and the AUC was also higher, with 94.16% for AST and 97.43% for PSLA. Furthermore, we qualitatively evaluated the ability of the models to capture the acoustic features of Parkinson's through various CAM (class activation map)-based XAI (eXplainable AI) models such as GradCAM and EigenCAM. Based on PSLA, we found that the model focuses well on the muffled frequency band of Parkinson's speech, and the heatmap analysis of false positives and false negatives shows that the speech features are also visually represented when the model actually makes incorrect predictions. The contribution of this paper is that we not only found a suitable model for diagnosing Parkinson's through speech using two different types of models but also validated the predictions of the model in practice.
Assuntos
Doença de Parkinson , Fala , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/classificação , Doença de Parkinson/fisiopatologia , Fala/fisiologia , Masculino , Feminino , Espectrografia do Som/métodos , Reprodutibilidade dos Testes , Redes Neurais de Computação , Idoso , Pessoa de Meia-IdadeRESUMO
Metastasis is one of the most malignant characteristics of cancer cells, in which metabolic reprogramming is crucial for promoting and sustaining multi-steps of metastasis, including invasion, migration and infiltration. Recently, it has been shown that melanoma cells undergo a metabolic switching toward the upregulation of fatty acid oxidation (FAO) during metastasis. However, the underlying mechanisms by which FAO contributes to metastasis of melanoma cells remain obscure. Here, we report that FAO contributes to melanoma cell migration and invasion by regulating the formation of autophagosomes. Pharmacological or genetic inhibition of FAO impairs migration of melanoma cells, which seems not to be linked to energy production or redox homeostasis. Importantly, we reveal that acetyl-CoA production by FAO contributes to melanoma cell migration through autophagy regulation. Mechanistically, FAO inhibition results in increased autophagosome formation, which suppresses migration and invasion properties of melanoma cells. Our results underscore the crucial role of FAO in melanoma cell migration and support the potential therapeutic relevance of modulating cellular acetyl-CoA levels to inhibit cancer metastasis.
Assuntos
Melanoma , Humanos , Acetilcoenzima A/metabolismo , Melanoma/metabolismo , Oxirredução , Movimento Celular/fisiologia , Autofagia , Ácidos Graxos/metabolismoRESUMO
Metastasis remains the leading cause of cancer mortality, and reactive oxygen species (ROS) signaling promotes the metastatic cascade. However, the molecular pathways that control ROS signaling relevant to metastasis are little studied. Here, we identify SIRT3, a mitochondrial deacetylase, as a regulator of cell migration via its control of ROS signaling. We find that, although mitochondria are present at the leading edge of migrating cells, SIRT3 expression is down-regulated during migration, resulting in elevated ROS levels. This SIRT3-mediated control of ROS represses Src oxidation and attenuates focal adhesion kinase (FAK) activation. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells. Finally, in human breast cancers, SIRT3 expression is inversely correlated with metastatic outcome and Src/FAK signaling. Our results reveal a role for SIRT3 in cell migration, with important implications for breast cancer progression.
Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular , Células Epiteliais/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Proteínas de Neoplasias/metabolismo , Sirtuína 3/biossíntese , Quinases da Família src/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ativação Enzimática , Células Epiteliais/patologia , Feminino , Humanos , Metástase Neoplásica , Espécies Reativas de Oxigênio , Sirtuína 3/metabolismoRESUMO
Glucagon is a peptide hormone generated by pancreatic α cells. It is the counterpart of insulin and plays an essential role in the regulation of blood glucose level. Therefore, a tight regulation of glucagon levels is pivotal to maintain homeostasis of blood glucose. However, little is known about the mechanisms regulating glucagon biosynthesis. In this study, we demonstrate that the RNA-binding protein HuD regulates glucagon expression in pancreatic α cells. HuD was found in α cells from mouse pancreatic islet and mouse glucagonoma αTC1 cell line. Ribonucleoprotein immunoprecipitation analysis, followed by RT-qPCR showed the association of HuD with glucagon mRNA. Knockdown of HuD resulted in a reduction in both proglucagon expression and cellular glucagon level by decreasing its de novo synthesis. Reporter analysis using the EGFP reporter containing 3' untranslated region (3'UTR) of glucagon mRNA showed that HuD regulates proglucagon expression via its 3'UTR. In addition, the relative level of glucagon in the islets and plasma was lower in HuD knockout (KO) mice compared to age-matched control mice. Taken together, these results suggest that HuD is a novel factor regulating the biosynthesis of proglucagon in pancreatic α cells.
Assuntos
Proteína Semelhante a ELAV 4/metabolismo , Células Secretoras de Glucagon/metabolismo , Proglucagon/metabolismo , Animais , Vias Biossintéticas , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo , Proteína Semelhante a ELAV 4/genética , Técnicas de Silenciamento de Genes , Células Secretoras de Glucagon/citologia , Camundongos , Proglucagon/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Contact inhibition (CI) is an important tumor-suppressive mechanism that arrests cell cycle when cells reach high density. Indeed, CI is aberrantly absent in cancer cells and the dysregulation of this can contribute to tumorigenesis. Previously, it has been shown that reactive oxygen species (ROS) levels are repressed at high cell density, which is required for CI, but no molecular mechanism of this ROS regulation has been reported. Here, we show that PGC1α regulates cell density-dependent CI. PGC1α is markedly induced in response to high cell density and suppresses ROS production. Although cellular ROS levels are progressively decreased with increasing cell density, knockdown of PGC1α results in a defect of density-dependent ROS suppression. Importantly, PGC1α knockdown cells become less sensitive to high cell density and exhibit loss of CI. Mechanistically, PGC1α represses ROS production by inducing mitochondrial SIRT3, and thus SIRT3 overexpression rescues the defects of CI by PGC1α knockdown. These results demonstrate that mitochondrial ROS production is a crucial regulator of cell proliferation and identify a new role of PGC1α in CI.
Assuntos
Proliferação de Células , Inibição de Contato , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Contagem de Células , Linhagem Celular , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genéticaRESUMO
The transferrin receptor (TfR1) is upregulated in malignant cells and its expression is associated with cancer progression. Because of its pre-eminent role in cell proliferation, TfR1 has been an important target for the development of cancer therapy. Although TfR1 is highly expressed in pancreatic cancers, what it carries out in these refractory cancers remains poorly understood. Here we report that TfR1 supports mitochondrial respiration and ROS production in human pancreatic ductal adenocarcinoma (PDAC) cells, which is required for their tumorigenic growth. Elevated TfR1 expression in PDAC cells contributes to oxidative phosphorylation, which allows for the generation of ROS. Importantly, mitochondrial-derived ROS are essential for PDAC growth. However, exogenous iron supplement cannot rescue the defects caused by TfR1 knockdown. Moreover, we found that TfR1 expression determines PDAC cells sensitivity to oxidative stress. Together, our findings reveal that TfR1 can contribute to the mitochondrial respiration and ROS production, which have essential roles in growth and survival of pancreatic cancer.
Assuntos
Antígenos CD/metabolismo , Mitocôndrias/metabolismo , Oxigênio/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores da Transferrina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Humanos , Estresse OxidativoRESUMO
Cellular stresses initiate well-coordinated signaling response pathways. As the proper regulation of stress is essential for cellular homeostasis, the defects of stress response pathways result in functional deficits and cell death. Although mitochondrial SIRT4 has been shown to be involved in cellular stress response and tumor suppression, its roles in survival and drug resistance of cancer cells are not well determined. Here we show that SIRT4 is a crucial regulator of the stress resistance of cancer cells. SIRT4 is highly induced by various cellular stresses and contributes to cell survival and growth after stresses. SIRT4 loss sensitizes cells to DNA damage or ER stress. Moreover, SIRT4 induction is required for tumorigenic transformation, as SIRT4 null cells are vulnerable to oncogene activation. Thus, these results suggest that SIRT4 has essential roles in stress resistance and may be an important therapeutic target for cancer treatment.
Assuntos
Dano ao DNA , Reparo do DNA , Estresse do Retículo Endoplasmático , Proteínas Mitocondriais/metabolismo , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Sirtuínas/metabolismo , Proliferação de Células , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , HumanosRESUMO
Glutamine metabolism plays an essential role for growth and proliferation of many cancer cells by providing metabolites for the maintenance of mitochondrial functions and macromolecular synthesis. Aberrant activation of the transcription factor c-Myc, e.g. caused by t(8;14) chromosomal translocation commonly found in Burkitt lymphoma, is a key driver of cellular glutamine metabolism in many tumors, highlighting the need to identify molecular mechanisms that can suppress glutamine usage in these cancers. Recently, the mitochondrial sirtuin SIRT4 has been reported to function as a tumor suppressor by regulating glutamine metabolism, suggesting that it might have therapeutic potential for treating glutamine-dependent cancers. Here, we report that SIRT4 represses Myc-induced B cell lymphomagenesis via inhibition of mitochondrial glutamine metabolism. We found that SIRT4 overexpression can dampen glutamine utilization even in Myc-driven human Burkitt lymphoma cells and inhibit glutamine-dependent proliferation of these cells. Importantly, SIRT4 overexpression sensitizes Burkitt lymphoma cells to glucose depletion and synergizes with pharmacological glycolysis inhibitors to induce cell death. Moreover, SIRT4 loss in a genetic mouse model of Myc-induced Burkitt lymphoma, Eµ-Myc transgenic mouse, greatly accelerates lymphomagenesis and mortality. Indeed, Eµ-Myc-induced B cell lymphoma cells from SIRT4 null mice exhibit increased glutamine uptake and glutamate dehydrogenase activity. Furthermore, we establish that SIRT4 regulates glutamine metabolism independent of Myc. Together, these results highlight the tumor-suppressive role of SIRT4 in Myc-induced B cell lymphoma and suggest that SIRT4 may be a potential target against Myc-induced and/or glutamine-dependent cancers.
Assuntos
Linfoma de Burkitt/metabolismo , Proteínas Mitocondriais/metabolismo , Modelos Genéticos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sirtuínas/metabolismo , Animais , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Linfoma de Burkitt/terapia , Linhagem Celular Tumoral , Feminino , Glucose/genética , Glucose/metabolismo , Glutamato Desidrogenase/genética , Glutamato Desidrogenase/metabolismo , Glutamina/genética , Glutamina/metabolismo , Glicólise/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Proteínas Proto-Oncogênicas c-myc/genética , Sirtuínas/genéticaRESUMO
Metabolic aberrations, notably deviations in glutamine metabolism, are crucial in the oncogenic process, offering vital resources for the unlimited proliferation and enhanced survival capabilities of cancer cells. The dependency of malignant cells on glutamine metabolism has led to the proposition of targeted therapeutic strategies. However, the capability of cancer cells to initiate adaptive responses undermines the efficacy of these therapeutic interventions. This review meticulously examines the multifaceted adaptive mechanisms that cancer cells deploy to sustain survival and growth following the disruption of glutamine metabolism. Emphasis is placed on the roles of transcription factors, alterations in metabolic pathways, the mechanistic target of rapamycin complex 1 signaling axis, autophagy, macropinocytosis, nucleotide biosynthesis, and the scavenging of ROS. Thus, the delineation and subsequent targeting of these adaptive responses in the context of therapies aimed at glutamine metabolism offer a promising avenue for circumventing drug resistance in cancer treatment.
Assuntos
Glutamina , Neoplasias , Humanos , Glutamina/metabolismo , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/patologia , Autofagia , Animais , Transdução de SinaisRESUMO
Senescent cells exhibit a diverse spectrum of changes in their morphology, proliferative capacity, senescence-associated secretory phenotype (SASP) production, and mitochondrial homeostasis. These cells often manifest with elongated mitochondria, a hallmark of cellular senescence. However, the precise regulatory mechanisms orchestrating this phenomenon remain predominantly unexplored. In this study, we provide compelling evidence for decreases in TIA-1, a pivotal regulator of mitochondrial dynamics, in models of both replicative senescence and ionizing radiation (IR)-induced senescence. The downregulation of TIA-1 was determined to trigger mitochondrial elongation and enhance the expression of senescence-associated ß-galactosidase, a marker of cellular senescence, in human foreskin fibroblast HS27 cells and human keratinocyte HaCaT cells. Conversely, the overexpression of TIA-1 mitigated IR-induced cellular senescence. Notably, we identified the miR-30-5p family as a novel factor regulating TIA-1 expression. Augmented expression of the miR-30-5p family was responsible for driving mitochondrial elongation and promoting cellular senescence in response to IR. Taken together, our findings underscore the significance of the miR-30-5p/TIA-1 axis in governing mitochondrial dynamics and cellular senescence.
Assuntos
Senescência Celular , MicroRNAs , Mitocôndrias , Dinâmica Mitocondrial , Antígeno-1 Intracelular de Células T , Humanos , MicroRNAs/metabolismo , MicroRNAs/genética , Senescência Celular/efeitos da radiação , Senescência Celular/genética , Dinâmica Mitocondrial/genética , Antígeno-1 Intracelular de Células T/metabolismo , Antígeno-1 Intracelular de Células T/genética , Mitocôndrias/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Linhagem Celular , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Queratinócitos/citologia , Transdução de Sinais , Radiação IonizanteRESUMO
The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor α (PPARα), accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.
Assuntos
Ácidos Graxos , PPAR alfa , Camundongos , Animais , Humanos , Oxirredução , Ácidos Graxos/metabolismo , PPAR alfa/metabolismo , Camundongos Obesos , Resistencia a Medicamentos Antineoplásicos , Obesidade/metabolismo , Morte CelularRESUMO
Senescence, a cellular process through which damaged or dysfunctional cells suppress the cell cycle, contributes to aging or age-related functional decline. Cell metabolism has been closely correlated with aging processes, and it has been widely recognized that metabolic changes underlie the cellular alterations that occur with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We found that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, increased formation of autophagosomes following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we found that inhibition of autophagy or enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence. [BMB Reports 2023; 56(12): 651-656].
Assuntos
Senescência Celular , Sirtuína 1 , Humanos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Senescência Celular/fisiologia , Envelhecimento/metabolismo , Autofagia , Ácidos GraxosRESUMO
Proliferating cells have metabolic dependence on glutamine to fuel anabolic pathways and to refill the mitochondrial carbon pool. The Hippo pathway is essential for coordinating cell survival and growth with nutrient availability, but no molecular connection to glutamine deprivation has been reported. Here, we identify a non-canonical role of YAP, a key effector of the Hippo pathway, in cellular adaptation to perturbation of glutamine metabolism. Whereas YAP is inhibited by nutrient scarcity, enabling cells to restrain proliferation and to maintain energy homeostasis, glutamine shortage induces a rapid YAP dephosphorylation and activation. Upon glutaminolysis inhibition, an increased reactive oxygen species production inhibits LATS kinase via RhoA, leading to YAP dephosphorylation. Activated YAP promotes transcriptional induction of ATF4 to induce the expression of genes involved in amino acid homeostasis, including Sestrin2. We found that YAP-mediated Sestrin2 induction is crucial for cell viability during glutamine deprivation by suppressing mTORC1. Thus, a critical relationship between YAP, ATF4, and mTORC1 is uncovered by our findings. Finally, our data indicate that targeting the Hippo-YAP pathway in combination with glutaminolysis inhibition may provide potential therapeutic approaches to treat tumors.
Assuntos
Fator 4 Ativador da Transcrição , Glutamina , Humanos , Fator 4 Ativador da Transcrição/metabolismo , Sobrevivência Celular , Homeostase , Alvo Mecanístico do Complexo 1 de Rapamicina , MitocôndriasRESUMO
DNA repair is a tightly coordinated stress response to DNA damage, which is critical for preserving genome integrity. Accruing evidence suggests that metabolic pathways have been correlated with cellular response to DNA damage. Here, we show that fatty acid oxidation (FAO) is a crucial regulator of DNA double-strand break repair, particularly homologous recombination repair. Mechanistically, FAO contributes to DNA repair by activating poly(ADP-ribose) polymerase 1 (PARP1), an enzyme that detects DNA breaks and promotes DNA repair pathway. Upon DNA damage, FAO facilitates PARP1 acetylation by providing acetyl-CoA, which is required for proper PARP1 activity. Indeed, cells reconstituted with PARP1 acetylation mutants display impaired DNA repair and enhanced sensitivity to DNA damage. Consequently, FAO inhibition reduces PARP1 activity, leading to increased genomic instability and decreased cell viability upon DNA damage. Finally, our data indicate that FAO serves as an important participant of cellular response to DNA damage, supporting DNA repair and genome stability.
Assuntos
Reparo do DNA , DNA , Humanos , Acetilação , DNA/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Ácidos GraxosRESUMO
Hypoxia, one of the key features of solid tumors, induces autophagy, which acts as an important adaptive mechanism for tumor progression under hypoxic environment. Cellular metabolic reprogramming has been correlated with hypoxia, but the molecular connection to the induction of autophagy remains obscure. Here, we show that suppression of fatty acid oxidation (FAO) by hypoxia induces autophagy in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for their growth and survival. Reduced cellular acetyl-CoA levels caused by FAO inhibition decreases LC3 acetylation, resulting in autophagosome formation. Importantly, PDAC cells are significantly dependent on this metabolic reprogramming, as improving FAO leads to a reduction in hypoxia-induced autophagy and an increase in cell death after chemotherapy. Thus, our study supports that suppression of FAO is an important metabolic response to hypoxia and indicates that targeting this pathway in PDAC may be an effective therapeutic approach.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Hipóxia , Autofagia , Ácidos Graxos/farmacologia , Ácidos Graxos/uso terapêutico , Neoplasias PancreáticasRESUMO
This study investigates the relationship between cancer cachexia and the gut microbiota, focusing on the influence of cancer on microbial composition. Lewis lung cancer cell allografts were used to induce cachexia in mice, and body and muscle weight changes were monitored. Fecal samples were collected for targeted metabolomic analysis for short chain fatty acids and microbiome analysis. The cachexia group exhibited lower alpha diversity and distinct beta diversity in gut microbiota, compared to the control group. Differential abundance analysis revealed higher Bifidobacterium and Romboutsia, but lower Streptococcus abundance in the cachexia group. Additionally, lower proportions of acetate and butyrate were observed in the cachexia group. The study observed that the impact of cancer cachexia on gut microbiota and their generated metabolites was significant, indicating a host-to-gut microbiota axis. [BMB Reports 2023; 56(7): 404-409].
Assuntos
Microbioma Gastrointestinal , Neoplasias , Animais , Camundongos , Microbioma Gastrointestinal/fisiologia , Caquexia , Modelos Animais de Doenças , Ácidos Graxos Voláteis/análise , Butiratos , Neoplasias/complicaçõesRESUMO
OBJECTIVE: This study investigated the effects of corn silage as a source of microbial inoculant containing antifungal and carboxylesterase-producing bacteria on fermentation, aerobic stability, and nutrient digestibility of fermented total mixed ration (FTMR) with different energy levels. METHODS: Corn silage was used as a bacterial source by ensiling for 72 d with an inoculant mixture of Lactobacillus brevis 5M2 and L. buchneri 6M1 at a 1:1 ratio. The corn silage without or with inoculant (CON vs MIX) was mixed with the other ingredients to formulate for low and high energy diets (LOW vs HIGH) for Hanwoo steers. All diets were ensiled into 20 L mini silo (5 kg) for 40 d in quadruplicate. RESULTS: The MIX diets had lower (p<0.05) acid detergent fiber with higher (p<0.05) in vitro digestibilities of dry matter and neutral detergent fiber compared to the CON diets. In terms of fermentation characteristics, the MIX diets had higher (p<0.05) acetate than the CON diets. The MIX diets had extended (p<0.05) lactic acid bacteria growth at 4 to 7 d of aerobic exposure and showed lower (p<0.05) yeast growth at 7 d of aerobic exposure than the CON diets. In terms of rumen fermentation, the MIX diets had higher (p<0.05) total fermentable fraction and total volatile fatty acid, with lower (p<0.05) pH than those of CON diets. The interaction (p = 0.036) between inoculant and diet level was only found in the immediately fermentable fraction, which inoculant was only effective on LOW diets. CONCLUSION: Application of corn silage with inoculant on FTMR presented an antifungal effect by inhibiting yeast at aerobic exposure and a carboxylesterase effect by improving nutrient digestibility. It also indicated that fermented feedstuffs could be used as microbial source for FTMR. Generally, the interaction between inoculant and diet level had less effect on this FTMR study.