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Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.
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Corteza Auditiva , Ratones , Animales , Corteza Auditiva/metabolismo , Tálamo/fisiología , Neuronas/metabolismo , Cuerpos Geniculados , Interneuronas/fisiología , Parvalbúminas/metabolismoRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000â m for 4â h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Ratones , Masculino , Animales , Trastorno Autístico/genética , Trastorno Autístico/terapia , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/terapia , Núcleo Dorsal del Rafe , Neuronas Serotoninérgicas/fisiología , Hipoxia , Fenotipo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X FrágilRESUMEN
Hereditary spastic paraplegia (HSP) is a severe neurodegenerative movement disorder, the underlying pathophysiology of which remains poorly understood. Mounting evidence has suggested that iron homeostasis dysregulation can lead to motor function impairment. However, whether deficits in iron homeostasis are involved in the pathophysiology of HSP remains unknown. To address this knowledge gap, we focused on parvalbumin-positive (PV+) interneurons, a large category of inhibitory neurons in the central nervous system, which play a critical role in motor regulation. The PV+ interneuron-specific deletion of the gene encoding transferrin receptor 1 (TFR1), a key component of the neuronal iron uptake machinery, induced severe progressive motor deficits in both male and female mice. In addition, we observed skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of HSP-related proteins in male mice with Tfr1 deletion in the PV+ interneurons. These phenotypes were highly consistent with the core clinical features of HSP cases. Furthermore, the effects on motor function induced by Tfr1 ablation in PV+ interneurons were mostly concentrated in the dorsal spinal cord; however, iron repletion partly rescued the motor defects and axon loss seen in both sexes of conditional Tfr1 mutant mice. Our study describes a new mouse model for mechanistic and therapeutic studies relating to HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons and its role in the regulation of motor functions.SIGNIFICANCE STATEMENT Iron is crucial for neuronal functioning. Mounting evidence suggests that iron homeostasis dysregulation can induce motor function deficits. Transferrin receptor 1 (TFR1) is thought to be the key component in neuronal iron uptake. We found that deletion of Tfr1 in parvalbumin-positive (PV+) interneurons in mice induced severe progressive motor deficits, skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of hereditary spastic paraplegia (HSP)-related proteins. These phenotypes were highly consistent with the core clinical features of HSP cases and partly rescued by iron repletion. This study describes a new mouse model for the study of HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons.
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Paraplejía Espástica Hereditaria , Masculino , Femenino , Animales , Ratones , Paraplejía Espástica Hereditaria/genética , Parvalbúminas/metabolismo , Proteínas/genética , Fenotipo , Interneuronas/metabolismo , AtrofiaRESUMEN
Decreased levels of Faecalibacterium prausnitzii (F. prausnitzii), whose supernatant plays an anti-inflammatory effect, are frequently found in inflammatory bowel disease (IBD) patients. However, the anti-inflammatory products in F. prausnitzii supernatant and the mechanism have not been fully investigated. Here we found that F. prausnitzii and F. prausnitzii-derived butyrate were decreased in the intestines of IBD patients. Supplementation with F. prausnitzii supernatant and butyrate could ameliorate colitis in an animal model. Butyrate, but not other substances produced by F. prausnitzii, exerted an anti-inflammatory effect by inhibiting the differentiation of T helper 17 (Th17) cells. The mechanism underlying the anti-inflammatory effects of the butyrate produced by F. prausnitzii involved the enhancement of the acetylation-promoted degradation of c-Myc through histone deacetylase 3 (HDAC3) inhibition. In conclusion, F. prausnitzii produced butyrate to decrease Th17 differentiation and attenuate colitis through inhibiting HDAC3 and c-Myc-related metabolism in T cells. The use of F. prausnitzii may be an effective new approach to decrease the level of Th17 cells in the treatment of inflammatory diseases.
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Antiinflamatorios/farmacología , Butiratos/farmacología , Diferenciación Celular/efectos de los fármacos , Faecalibacterium prausnitzii/metabolismo , Histona Desacetilasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Células Th17/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Butiratos/química , Butiratos/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Faecalibacterium prausnitzii/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Células Th17/citología , Células Th17/metabolismo , Ácido Trinitrobencenosulfónico/administración & dosificaciónRESUMEN
Liver fibrosis is a wound-healing response represented by excessive extracellular matrix deposition. Activation of hepatic stellate cell (HSC) is the critical cellular basis for hepatic fibrogenesis, whereas hepatocyte undergoes epithelial-mesenchymal transition (EMT) which is also involved in chronic liver injury. Long noncoding RNA H19 has been found to be associated with cholestatic liver fibrosis lately. However, the role of H19 in liver fibrosis remains largely to be elucidated. In this study, we found that the expression of H19 was significantly upregulated in the liver tissue of CCl4 -induced mice, a toxicant-induced liver fibrogenesis model. Overexpression of H19 significantly aggravated activation of HSC and EMT of hepatocyte both by stimulating transforming growth factor-ß (TGF-ß) pathway. In terms of mechanism, H19 functioned as a competing endogenous RNA to sponge miR-148a and subsequently sustained the level of ubiquitin-specific protease 4 (USP4), which was an identified target of miR-148a and was able to stabilize TGF-ß receptor I. In conclusion, our findings revealed a novel H19/miR-148a/USP4 axis which promoted liver fibrosis via TGF-ß pathway in both HSC and hepatocyte, indicating that H19 could become a promising target for the treatment of liver fibrosis.
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Células Estrelladas Hepáticas/patología , Hepatocitos/patología , Cirrosis Hepática/patología , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Animales , Secuencia de Bases , Tetracloruro de Carbono , Línea Celular , Transición Epitelial-Mesenquimal/genética , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/metabolismo , Humanos , Cirrosis Hepática/genética , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , ARN Largo no Codificante/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Following publication of the original article [1], the authors reported an error in.
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BACKGROUND: Cancer cells avidly consume glucose and convert it to lactate, resulting in a low pyruvate level. This phenomenon is known as the Warburg effect, and is important for cell proliferation. Although cMyc has often been described as an oncoprotein that preferentially contributes to the Warburg effect and tumor proliferation, mechanisms of action remain unclear. Histone deacetylase 3 (HDAC3) regulates gene expression by removing acetyl groups from lysine residues, as well as has an oncogenic role in apoptosis and contributes to the proliferation of many cancer cells including cholangiocarcinoma (CCA). HDAC inhibitors display antitumor activity in many cancer cell lines. Cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC but the mechanisms remain elusive. The purpose of our study was to explore the role of cMyc in regulating pyruvate metabolism, as well as to investigate whether the inhibitory effect of pyruvate on HDAC3 could hold promise in the treatment of cancer cells. METHODS: We studied pyruvate levels in CCA cell lines using metabolite analysis, and analyzed the relationship of pyruvate levels and cell proliferation with cell viability analysis. We cultivated CCA cell lines with high or low levels of pyruvate, and then analyzed the protein levels of HDAC3 and apoptotic markers via Western Blotting. We then explored the reasons of low levels of pyruvate by using seahorse analysis and 13C6 metabolites tracing analysis, and then confirmed the results using patient tissue protein samples through Western Blotting. Bioinformatics analysis and transfection assay were used to confirm the upstream target of the low levels of pyruvate status in CCA. The regulation of cMyc by HDAC3 was studied through immunoprecipitation and Western Blotting. RESULTS: We confirmed downregulated pyruvate levels in CCA, and defined that high pyruvate levels correlated with reduced cell proliferation levels. Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis. Synergistically upregulated LDHA, PKM2 levels resulted in low levels of pyruvate, as well as poor patient survival. We also found that low levels of pyruvate contributed to proliferation of CCA cells and confirmed that the upstream target is cMyc. Conversely, high activity of HDAC3 stabilized cMyc protein by preferential deacetylating cMyc at K323 site, which further contributed to the low pyruvate levels. Finally, this creates a positive feedback loop that maintained the low levels of pyruvate and promoted CCA proliferation. CONCLUSIONS: Collectively, our findings identify a role for promoting the low pyruvate levels regulated by c-Myc, and its dynamic acetylation in cancer cell proliferation. These targets, as markers for predicting tumor proliferation in patients undergoing clinical treatments, could pave the way towards personalized therapies.
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Apoptosis , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Histona Desacetilasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ácido Pirúvico/metabolismo , Animales , Neoplasias de los Conductos Biliares/metabolismo , Carcinogénesis , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Proliferación Celular , Colangiocarcinoma/metabolismo , Humanos , L-Lactato Deshidrogenasa/metabolismo , Proteínas de la Membrana/metabolismo , Ratones Desnudos , Hormonas Tiroideas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas de Unión a Hormona TiroideRESUMEN
BACKGROUND: Liver biopsy is the gold standard to assess pathological features (eg inflammation grades) for hepatitis B virus-infected patients although it is invasive and traumatic; meanwhile, several gene profiles of chronic hepatitis B (CHB) have been separately described in relatively small hepatitis B virus (HBV)-infected samples. We aimed to analyse correlations among inflammation grades, gene expressions and clinical parameters (serum alanine amino transaminase, aspartate amino transaminase and HBV-DNA) in large-scale CHB samples and to predict inflammation grades by using clinical parameters and/or gene expressions. METHODS: We analysed gene expressions with three clinical parameters in 122 CHB samples by an improved regression model. Principal component analysis and machine-learning methods including Random Forest, K-nearest neighbour and support vector machine were used for analysis and further diagnosis models. Six normal samples were conducted to validate the predictive model. RESULTS: Significant genes related to clinical parameters were found enriching in the immune system, interferon-stimulated, regulation of cytokine production, anti-apoptosis, and etc. A panel of these genes with clinical parameters can effectively predict binary classifications of inflammation grade (area under the ROC curve [AUC]: 0.88, 95% confidence interval [CI]: 0.77-0.93), validated by normal samples. A panel with only clinical parameters was also valuable (AUC: 0.78, 95% CI: 0.65-0.86), indicating that liquid biopsy method for detecting the pathology of CHB is possible. CONCLUSIONS: This is the first study to systematically elucidate the relationships among gene expressions, clinical parameters and pathological inflammation grades in CHB, and to build models predicting inflammation grades by gene expressions and/or clinical parameters as well.
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Expresión Génica , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/genética , Inflamación/diagnóstico , Alanina Transaminasa/sangre , Área Bajo la Curva , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , ADN Viral/sangre , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B , Humanos , Inflamación/virología , Modelos Lineales , Hígado/patología , Aprendizaje Automático , Curva ROCRESUMEN
Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.
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Trastorno Depresivo Mayor , Resiliencia Psicológica , Humanos , Ratones , Animales , Núcleo Dorsal del Rafe/metabolismo , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Serotonina/farmacología , Antidepresivos/farmacología , Hipoxia , Receptores Purinérgicos P2X2/metabolismoRESUMEN
Perineuronal nets (PNNs) are structures that contain extracellular matrix chondroitin sulfate proteoglycan and surround the soma and dendrites of various neuronal cell types. They are involved in synaptic plasticity and undertake important physiological functions. Altered expression of PNNs has been demonstrated in the brains of autism-related animal models. However, the underlying mechanism is still unknown. In this study, we demonstrated that the PNNs in the cerebellum are involved in modulating social and repetitive/inflexible behaviors in Shank3B-/- mice, an established animal model of autism spectrum disorder. First, we performed wisteria floribunda agglutinin staining of the whole brain of Shank3B-/- mice, and found wisteria floribunda agglutinin-positive PNNs are significantly increased in the cerebellar interpositus nucleus (IntP) in Shank3B-/- mice compared to control littermates. After degradation of PNNs in the IntP by chondroitinase ABC, the repetitive behaviors of Shank3B-/- mice were decreased, while their social behaviors were ameliorated. These results suggested that PNNs homeostasis is involved in the regulation of social behavior, revealing a potential therapeutic strategy targeting PNNs in the IntP for the treatment of autism spectrum disorder.
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Trastorno del Espectro Autista , Ratones , Animales , Trastorno del Espectro Autista/metabolismo , Matriz Extracelular/metabolismo , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Neuronas/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR)-modified T cells has revolutionized the field of immune-oncology, showing remarkable efficacy against hematological malignancies. However, its success in solid tumors is limited by factors such as easy recurrence and poor efficacy. The effector function and persistence of CAR-T cells are critical to the success of therapy and are modulated by metabolic and nutrient-sensing mechanisms. Moreover, the immunosuppressive tumor microenvironment (TME), characterized by acidity, hypoxia, nutrient depletion, and metabolite accumulation caused by the high metabolic demands of tumor cells, can lead to T cell "exhaustion" and compromise the efficacy of CAR-T cells. In this review, we outline the metabolic characteristics of T cells at different stages of differentiation and summarize how these metabolic programs may be disrupted in the TME. We also discuss potential metabolic approaches to improve the efficacy and persistence of CAR-T cells, providing a new strategy for the clinical application of CAR-T cell therapy.
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Neoplasias Hematológicas , Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Linfocitos T , Inmunoterapia Adoptiva , Neoplasias Hematológicas/metabolismo , Microambiente TumoralRESUMEN
Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-ß (Aß) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aß metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aß is essential for preventing Aß deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepatic sEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology, and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention.
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Enfermedad de Alzheimer , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/metabolismo , Hígado/metabolismo , Hígado/patologíaRESUMEN
Hepatocellular carcinoma (HCC) is one of the largest causes of cancer-related deaths worldwide owing to the limitation of effective treatment options. The ubiquitin-proteasome system has been rapidly recognized as a frequent target of deregulation leading to cancers. Enhanced DNA damage response (DDR) promotes HCC growth and prevents chemosensitivity, and ubiquitin E3 ligases are key modulators in DDR. Therefore, a better understanding of how E3 ligases regulate cell growth and DNA damage may provide novel insights in understanding the oncogenic mechanism and improving the efficacy of DNA damage therapeutic agents. Here, we performed a high-content RNAi screening targeting 52 DDR-related E3 ligases in HCC and found that ring finger protein 4 (RNF4) was essential for HCC growth. RNF4 was highly expressed in HCC tissues, and the expression levels of RNF4 were associated with poor outcomes. RNF4 silencing significantly suppressed the cell growth, and subsequently induced G2/M arrest and apoptosis of HCC cells in vitro; RNF4 silencing also demonstrated the tumor-suppressive efficacy on HCC in vivo. Moreover, RNF4 silencing increased DNA damage, and rendered HCC cells more sensitive to DNA damage drugs and radiation. We found RNF4 functionally interacts with p62, and mechanistic analyses indicated that RNF4 silencing triggered the nuclear enrichment of p62. Moreover, the p62 nuclear targeting was required for increased DNA damage and growth suppression mediated by RNF4 silencing. Thus, our findings suggest RNF4 is essential for HCC proliferation via preventing nuclear translocation of p62. RNF4 silencing promotes DNA damage and may serve as a novel strategy to suppress cell growth and increase the sensitivity of DNA damage therapeutic agents in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Nucleares , Proteínas de Unión al ARN , Factores de Transcripción , Apoptosis/genética , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Daño del ADN/genética , Puntos de Control de la Fase G2 del Ciclo Celular , Humanos , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/genética , Factores de Transcripción/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Exosomes, a subset of small extracellular vesicles, carry various nucleic acids, proteins, lipids, amino acids and metabolites. They function as a mode of intercellular communication and molecular transfer. Exosome cargo molecules, including small non-coding RNAs (sncRNAs), are involved in the immune response in various organisms. However, the role of exosome-derived sncRNAs in immune responses in molluscs remains unclear. Here, we aimed to reveal the sncRNAs involved in the immune response during grafting transplantation by the pearl oyster Pinctada fucata. Exosomes were successfully extracted from the P. fucata haemolymph during graft transplantation. Abundant microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) were simultaneously discovered in P. fucata exosomes by small RNA sequencing. The expression patterns of the miRNAs and piRNAs at the grafting and initial stages were not substantially different, but varied significantly between the initial and later stages. Target prediction and functional analysis indicate that these miRNAs and piRNAs are related to immune response upon grafting transplantation, whereas piRNAs may also be associated with transposon silencing by targeting with genome transposon elements. This work provides the basis for a functional understanding of exosome-derived sncRNAs and helps to gain further insight into the PIWI/piRNA pathway function outside of germline cells in molluscs.
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Exosomas , MicroARNs , Pinctada , ARN Pequeño no Traducido , Animales , Exosomas/genética , Exosomas/metabolismo , Inmunidad , MicroARNs/genética , Pinctada/genética , Pinctada/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismoRESUMEN
Cryoablation has been used for the treatment of various sorts of solid visceral tumors, but few are reported on gastric tumor via endoscope, in terms of accurate control of ablation site, freezing depth and effective temperature. Thus, we developed a novel device, which could perform accurate cryoablation on the stomach via endoscope. This study aimed to evaluate the efficacy and safety of the device on porcine stomach. Results showed that the novel device could provide direct view of the operation space, allowing accurate and safe ablation of the stomach. Three minutes cryoablation caused a transmural, 1 cm radius gastric lesion. On serosal side, the temperature dropped to -64.2 °C, -34.1 °C, 26.1 °C at the center, 1 cm and 2 cm from center, respectively. Histopathology revealed acute ruptured cells with damaged glands in mucosa, partial disruption in muscularis propria and serosal slight exudation. Three months later, scar formed with complete recovery of gastric structure. No active bleeding or perforation of stomach, nor injury or adhesion of adjacent organs was observed. This endoscopic cryoablation device allowed safe, full-thickness cryoablation with effective temperature, which may provide an alternative treatment for gastric tumor.
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Criocirugía/instrumentación , Gastroscopios , Gastroscopía/instrumentación , Estómago/cirugía , Animales , Apoptosis , Técnicas de Cultivo de Célula , Línea Celular , Cicatriz/patología , Frío , Colágeno , Combinación de Medicamentos , Diseño de Equipo , Mucosa Gástrica/patología , Humanos , Laminina , Proteoglicanos , Estómago/patología , Porcinos , Temperatura , Adherencias Tisulares , Cicatrización de HeridasRESUMEN
Following the publication of the article, the authors have realized that Fig. 1A contained an error (essentially, the scale bars were drawn incorrectly). The corrected version of Fig. 1 is shown below, also including a modified version of the legend for Fig. 1A. Note that these revisions do not affect the overall conclusions reported in the paper. The authors apologize to the Editor of Oncology Reports and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 39: 19571965, 2018; DOI: 10.3892/or.2018.6275].
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BACKGROUND: The GKN2 is a secretory protein, whose levels decrease in gastric cancer. The present study aimed to investigate the expression, function and mechanism of action of GKN2 in gastric cancer. METHODS: Molecular biology assays were performed to elucidate the function and underlying mechanisms of GKN2 in gastric cancer under stress-induced condition in vivo and in vitro. Clinical specimens were used to assess the correlation of GKN2 and prognosis. RESULTS: We found that overexpression of GKN2 significantly enhanced apoptosis and growth arrest in vitro. GKN2 expression increased in gastric cancer cells exposed to hydrogen peroxide and promoted reactive oxygen species-induced mitochondrial dysfunction and resulted in increased cell apoptosis via inhibition of NF-κB signaling pathway and activation of JNK signaling pathway through the direct interaction of GKN2 with Hsc70. Trefoil factor 1 might contribute to the tumor suppressing effects of GKN2. MiR-216a downregulated GKN2 expression. GKN2 also inhibited xenograft tumor growth and was an independent and significant prognostic factor for patients with gastric cancer treated with oxaliplatin. CONCLUSIONS: Taken together, our data indicate that GKN2 may increase sensitivity of GC cells to the drugs which increase ROS levels in tumors. Inhibition of the interaction between GKN2 and Hsc70 could attenuate the effects induced by GKN2. GKN2 overexpression could be used to determine the subgroup of patients to obtain the more favorable outcome of oxaliplatin treatment and may be used as biomarker of the prognosis of this cancer.
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Apoptosis , Proteínas Portadoras/metabolismo , Proteínas del Choque Térmico HSC70/metabolismo , Estrés Oxidativo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Animales , Antineoplásicos/uso terapéutico , Proteínas Portadoras/genética , Caspasas , Línea Celular Tumoral , Dioxolanos/farmacología , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Genes Reporteros , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , FN-kappa B/metabolismo , Oxidación-Reducción , Unión Proteica , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cholangiocarcinoma (CCA) is a malignant cancer with an unknown etiology and an unfavorable prognosis. Most patients are diagnosed at an advanced stage, thus making it essential to find novel curative targets for CCA. Metabolic reprogramming of the tumor cells includes metabolic abnormalities in glucose (known as the Warburg effect) and other substances such as amino acids and fats. Metabolic reprogramming produces anti-oxidant substances, reduces tumor oxidative stress, and finally promotes the proliferation of tumors. There is increasing evidence to imply that SIRT2, a histone deacetylase, and its downstream target cMYC, play metabolic regulatory roles in tumor cells. However, the role of the SIRT2/cMYC pathway in CCA is unclear. To assess the metabolic reprogramming function of the SIRT2/cMYC pathway in CCA and to determine the downstream targets as well as evaluate the therapeutic effect, the CCA RNA-Seq data were downloaded from the TCGA database. Differentially expressed genes were confirmed and KEGG pathway enrichment analysis was performed. Overall, 48 paired CCA samples were collected and subjected to immunohistochemical detection, and the clinical characteristics of participants were summarized. The CCA cells were suppressed or overexpressed with different downstream targets of SIRT2 and then subjected to apoptosis, immunoblotting, seahorse, and metabolites tracing analysis. In vivo experiments were also performed. We found that the SIRT2/cMYC pathway contributed to the proliferation of CCA cells and confirmed that the downstream target is PHDA1 and the serine synthesis pathway. The up-regulated SIRT2 and cMYC levels resulted in low levels of mitochondrial oxidative phosphorylation and increased conversion of glucose to serine and led to poor patient survival. The highly active SIRT2/cMYC pathway up-regulated the serine synthesis pathway pyruvate and increased antioxidant production, thus consequently protecting the CCA cells from oxidative stress-induced apoptosis. Our data revealed that the SIRT2/cMYC pathway plays a critical role in transforming glucose oxidative metabolism to serine anabolic metabolism, thus providing antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may represent a new therapeutic target for treating CCA.
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Neoplasias de los Conductos Biliares/patología , Reprogramación Celular , Colangiocarcinoma/patología , Regulación Neoplásica de la Expresión Génica , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Sirtuina 2/metabolismo , Animales , Apoptosis , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Movimiento Celular , Proliferación Celular , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , Fosforilación Oxidativa , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Piruvato Deshidrogenasa (Lipoamida)/genética , Piruvato Deshidrogenasa (Lipoamida)/metabolismo , Serina/metabolismo , Sirtuina 2/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD)-associated dysbiosis is characterized by a loss of Faecalibacterium prausnitzii, whose supernatant exerts an anti-inflammatory effect. However, the anti-inflammatory substances in F. prausnitzii supernatant and the mechanism in ameliorating colitis in IBD have not yet been fully investigated. METHODS: Experimental colitis models were induced and evaluated by clinical examination and histopathology. Levels of cytokines and ratio of T cells were detected by enzyme-linked immunosorbent assay and flow cytometry analysis, respectively. F. prausnitzii supernatant was separated by macroporous resins. After extraction, the substances in supernatant were identified by gas chromatography-mass spectrometer. T-cell differentiation assay was conducted in vitro. Changes in signaling pathways were examined by immunoblot, immunohistochemistry, and immunofluorescent staining. RESULTS: We found that the supernatant of F. prausnitzii could regulate T helper 17 cell (Th17)/regulatory T cell (Treg) differentiation. Then, we identified butyrate produced by F. prausnitzii that played the anti-inflammatory effects by inhibiting interleukin (IL)-6/signal transducer and the activator of transcription 3 (STAT3)/IL-17 pathway and promoting forkhead box protein P3 (Foxp3). Finally, we demonstrated that the target of butyrate was histone deacetylase 1 (HDAC1). CONCLUSIONS: It is butyrate, instead of other substances produced by F. prausnitzii, that maintains Th17/Treg balance and exerts significant anti-inflammatory effects in colorectal colitis rodents, by inhibiting HDAC1 to promote Foxp3 and block the IL-6/STAT3/IL-17 downstream pathway. F. prausnitzii could be an option for further investigation for IBD treatment. Targeting the butyrate-HDAC1-T-cell axis offers an effective novel approach in the treatment of inflammatory disease.
Asunto(s)
Butiratos/metabolismo , Colitis/microbiología , Faecalibacterium prausnitzii/metabolismo , Histona Desacetilasa 1/metabolismo , Linfocitos T Reguladores/microbiología , Células Th17/microbiología , Animales , Diferenciación Celular , Colitis/inducido químicamente , Colon/microbiología , Modelos Animales de Enfermedad , Disbiosis/microbiología , Histona Desacetilasa 1/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Recto/microbiología , Transducción de SeñalRESUMEN
Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells in vitro. Furthermore, in vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA.