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Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Cocaína , Consolidação da Memória , Neurônios , Córtex Pré-Frontal , Animais , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Cocaína/farmacologia , Masculino , Ratos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Memória de Longo Prazo/fisiologia , Sinais (Psicologia) , Ratos Sprague-Dawley , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Autoadministração , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/fisiologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Memória/efeitos dos fármacos , Memória/fisiologiaRESUMO
In 1986, Gawin and Kleber reported a progressive increase in cue-induced drug craving in individuals with cocaine use disorders during prolonged abstinence. After years of controversy, as of 2001, this phenomenon was confirmed in rodent studies using self-administration model, and defined as the incubation of drug craving. The intensification of cue-induced drug craving after withdrawal exposes abstinent individuals to a high risk of relapse, which urged us to develop effective interventions to prevent incubated craving. Substantial achievements have been made in deciphering the neural mechanisms, with potential implications for reducing drug craving and preventing the relapse. The present review discusses promising drug targets that have been well investigated in animal studies, including some neurotransmitters, neuropeptides, neurotrophic factors, and epigenetic markers. We also discuss translational exploitation and challenges in the field of the incubation of drug craving, providing insights into future investigations and highlighting the potential of pharmacological interventions, environment-based interventions, and neuromodulation techniques.
Assuntos
Cocaína , Transtornos Relacionados ao Uso de Substâncias , Animais , Fissura , Preparações Farmacêuticas , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Autoadministração , Recidiva , Sinais (Psicologia) , Cocaína/farmacologia , Comportamento de Procura de DrogaRESUMO
The extracellular matrix (ECM) within the brain possesses a distinctive composition and functionality, influencing a spectrum of physiological and pathological states. Among its constituents, perineuronal nets (PNNs) are unique ECM structures that wrap around the cell body of many neurons and extend along their dendrites within the central nervous system (CNS). PNNs are pivotal regulators of plasticity in CNS, both during development and adulthood stages. Characterized by their condensed glycosaminoglycan-rich structures and heterogeneous molecular composition, PNNs not only offer neuroprotection but also participate in signal transduction, orchestrating neuronal activity and plasticity. Interfering with the PNNs in adult animals induces the reactivation of critical period plasticity, permitting modifications in neuronal connections and promoting the recovery of neuroplasticity following spinal cord damage. Interestingly, in the adult brain, PNN expression is dynamic, potentially modulating plasticity-associated states. Given their multifaceted roles, PNNs have emerged as regulators in the domains of learning, memory, addiction behaviors, and other neuropsychiatric disorders. In this review, we aimed to address how PNNs contribute to the memory processes in physiological and pathological conditions.
Assuntos
Encéfalo , Sistema Nervoso Central , Animais , Sistema Nervoso Central/fisiologia , Encéfalo/metabolismo , Neurônios/metabolismo , Memória/fisiologia , Matriz Extracelular/metabolismo , Plasticidade Neuronal/fisiologiaRESUMO
Resistance toward imatinib (IM) and other BCR/ABL tyrosine kinase inhibitors remains troublesome in the treatment of advanced stage chronic myeloid leukemia (CML). The aim of this study was to estimate the reversal effects of down-regulation of Na(+)/H(+) exchanger 1 (NHE1) on the chemoresistance of BCR-ABL-positive leukemia patients' cells and cell lines. After treatment with the specific NHE1 inhibitor cariporide to decrease intracellular pH (pHi), the heme oxygenase-1 (HO-1) levels of the K562R cell line and cells from IM-insensitive CML patients decreased. HO-1, as a Bcr/Abl-dependent survival molecule in CML cells, is important for the resistance to tyrosine kinase inhibitors in patients with newly diagnosed CML or IM-resistant CML. Silencing PKC-ß and Nrf-2 or treatment with inhibitors of p38 pathways obviously blocked NHE1-induced HO-1 expression. Furthermore, treatment with HO-1 or p38 inhibitor plus IM increased the apoptosis of the K562R cell line and IM-insensitive CML patients' cells. Inhibiting HO-1 enhanced the activation of caspase-3 and poly(ADP-ribose) polymerase-1. Hence, the results support the anti-apoptotic role of HO-1 induced by NHE1 in the K562R cell line and IM-insensitive CML patients and provide a mechanism by which inducing HO-1 expression via the PKC-ß/p38-MAPK pathway may promote tumor resistance to oxidative stress.
Assuntos
Benzamidas/farmacologia , Proteínas de Transporte de Cátions/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Heme Oxigenase-1/biossíntese , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas de Neoplasias/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Trocadores de Sódio-Hidrogênio/metabolismo , Adulto , Idoso , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Transporte de Cátions/genética , Resistencia a Medicamentos Antineoplásicos/genética , Indução Enzimática/efeitos dos fármacos , Indução Enzimática/genética , Feminino , Regulação Leucêmica da Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Proteína Quinase C beta/antagonistas & inibidores , Proteína Quinase C beta/genética , Proteína Quinase C beta/metabolismo , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/genéticaRESUMO
Failure in behavioral suppression is a key feature in substance use disorders, potentially leading to compulsive drug seeking and relapse. In this issue of Neuron, Paniccia et al.1 elucidated a heroin-damaged paraventricular nucleus of the thalamus (PVT)-accumbal circuit and how recovery of PVT function could prevent heroin relapse.
Assuntos
Analgésicos Opioides , Heroína , Tálamo/fisiologia , Neurônios/fisiologia , Comportamento de Procura de DrogaRESUMO
The pursuit of groundbreaking health care innovations has led to the convergence of artificial intelligence (AI) and traditional Chinese medicine (TCM), thus marking a new frontier that demonstrates the promise of combining the advantages of ancient healing practices with cutting-edge advancements in modern technology. TCM, which is a holistic medical system with >2000 years of empirical support, uses unique diagnostic methods such as inspection, auscultation and olfaction, inquiry, and palpation. AI is the simulation of human intelligence processes by machines, especially via computer systems. TCM is experience oriented, holistic, and subjective, and its combination with AI has beneficial effects, which presumably arises from the perspectives of diagnostic accuracy, treatment efficacy, and prognostic veracity. The role of AI in TCM is highlighted by its use in diagnostics, with machine learning enhancing the precision of treatment through complex pattern recognition. This is exemplified by the greater accuracy of TCM syndrome differentiation via tongue images that are analyzed by AI. However, integrating AI into TCM also presents multifaceted challenges, such as data quality and ethical issues; thus, a unified strategy, such as the use of standardized data sets, is required to improve AI understanding and application of TCM principles. The evolution of TCM through the integration of AI is a key factor for elucidating new horizons in health care. As research continues to evolve, it is imperative that technologists and TCM practitioners collaborate to drive innovative solutions that push the boundaries of medical science and honor the profound legacy of TCM. We can chart a future course wherein AI-augmented TCM practices contribute to more systematic, effective, and accessible health care systems for all individuals.
RESUMO
Addiction, particularly in relation to psychostimulants and opioids, persists as a global health crisis with profound social and economic ramifications. Traditional interventions, including medications and behavioral therapies, often encounter limited success due to the chronic and relapsing nature of addictive disorders. Consequently, there is significant interest in the development of innovative therapeutics to counteract the effects of abused substances. In recent years, vaccines have emerged as a novel and promising strategy to tackle addiction. Anti-drug vaccines are designed to stimulate the immune system to produce antibodies that bind to addictive compounds, such as nicotine, cocaine, morphine, methamphetamine, and heroin. These antibodies effectively neutralize the target molecules, preventing them from reaching the brain and eliciting their rewarding effects. By obstructing the rewarding sensations associated with substance use, vaccines aim to reduce cravings and the motivation to engage in drug use. Although anti-drug vaccines hold significant potential, challenges remain in their development and implementation. The reversibility of vaccination and the potential for combining vaccines with other addiction treatments offer promise for improving addiction outcomes. This review provides an overview of anti-drug vaccines, their mechanisms of action, and their potential impact on treatment for substance use disorders. Furthermore, this review summarizes recent advancements in vaccine development for each specific drug, offering insights for the development of more effective and personalized treatments capable of addressing the distinct challenges posed by various abused substances.
RESUMO
We aim to systematically review and meta-analyze the effectiveness and safety of psychedelics [psilocybin, ayahuasca (active component DMT), LSD and MDMA] in treating symptoms of various mental disorders. Web of Science, Embase, EBSCO, and PubMed were searched up to February 2024 and 126 articles were finally included. Results showed that psilocybin has the largest number of articles on treating mood disorders (N = 28), followed by ayahuasca (N = 7) and LSD (N = 6). Overall, psychedelics have therapeutic effects on mental disorders such as depression and anxiety. Specifically, psilocybin (Hedges' g = -1.49, 95% CI [-1.67, -1.30]) showed the strongest therapeutic effect among four psychedelics, followed by ayahuasca (Hedges' g = -1.34, 95% CI [-1.86, -0.82]), MDMA (Hedges' g = -0.83, 95% CI [-1.33, -0.32]), and LSD (Hedges' g = -0.65, 95% CI [-1.03, -0.27]). A small amount of evidence also supports psychedelics improving tobacco addiction, eating disorders, sleep disorders, borderline personality disorder, obsessive-compulsive disorder, and body dysmorphic disorder. The most common adverse event with psychedelics was headache. Nearly a third of the articles reported that no participants reported lasting adverse effects. Our analyses suggest that psychedelics reduce negative mood, and have potential efficacy in other mental disorders, such as substance-use disorders and PTSD.
Assuntos
Alucinógenos , Transtornos Mentais , Humanos , Alucinógenos/efeitos adversos , Alucinógenos/uso terapêutico , Alucinógenos/farmacologia , Transtornos Mentais/tratamento farmacológico , Psilocibina/farmacologia , Psilocibina/efeitos adversos , Psilocibina/uso terapêutico , Banisteriopsis , Dietilamida do Ácido Lisérgico/farmacologia , Dietilamida do Ácido Lisérgico/efeitos adversos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversosRESUMO
The coronavirus disease 2019 (COVID-19) pandemic has been looming globally for three years, yet the diagnostic and treatment methods for COVID-19 are still undergoing extensive exploration, which holds paramount importance in mitigating future epidemics. Host non-coding RNAs (ncRNAs) display aberrations in the context of COVID-19. Specifically, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) exhibit a close association with viral infection and disease progression. In this comprehensive review, an overview was presented of the expression profiles of host ncRNAs following SARS-CoV-2 invasion and of the potential functions in COVID-19 development, encompassing viral invasion, replication, immune response, and multiorgan deficits which include respiratory system, cardiac system, central nervous system, peripheral nervous system as well as long COVID. Furthermore, we provide an overview of several promising host ncRNA biomarkers for diverse clinical scenarios related to COVID-19, such as stratification biomarkers, prognostic biomarkers, and predictive biomarkers for treatment response. In addition, we also discuss the therapeutic potential of ncRNAs for COVID-19, presenting ncRNA-based strategies to facilitate the development of novel treatments. Through an in-depth analysis of the interplay between ncRNA and COVID-19 combined with our bioinformatic analysis, we hope to offer valuable insights into the stratification, prognosis, and treatment of COVID-19.
Assuntos
COVID-19 , Humanos , COVID-19/genética , Síndrome de COVID-19 Pós-Aguda , Relevância Clínica , SARS-CoV-2/genética , RNA não Traduzido/genética , BiomarcadoresRESUMO
Psychiatric disorders are now responsible for the largest proportion of the global burden of disease, and even more challenges have been seen during the COVID-19 pandemic. Artificial intelligence (AI) is commonly used to facilitate the early detection of disease, understand disease progression, and discover new treatments in the fields of both physical and mental health. The present review provides a broad overview of AI methodology and its applications in data acquisition and processing, feature extraction and characterization, psychiatric disorder classification, potential biomarker detection, real-time monitoring, and interventions in psychiatric disorders. We also comprehensively summarize AI applications with regard to the early warning, diagnosis, prognosis, and treatment of specific psychiatric disorders, including depression, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, addiction, sleep disorders, and Alzheimer's disease. The advantages and disadvantages of AI in psychiatry are clarified. We foresee a new wave of research opportunities to facilitate and improve AI technology and its long-term implications in psychiatry during and after the COVID-19 era.
Assuntos
Transtorno do Espectro Autista , COVID-19 , Psiquiatria , Humanos , Inteligência Artificial , Pandemias , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/terapia , Teste para COVID-19RESUMO
Repeated cocaine exposure causes compensatory neuroadaptations in neurons in the nucleus accumbens (NAc), a region that mediates reinforcing effects of drugs. Previous studies suggested a role for adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor, in modulating neuronal morphology and membrane excitability. However, the potential involvement of AMPK in cocaine use disorder is still unclear. The present study employed a cocaine self-administration model in rats to investigate the effect of AMPK and its target cyclic adenosine monophosphate response element binding protein-regulated transcriptional co-activator 1 (CRTC1) on cocaine reinforcement and the motivation for cocaine. We found that intravenous cocaine self-administration significantly decreased AMPK activity in the NAc shell (NAcsh), which persisted for at least 7 days of withdrawal. Cocaine reinforcement, reflected by self-administration behavior, was significantly prevented or enhanced by augmenting or suppressing AMPK activity pharmacologically and genetically, respectively. No difference in sucrose self-administration behavior was found after the same manipulations. The inhibition of AMPK activity in the NAcsh also increased the motivation for cocaine in progressive-ratio schedules of reinforcement, whereas the activation of AMPK had no effect. The knockdown of CRTC1 in the NAcsh significantly impaired cocaine reinforcement, which was rescued by pharmacologically increasing AMPK activity. Altogether, these results indicate that AMPK in the NAcsh is critical for cocaine reinforcement, possibly via the regulation of CRTC1 signaling. These findings may help reveal potential therapeutic targets and have important implications for the treatment of cocaine use disorder and relapse.
Assuntos
Cocaína , Ratos , Animais , Cocaína/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/farmacologia , Ratos Sprague-Dawley , Reforço Psicológico , Fatores de Transcrição/metabolismo , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Núcleo Accumbens , AutoadministraçãoRESUMO
Sleep is a complex physiological process and is a critical determinant of physical and mental health. In the past decades, significant progress has been made in understanding the neural mechanisms of sleep and awakening. However, the initiation and maintenance of the sleep-wake cycle is regulated not only by the central system but is also affected by signals from peripheral tissues. Growing evidence shows that the microbiota-gut-brain axis contributes to the regulation of sleep behavior both directly and indirectly and may play a critical role in the etiology and pathogenesis of sleep disorders. Sleep deprivation leads to dysfunction of gut microbiota and sleep disorders are accompanied by altered gut microbiota composition. In this review, we describe the bidirectional relationships between sleep and gut microbiota and summarize the abnormal characteristics of gut bacteria in distinct conditions including sleep disturbances, sleep disorders and sleep disorders comorbid with neuropsychiatric disorders. We also examine the potential routes of microbiota-gut-brain axis in sleep and gut microbiome interactions, including metabolic, immune, and neural pathways, and propose microbiota-targeted interventions for improving sleep. Manipulating gut microbiota may be a promising avenue for the development of novel interventions for sleep disorders.
Assuntos
Microbioma Gastrointestinal , Microbiota , Transtornos do Sono-Vigília , Encéfalo , Eixo Encéfalo-Intestino , Microbioma Gastrointestinal/fisiologia , HumanosRESUMO
BACKGROUND: Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP. METHODS: In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate. FINDINGS: Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01). INTERPRETATION: The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse. FUNDING: National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800).
Assuntos
Transtornos Relacionados ao Uso de Opioides , Síndrome de Abstinência a Substâncias , Humanos , Masculino , Animais , Ratos , Metadona/farmacologia , Metadona/uso terapêutico , Heroína/efeitos adversos , Entorpecentes/efeitos adversos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/psicologia , Síndrome de Abstinência a Substâncias/reabilitação , Recidiva Local de Neoplasia/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológicoRESUMO
Major depressive disorder (MDD) is a severe mental disorder with a high disability rate worldwide. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are the most common agents for antidepressant use. SSRIs and SNRIs are believed to achieve antidepressant effects through the activation of serotonergic or noradrenergic systems. However, whether the dopaminergic system is involved remains unclear. In our study, a genetically encoded dopamine sensor and in vivo fiber photometry recordings were used to measure the dopamine concentrations in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute intraperitoneal injection of SSRIs or SNRIs. Combined with the behavioral tests, we found that SNRIs increased dopamine concentrations in both the mPFC and the NAc and showed faster antidepressant effects than SSRIs. To verify the enhanced dopamine levels induce the faster antidepressant effects of SNRIs, we employed dopamine receptor antagonists to specifically block the dopaminergic function. The results showed that the faster antidepressant effects of SNRIs were weakened by the dopamine receptor antagonists. Altogether, our study reveals that SNRIs achieve faster antidepressant effects than SSRIs by elevating the dopamine concentrations in the mPFC and the NAc. Our work proposes further mechanisms for the first-line antidepressants, which provides more basis for clinical treatments. This article is part of the special issue on Stress, Addiction and Plasticity.
Assuntos
Antidepressivos/administração & dosagem , Depressão/metabolismo , Dopamina/metabolismo , Prosencéfalo/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Animais , Depressão/tratamento farmacológico , Depressão/psicologia , Dopamina/análise , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fotometria/métodos , Prosencéfalo/química , Prosencéfalo/efeitos dos fármacos , Restrição Física/efeitos adversos , Restrição Física/psicologia , Resultado do TratamentoRESUMO
Interleukin (IL)-6 is one of the most important survival factors in multiple myeloma (MM), and determines the poor prognosis of MM. IL-6 mainly has a paracrine bone marrow stromal cell origin and an autocrine MM cell origin. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. HO-1 expression levels in bone marrow CD138(+) cells of MM patients were significantly higher than those in healthy donors, and positively correlated with both serum IL-6 and intracellular IL-6 mRNA expression levels. Culture of U266, RPMI8226 and CD138(+) cells with exogenous IL-6 in vitro induced high HO-1 expression levels and allowed them to resist lenalidomide. It is hypothesized that this was probably attributable to IL-6-mediated activation of the Janus kinase 2-signal transducer and activator of transcription 3 pathway. In contrast, without IL-6 coculture, enhanced HO-1 expression in U266, RPMI8226 and bone marrow CD138(+) cells from MM patients significantly inreased IL-6 mRNA expression levels and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced p38 mitogen-activated protein kinase phosphorylation. Reduced HO-1 expression sensitized MM cells to lenalidomide. Therefore, we postulated that IL-6 in the bone marrow microenvironment of MM patients stimulated high HO-1 expression in MM cells and their resistance to lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, and exacerbated drug resistance and disease. This study supports the use of HO-1 as a possible marker for both MM prognosis and drug resistance, and as a potential therapeutic target.
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Resistencia a Medicamentos Antineoplásicos , Heme Oxigenase-1/metabolismo , Interleucina-6/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Talidomida/análogos & derivados , Adulto , Idoso , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Janus Quinase 2/metabolismo , Lenalidomida , Masculino , Pessoa de Meia-Idade , Fosforilação , Fator de Transcrição STAT3/metabolismo , Sindecana-1/metabolismo , Talidomida/farmacologiaRESUMO
Heme oxygenase-1 was reported previously as a resistance target on acute myelocytic leukemia (AML). We found that HO-1 was resistant to 5-azacytidine (AZA) treatment of myelodysplastic syndrome (MDS), and explored further the relative mechanisms. Patient bone marrow mononuclear cells (n=48) diagnosed as different levels of MDS were collected. Cell growth was evaluated by MTT assay; cell cycle and apoptosis were detected by flow cytometry; mRNA expression was assessed by real-time PCR, protein expression was analyzed through western blotting. Methylation was assessed by MSP. The survival time, and weight of mice were recorded. HO-1 overexpression was observed in SKM-1 cells after AZA treatment comparing to other cell lines. The HO-1 expression in MDS patients with high-risk was higher than in low-risk patients. After HO-1 was silenced by lentivirus-mediated siRNA, the proliferation of SKM-1 cells was effectively inhibited by low concentration AZA, and the cell cycle was arrested in the G0/G1 phase. Upregulation of p16 and changing of p16-relative cell cycle protein was observed after silencing HO-1 in AZA treated SKM-1 cells. In addition, DNMT1 was downregulated following the decrease of HO-1 expression. In vivo, silencing HO-1 inhibited SKM-1 cell growth induced by AZA in a NOD/SCID mouse model. Silencing HO-1 sensitized SKM-1 cells toward AZA, which may be attributed to the influence of HO-1 on AZA-induced p16 demethylation. HO-1 may be one of the targets that enhance the therapeutic effects of AZA on MDS malignant transformation inspiring new treatment methods for high-risk and very high-risk MDS patients in clinical practice.