RESUMO
We described the diagnosis and treatment of a patient with autoinflammatory disease, named "Deficiency in ELF4, X-linked (DEX)". A novel ELF4 variant was discovered and its pathogenic mechanism was elucidated. The data about clinical, laboratory and endoscopic features, treatment, and follow-up of a patient with DEX were analyzed. Whole exome sequencing and Sanger sequencing were performed to identify potential pathogenic variants. The mRNA and protein levels of ELF4 were analyzed by qPCR and Western blotting, respectively. The association of ELF4 frameshift variant with nonsense-mediated mRNA decay (NMD) in the pathogenesis DEX was examined. Moreover, RNA-seq was performed to identify the key molecular events triggered by ELF4 variant. The relationship between ELF4 and IFN-ß activity was validated using a dual-luciferase reporter assay and a ChIP-qPCR assay. An 11-year-old boy presented with a Behçet's-like phenotype. The laboratory abnormality was the most obvious in elevated inflammatory indicators. Endoscopy revealed multiple ileocecal ulcers. Intestinal histopathology showed inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-α blocker (adalimumab), which reaped an excellent response over 16 months of follow-up. Genetic analysis identified a maternal hemizygote frameshift variant (c.1022del, p.Q341Rfs*30) in ELF4 gene in the proband. The novel variant decreased the mRNA level of ELF4 via the NMD pathway. Mechanistically, insufficient expression of ELF4 disturbed the immune system, leading to immunological disorders and pathogen susceptibility, and disrupted ELF4-activating IFN-ß responses. This analysis detailed the clinical characteristics of a Chinese patient with DEX who harbored a novel ELF4 frameshift variant. For the first time, we used patient-derived cells and carried out transcriptomic analysis to delve into the mechanism of ELF4 variant in DEX.
Assuntos
Mutação da Fase de Leitura , Perfilação da Expressão Gênica , Criança , Humanos , Masculino , Sequenciamento do Exoma , Predisposição Genética para Doença , Degradação do RNAm Mediada por Códon sem Sentido , Linhagem , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , TranscriptomaRESUMO
Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.
Assuntos
Artrite , Síndrome de Behçet , Produtos Biológicos , Doenças Inflamatórias Intestinais , Masculino , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Artralgia , Proteínas de Ligação a DNA , Fatores de Transcrição/genéticaRESUMO
Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with sedative effects on sleep homeostasis. Oxytocin-expressing (OXT) neurons in the paraventricular nucleus (PVN) of the hypothalamus (PVNOXT) regulate sexual reproduction, drinking, sleep-wakefulness, and other instinctive behaviors. To investigate the effect of DEX on the activity and signal transmission of PVNOXT in regulating the sleep-wakefulness cycle. Here, we employed OXT-cre mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in PVNOXT neurons. Combining chemogenetic methods with electroencephalogram (EEG) /electromyogram (EMG) recordings, we found that cannula injection of DEX in PVN significantly increased the duration of non-rapid eye movement (NREM) sleep in mice. Furthermore, the chemogenetic activation of PVNOXT neurons using i.p. injection of clozapine N-oxide (CNO) after cannula injection of DEX to PVN led to a substantial increase in wakefulness. Electrophysiological results showed that DEX decreased the frequency of action potential (AP) and the spontaneous excitatory postsynaptic current (sEPSC) of PVNOXT neurons through α2-adrenoceptors. Therefore, these results identify that DEX promotes sleep and maintains sleep homeostasis by inhibiting PVNOXT neurons through the α2-adrenoceptor.
Assuntos
Dexmedetomidina , Neurônios , Ocitocina , Núcleo Hipotalâmico Paraventricular , Animais , Dexmedetomidina/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Ocitocina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Camundongos , Masculino , Vigília/efeitos dos fármacos , Vigília/fisiologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Hipnóticos e Sedativos/farmacologia , Sono/efeitos dos fármacos , Sono/fisiologiaRESUMO
PURPOSE: The aim of this prospective, randomized, controlled, double-blinded pilot study was to determine the rates of post-traumatic osteoarthritis and assess joint space width in the presence or absence of a single intra-articular injection of corticosteroid after an acute, intra-articular distal radius fracture (DRF). METHODS: Forty patients received a single, intra-articular, radiocarpal joint injection of 4 mg of dexamethasone (DEX) (n = 19) or normal saline placebo (n = 21) within 2 weeks of a surgically or nonsurgically treated intra-articular DRF. The primary outcome measure was minimum radiocarpal joint space width (mJSW) on noncontrast computed tomography scans at 2 years postinjection. Secondary outcomes were obtained at 3 months, 6 months, 1 year, and 2 years postinjection and included Disabilities of the Arm, Shoulder, and Hand; Michigan Hand Questionnaire; Patient-Rated Wrist Evaluation; wrist range of motion; and grip strength. RESULTS: At 2-year follow-up, there was no difference in mean mJSW between the DEX group (2.2 mm; standard deviation, 0.6; range, 1.4-3.2) and the placebo group (2.3 mm; standard deviation, 0.7; range, 0.9-3.9). Further, there were no differences in any secondary outcome measures at any postinjection follow-up interval. CONCLUSIONS: Radiocarpal joint injection of corticosteroid within 2 weeks of an intra-articular DRF does not appear to affect the development of post-traumatic osteoarthritis within 2 years follow-up in a small pilot cohort. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.
Assuntos
Dexametasona , Glucocorticoides , Osteoartrite , Fraturas do Rádio , Fraturas do Punho , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Método Duplo-Cego , Glucocorticoides/administração & dosagem , Força da Mão , Injeções Intra-Articulares , Fraturas Intra-Articulares/complicações , Fraturas Intra-Articulares/diagnóstico por imagem , Fraturas Intra-Articulares/tratamento farmacológico , Osteoartrite/etiologia , Osteoartrite/prevenção & controle , Projetos Piloto , Estudos Prospectivos , Fraturas do Rádio/complicações , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/tratamento farmacológico , Amplitude de Movimento Articular , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Fraturas do Punho/complicações , Fraturas do Punho/diagnóstico por imagem , Fraturas do Punho/tratamento farmacológico , Articulação do PunhoRESUMO
BACKGROUND: Cerebrovascular disease is one of the leading causes of death worldwide. Middle cerebral artery (MCA) is the largest and most complex of cerebral arteries. The prenatal period is a critical time for development, which largely determines lifelong health. Clinically, glucocorticoids (GCs) administration to accelerate preterm fetal lung maturation has become standard practice. Prenatal GCs administration increases cardiovascular risks in offspring, but little is known regarding the side effects on offspring MCA function. OBJECTIVE: We investigated the alterations of MCA reactivity following prenatal GCs administration in postnatal offspring. METHOD AND RESULTS: Pregnant Sprague-Dawley rats received synthetic GCs (dexamethasone, DEX) during the last week of pregnancy, and we examined vascular reactivity, cellular electrophysiology, and gene promoter epigenetic modifications in the male offspring MCA. Our results showed that prenatal DEX exposure increased the sensitivity of offspring MCA to Angiotensin II, which was resulted from the increased Cav1.2 (L-type Ca2+ channels subunit alpha1 C). Mechanistically, prenatal DEX exposure resulted in a transcriptionally active chromatin structure at the Cav1.2 gene promoter by altering histone modifications. This activation led to increased expression of vascular Cav1.2 gene, ultimately resulting in increased MCA contractility in offspring. CONCLUSION: The present study is the first to demonstrate that the adverse effects of prenatal GCs administration on cerebrovascular tone persist into adulthood, providing new insights into developmental origins of cerebrovascular disease.
Assuntos
Transtornos Cerebrovasculares , Efeitos Tardios da Exposição Pré-Natal , Ratos , Animais , Gravidez , Humanos , Feminino , Masculino , Ratos Sprague-Dawley , Glucocorticoides/efeitos adversos , Transtornos Cerebrovasculares/induzido quimicamente , Dexametasona/efeitos adversos , Artérias Cerebrais/metabolismoRESUMO
Patients with DEX (deficiency in ELF4, X-linked) were recently reported by our team and others, and cases are very limited worldwide. Our knowledge of this new disease is currently preliminary. In this study, we described 5 more cases presenting mainly with oral ulcer, inflammatory bowel disease-like symptoms, fever of unknown origin, anemia, or systemic lupus erythematosus. Whole exome sequencing identified potential pathogenic ELF4 variants in all cases. The pathogenicity of these variants was confirmed by the detection of ELF4 expression in peripheral blood mononuclear cells from patients and utilizing a simple IFN-b luciferase reporter assay, as previously reported. Our findings significantly contribute to the current understanding of DEX.
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Doenças do Sistema Imunitário , Lúpus Eritematoso Sistêmico , Humanos , Leucócitos Mononucleares , China , Estudos de Coortes , Proteínas de Ligação a DNA , Fatores de TranscriçãoRESUMO
PURPOSE: Breast cancer-related lymphedema (BCRL) represents a significant concern for patients following breast cancer treatment, and assessment for BCRL represents a key component of survivorship efforts. Growing data has demonstrated the benefits of early detection and treatment of BCRL. Traditional diagnostic modalities are less able to detect reversible subclinical BCRL while newer techniques such as bioimpedance spectroscopy (BIS) have shown the ability to detect subclinical BCRL, allowing for early intervention and low rates of chronic BCRL with level I evidence. We present updated clinical practice guidelines for BIS utilization to assess for BCRL. METHODS AND RESULTS: Review of the literature identified a randomized controlled trial and other published data which form the basis for the recommendations made. The final results of the PREVENT trial, with 3-year follow-up, demonstrated an absolute reduction of 11.3% and relative reduction of 59% in chronic BCRL (through utilization of compression garment therapy) with BIS as compared to tape measurement. This is in keeping with real-world data demonstrating the effectiveness of BIS in a prospective surveillance model. For optimal outcomes patients should receive an initial pre-treatment measurement and subsequently be followed at a minimum quarterly for first 3 years then biannually for years 4-5, then annually as appropriate, consistent with previous guidelines; the target for intervention has been changed from a change in L-Dex of 10 to 6.5. The lack of pre-operative measure does not preclude inclusion in the prospective surveillance model of care. CONCLUSION: The updated clinical practice guidelines present a standardized approach for a prospective model of care using BIS for BCRL assessment and supported by evidence from a randomized controlled trial as well as real-world data.
Assuntos
Linfedema Relacionado a Câncer de Mama , Neoplasias da Mama , Linfedema , Humanos , Feminino , Neoplasias da Mama/complicações , Neoplasias da Mama/terapia , Espectroscopia Dielétrica/métodos , Detecção Precoce de Câncer , Linfedema Relacionado a Câncer de Mama/diagnóstico , Linfedema Relacionado a Câncer de Mama/etiologia , Linfedema Relacionado a Câncer de Mama/terapia , Excisão de Linfonodo/efeitos adversos , Linfedema/diagnóstico , Linfedema/etiologia , Linfedema/terapia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: Multiple myeloma is a heterogeneous disorder and the intratumor genetic heterogeneity contributes to emergency of drug resistance. Dexamethasone has been used clinically for decades for MM. Nevertheless, their use is severely hampered by the risk of developing side effects and the occurrence of Dex resistance. LncRNA NEAT1 plays a oncogenic role and participates in drug resistance in many solid tumors. Therefore, we investigated a potential usefulness of this molecular as a biomarker for diagnosis of MM and possible correlations of NEAT1 expression with drug resistance and prognosis. METHODS: Bone marrow and peripheral blood mononuclear cells samples were collected from 60 newly diagnosed MM patients. The expression of NEAT1expression level were detected by quantitative real-time PCR analyses. The relationship about the expression levels of lncRNA with other clinical and cytogenetic features was analyzed. In addition, we measured to analysis the correlation between the expression of NEAT1 and Dex resistance in MM patients. RESULTS: It was found that the expression of NEAT1 is significantly higher in multiple myeloma patients compared to controls and does not change with other clinical features and cytogenetic features. We further discovered that overexpression of NEAT1 was associated with Dex resistance and a poor prognosis in MM patients. CONCLUSION: LncRNA NEAT1 has a significant value that might act as a promoting factor in the development of MM and may be severed as a diagnostic factor in MM. NEAT1 invovled in Dex resistance, which provide a new interpretation during the chemotherapy for MM.
Assuntos
Mieloma Múltiplo , RNA Longo não Codificante , Humanos , Biomarcadores , Leucócitos Mononucleares/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Prognóstico , RNA Longo não Codificante/metabolismoRESUMO
Dexmedetomidine has been demonstrated to be effective in the management of pain in total knee replacement (TKA). Nevertheless, a combination of a local anaesthetic and a dose of dexmedetomidine might be a better choice for post-operative pain management of TKA. The aim of this research is to determine if the combination of a local anaesthetic with dexmedetomidine during a knee replacement operation can decrease the post-operation pain. Furthermore, the effectiveness and security of dexmedetomidine combined with topical anaesthetic were evaluated for the management of post-operative TKA. Based on the research results, the author made a research on the basis of four big databases. The Cochrane Handbook on Intervention Systems Evaluation has also evaluated the quality of the literature. Seven randomized controlled trials have been established from this. It was found that the combination of local anaesthesia and dexmedetomidine had a greater effect on postoperative pain in 4 h (mean difference [MD], -0.9; 95% CI, -1.71, -0.09; p = 0.03), 8 h (MD, -0.52; 95% CI, -0.66, -0.38; p < 0.0001), 12 h (MD, -0.72; 95% CI, -1.04, -0.40; p < 0.0001), 24 h (MD, -0.49; 95% CI, -0.83, -0.14; p = 0.006), 48 h (MD, -0.51; 95% CI, -0.92, -0.11; p = 0.01). Nevertheless, because of the limited number of randomized controlled trials covered by this meta-analysis, caution should be exercised with regard to data treatment. More high quality research will be required to confirm the results.
RESUMO
Currently, there is very limited information on the electrophoretic behavior of particles at a liquid-liquid interface formed by two conducting liquid solutions. Here, electrophoretic velocities of polystyrene particles at a polyethylene glycol (PEG)-dextran (DEX) interface were investigated in this paper. Experimental results show that the particle at the interface moves in the opposite direction to the applied electric field, with a velocity much lower than that in the PEG-rich phase and a litter larger than that in the DEX-rich phase. Similarly to the movement in Newtonian fluids, the velocity increases linearly with the increase in the applied electric field. Different to particle electrophoresis in Newtonian fluids, the velocities of the particles at the PEG-DEX interface increase linearly with the decrease in particle's diameters, implying a possible size-based particle differentiation at an interface.
Assuntos
Polietilenoglicóis , Poliestirenos , Dextranos , Tamanho da Partícula , EletroforeseRESUMO
Vital organ injury is one of the leading causes of global deaths. Accumulating studies have demonstrated that dexmedetomidine (DEX) has an outstanding protective effect on multiple organs for its antiinflammatory and antiapoptotic properties, while the underlying molecular mechanism is not clearly understood. Autophagy, an adaptive catabolic process, has been found to play a crucial role in the organ-protective effects of DEX. Herein, we present a first attempt to summarize all the evidence on the proposed roles of autophagy in the action of DEX protecting against vital organ injuries via a comprehensive review. We found that most of the relevant studies (17/24, 71%) demonstrated that the modulation of autophagy was inhibited under the treatment of DEX on vital organ injuries (e.g. brain, heart, kidney, and lung), but several studies suggested that the level of autophagy was dramatically increased after administration of DEX. Albeit not fully elucidated, the underlying mechanisms governing the roles of autophagy involve the antiapoptotic properties, inhibiting inflammatory response, removing damaged mitochondria, and reducing oxidative stress, which might be facilitated by the interaction with multiple associated genes (i.e., hypoxia inducible factor-1α, p62, caspase-3, heat shock 70 kDa protein, and microRNAs) and signaling cascades (i.e., mammalian target of rapamycin, nuclear factor-kappa B, and c-Jun N-terminal kinases pathway). The authors conclude that DEX hints at a promising strategy in the management of vital organ injuries, while autophagy is crucially involved in the protective effect of DEX.
Assuntos
Dexmedetomidina , Apoptose , Autofagia , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Estresse Oxidativo , Transdução de SinaisRESUMO
BACKGROUND: Reperfusion of ischemic tissue has adverse impact on the myocardium. Dexmedetomidine (Dex) is a α2-adrenergic receptor (α2-AR) agonist with sedative and analgesic effects. Macrophage migration inhibition factor (MIF) is a pressure-regulating cytokine and is responsible for inflammatory and immune diseases. This study aims to reveal the consequences of Dex on myocardial ischemia-reperfusion injury (IRI) in young mice. METHODS: Fifty mice were raised and examined. At the end of the experiment, all mice were euthanized. The anterior descending department of the left coronary artery in mice was under ischemia for 60 min, then the ligation line was released and reperfused for 120 min to establish the IRI model. Mice were randomly divided into Sham, control, treatment using 4,5-dihydro-3-(4-hydroxyphenyl)-5-isoxazoleacetic acid (ISO-1), Dex treatment, and Dex combined ISO-1 treatment groups. Interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and ATP levels were recorded. The expressions of MIF, P-adenosine monophosphate-activated kinase α (AMPKα), glucose transporter (GLUT)4, Bax and Bcl-2 were detected by Western Blot (WB). Hematoxylin and Eosin (H&E) staining was used to study cell morphology. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Echocardiography was carried out at the end of reperfusion, and the infarct size was calculated by Electron microscopy. RESULTS: I/R + Dex group showed significantly increased IL-6 and TNF-α levels and reduced myocardial cell necrosis and apoptosis. H&E staining showed alleviated myocardial disorder, myocardial cell swelling, myocardial fiber fracture, and inflammatory cell infiltration in I/R + Dex group. Myocardial cell necrosis and apoptosis were significantly reduced in I/R + Dex group. ATP level in myocardial tissue of mice in I/R group was substantially decreased, while that in Dex group was increased. WB results showed that MIF, P-AMPK α, GLUT4 and Bcl-2 levels were increased and Bax levels were decreased in I/R + Dex group. CONCLUSION: Dex may exert myocardial protection in young mice through MIF/AMPK/GLUT4 axis.
Assuntos
Dexmedetomidina , Fatores Inibidores da Migração de Macrófagos , Traumatismo por Reperfusão Miocárdica , Proteínas Quinases Ativadas por AMP , Trifosfato de Adenosina , Agonistas de Receptores Adrenérgicos alfa 2 , Animais , Dexmedetomidina/farmacologia , Interleucina-6 , Camundongos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Necrose , Proteínas Proto-Oncogênicas c-bcl-2 , Fator de Necrose Tumoral alfa , Proteína X Associada a bcl-2RESUMO
BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease associated with myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine (Dex), an α2-adrenoceptor agonist, has been reported to protect against I/R injury. We examined the cardioprotective effects of Dex on cardiomyocytes under hypoxia/reoxygenation (H/R) conditions and explored the underlying mechanisms. MATERIALS AND METHODS: A H/R model was established to mimic the MI injury. The CCK-8 assay was performed to measure cell viability. Cellular apoptosis was measured using the Annexin V fluorescein isothiocyanate (FITC)-propidium iodide (PI) staining. The levels of interleukin (IL)-1α and tumor necrosis factor (TNF)-α, and the activity of lactate dehydrogenase (LDH) were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Reactive oxygen species (ROS) were measured using the 2'-7' dichlorofluorescein diacetate (DCFH-DA) staining assay. In addition, the levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), catalase (CAT), and caspase-3 were measured using a commercial kit. siRNA was used to silence Bcl-2, catalase, or STAT3. Western blotting was used to measure the change in the levels of proteins. RESULTS: Dex improved the cell viability and inhibited the inflammatory response in H9c2 cells exposed to H/R treatment. In addition, Dex inhibited apoptosis and alleviated the endoplasmic reticulum (ER) stress and oxidative stress in H9c2 cells under the H/R treatment. Mechanism investigation showed that Dex inhibited the intrinsic pathway of apoptosis. Moreover, Dex enhanced the activation of the JAK2/STAT3 signaling pathway in H/R-treated H9c2 cells. CONCLUSION: Altogether, our findings suggested Dex as a promising therapeutic agent for myocardial I/R.
Assuntos
Dexmedetomidina , Traumatismo por Reperfusão Miocárdica , Apoptose , Catalase , Dexmedetomidina/metabolismo , Dexmedetomidina/farmacologia , Humanos , Hipóxia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , Estresse OxidativoRESUMO
Muscular atrophy (MA) is a disease of various origins, i.e., genetic or the most common, caused by mechanical injury. So far, there is no universal therapeutic model because this disease is often progressive with numerous manifested symptoms. Moreover, there is no safe and low-risk therapy dedicated to muscle atrophy. For this reason, our research focuses on finding an alternative method using natural compounds to treat MA. This study proposes implementing natural substances such as celastrol and Rhynchophylline on the cellular level, using a simulated and controlled atrophy process. Methods: Celastrol and Rhynchophylline were used as natural compounds against simulated atrophy in C2C12 cells. Skeletal muscle C2C12 cells were stimulated for the differentiation process. Atrophic conditions were obtained by the exposure to the low concertation of doxorubicin and validated by FoxO3 and MAFbx. The protective and regenerative effect of drugs on cell proliferation was determined by the MTT assay and MT-CO1, VDAC1, and prohibitin expression. Results: The obtained results revealed that both natural substances reduced atrophic symptoms. Rhynchophylline and celastrol attenuated atrophic cells in the viability studies, morphology analysis by diameter measurements, modulated prohibitin VDAC, and MT-CO1 expression. Conclusions: The obtained results revealed that celastrol and Rhynchophylline could be effectively used as a supportive treatment in atrophy-related disorders. Thus, natural drugs seem promising for muscle regeneration.
RESUMO
BACKGROUND: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising tool for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes. OBJECTIVE: To improve the electrophysiological maturation of hiPSC-CMs. METHODS AND RESULTS: On day 16 of cardiac differentiation, hiPSC-CMs were treated with 100 nmol/L triiodothyronine (T3) and 1 µmol/L Dexamethasone (Dex) or vehicle for 14 days. On day 30, vehicle- and T3 + Dex-treated hiPSC-CMs were dissociated and replated either as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3 + Dex-treated hiPSC-CMs. Compared to vehicle, T3 + Dex-treated hiPSC-CMs had a slower spontaneous beating rate, more hyperpolarized resting membrane potential, faster maximal upstroke velocity, and shorter action potential duration. Changes in spontaneous activity and action potential were mediated by decreased hyperpolarization-activated current (If) and increased inward rectifier potassium currents (IK1), sodium currents (INa), and the rapidly and slowly activating delayed rectifier potassium currents (IKr and IKs, respectively). Furthermore, T3 + Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter action potential duration than the vehicle. Inhibition of IK1 by 100 µM BaCl2 significantly slowed conduction velocity and prolonged action potential duration in T3 + Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the importance of IK1 for conduction velocity and action potential duration. CONCLUSION: T3 + Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.
Assuntos
Dexametasona/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/fisiologia , Canais de Potássio/genética , Tri-Iodotironina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Canais de Potássio/metabolismo , Análise de Célula ÚnicaRESUMO
Previous studies have shown that dexamethasone (Dex) reduces the levels of anti-nuclear (ANA) and anti-dsDNA antibodies in MRL/lpr mice (a mouse model of SLE). However, the effect of Dex on T follicular helper (Tfh) cells is less documented. Here, using the MRL/lpr mouse model, we investigated the influence of Dex on Tfh cells and potential underlying mechanisms. The data showed that the proportion of Tfh cells, identified as CD4+ CXCR5+ ICOS+ , CD4+ CXCR5+ PD-1+ or CD4+ BCL-6+ cells, markedly decreased after treatment with the Dex, in both Balb/c mice and MRL/lpr mice. Dex significantly inhibited IL-21 expression at both the mRNA and the protein levels. Dex also significantly reduced the proportion of germinal centre B cells and decreased serum IgG, IgG2a/b and IgA levels. Moreover, a positive correlation between the proportion of Tfh cells (CD4+ CXCR5+ ICOS+ , CD4+ CXCR5+ PD-1+ or CD4+ BCL-6+ ) and autoantibodies was observed. Dex significantly increased the Prdm1 and Stat5b mRNA expression and decreased the Bcl-6 and c-Maf mRNA expression of CD4+ T cells. In brief, Dex inhibited the Tfh development, which relies on many other transcription factors in addition to Bcl-6. Our data indicate that Dex can be used as a Tfh cell inhibitor in SLE.
Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos B/efeitos dos fármacos , Dexametasona/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Células T Auxiliares Foliculares/efeitos dos fármacos , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Feminino , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos MRL lpr , Células T Auxiliares Foliculares/citologia , Células T Auxiliares Foliculares/imunologiaRESUMO
Glucocorticoid-induced osteoporosis (GIOP) has emerged as a challenge after long-term glucocorticoid administration during the clinical therapy of diverse diseases. Although some candidates for GIOP treatment have been explored, there is still a lack of reliable drugs for GIOP prevention. In this study, rat bone marrow stem cells (rBMSCs) were utilized to investigate the feasibility of applying strontium gluconate (GluSr), which displays mild activity, easy absorption and good biocompatibility, for GIOP prevention. Thirty-two SD rats were divided into 4 groups to explore the effects of GluSr on osteoporosis rescue in vivo. Our results suggested that GluSr markedly alleviated dexamethasone (DEX)-induced apoptosis of osteoblast precursor cells and rBMSCs and enhanced rBMSC osteogenesis differentiation in vitro. GluSr also effectively promoted osteoblast survival, inhibited osteoclast differentiation and restored bone formation in GIOP rat models. Microarray analysis of the femora from GIOP rats treated with GluSr revealed that the signalling pathways of the glucocorticoid receptor (GR), oestrogen receptor gene (ESR) and vitamin D receptor (VDR) were involved in bone restoration by GluSr. In summary, our study proved that GluSr enhanced osteoblast differentiation and suppressed osteoclast activity both in vitro and in vivo. GluSr might function as a novel strontium reagent for GIOP prevention.
Assuntos
Glucocorticoides/efeitos adversos , Gluconatos/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Células-Tronco/efeitos dos fármacos , Estrôncio/farmacologia , Animais , Medula Óssea/metabolismo , Células Cultivadas , Dexametasona/efeitos adversos , Modelos Animais de Doenças , Masculino , Camundongos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/patologia , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
BACKGROUND: Radiotherapy is the mainstay of brain metastasis (BM) management. Radiation necrosis (RN) is a serious complication of radiotherapy. Bevacizumab (BV), an anti-vascular endothelial growth factor monoclonal antibody, has been increasingly used for RN treatment. We systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab for treatment of RN in BM patients. MATERIALS AND METHODS: PubMed, Medline, EMBASE, and Cochrane library were searched with various search keywords such as "bevacizumab" OR "anti-VEGF monoclonal antibody" AND "radiation necrosis" OR "radiation-induced brain necrosis" OR "RN" OR "RBN" AND "Brain metastases" OR "BM" until 1st Aug 2020. Studies reporting the efficacy and safety of BV treatment for BM patients with RN were retrieved. Study selection and data extraction were carried out by independent investigators. Open Meta Analyst software was used as a random effects model for meta-analysis to obtain mean reduction rates. RESULTS: Two prospective, seven retrospective, and three case report studies involving 89 patients with RN treated with BV were included in this systematic review and meta-analysis. In total, 83 (93%) patients had a recorded radiographic response to BV therapy, and six (6.7%) had experienced progressive disease. Seven studies (n = 73) reported mean volume reductions on gadolinium-enhanced T1 (mean: 47.03%, +/- 24.4) and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI images (mean: 61.9%, +/- 23.3). Pooling together the T1 and T2 MRI reduction rates by random effects model revealed a mean of 48.58 (95% CI: 38.32-58.85) for T1 reduction rate and 62.017 (95% CI: 52.235-71.799) for T2W imaging studies. Eighty-five patients presented with neurological symptoms. After BV treatment, nine (10%) had stable symptoms, 39 (48%) had improved, and 34 (40%) patients had complete resolution of their symptoms. Individual patient data was available for 54 patients. Dexamethasone discontinuation or reduction in dosage was observed in 30 (97%) of 31 patients who had recorded dosage before and after BV treatment. Side effects were mild. CONCLUSIONS: Bevacizumab presents a promising treatment strategy for patients with RN and brain metastatic disease. Radiographic response and clinical improvement was observed without any serious adverse events. Further class I evidence would be required to establish a bevacizumab recommendation in this group of patients.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/radioterapia , Lesões por Radiação/tratamento farmacológico , Radioterapia/efeitos adversos , Neoplasias Encefálicas/patologia , Humanos , Necrose , Prognóstico , Lesões por Radiação/etiologia , Lesões por Radiação/patologiaRESUMO
Undoubtedly, various kinds of nanomaterials are of great significance due to their enormous applications in diverse areas. The structure and productivity of nanomaterials are heavily dependent on the process used for their synthesis. The synthesizing process plays a vital role in shaping nanomaterials effectively for better productivity. The conventional method requires expensive and massive thermal instruments, a huge volume of reagents. This paper aims to develop an Automatic Miniaturized Temperature Controller (AMTC) device for the synthesis of nickel oxide (NiO), copper oxide (CuO) nanoparticles, and nanomicelles. The device features a low-cost, miniaturized, easy-to-operate with plug-and-play power source, precise temperature control, and geotagged real-time data logging facility for the producing nanoparticles. With a temperature accuracy of ± 2 °C, NiO and CuO nanoparticles, and nanomicelles are synthesized on AMTC device, and are subjected to different characterizations to analyze their morphological structure. The obtained mean size of NiO and CuO is 27.14 nm and 85.13 nm respectively. As a proof-of-principle, the synthesized NiO and CuO nanomaterials are validated for electrochemical sensing of dopamine, hydrazine, and uric acid. Furthermore, the study is conducted, wherein, Dexamethasone (Dex) loaded nanomicelles are developed using AMTC device and compared to the conventional thin-film hydration method. Subsequently, as a proof-of-application, the developed nanomicelles are evaluated for transcorneal penetration using exvivo goat cornea model. Ultimately, the proposed device can be utilized for performing a variety of controlled thermal reactions on a minuscule platform with an integrated and miniaturized approach for various applications.
Assuntos
Nanopartículas , Preparações Farmacêuticas , Cobre , Smartphone , TemperaturaRESUMO
Infrared thermography (IRT) is increasingly applied as a noninvasive technique for measuring surface body temperature changes related to physiological stress. As a basis for validation of IRT as a tool for diagnostic use, we need to assess its potential to measure hypothalamic-pituitary-adrenal (HPA) axis reactivity. We used experimental manipulations of the HPA axis in house sparrows (Passer domesticus), i.e. adrenal tissue responsiveness to exogenous adrenocorticotropin (ACTH) and the efficacy of negative feedback using the synthetic glucocorticoid dexamethasone (DEX), to test whether IRT is an effective tool for measuring HPA reactivity. Experimental birds showed a pronounced decrease in skin temperatures after ACTH injection and an increase in temperature after DEX injection. However, individual variation in glucocorticoid levels were not related to skin temperatures except after ACTH injection in experimental birds. We show that IRT can be used to measure HPA reactivity but that skin-temperature is not a good index for glucocorticoid secretion at baseline levels. These results suggest that while IRT of skin temperatures is a useful, noninvasive measure of HPA axis reactivity under acute activation, this technique might not be suitable for measuring natural variation of circulating glucocorticoid levels.