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1.
Neurosurg Rev ; 45(2): 1401-1411, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34606021

RESUMO

A subset of large non-functioning pituitary adenomas (lNFPA) and giant non-functioning pituitary adenomas (gNFPA) undergoes early progression/recurrence (P/R) after surgery. This study revealed the clinical and image predictors of P/R in lNFPA and gNFPA, with emphasis on solid tumor size. This retrospective study investigated the preoperative MR imaging features for the prediction of P/R in lNFPA (> 3 cm) and gNFPA (> 4 cm). Only the patients with a complete preoperative brain MRI and undergone postoperative MRI follow-ups for more than 1 year were included. From November 2010 to December 2020, a total of 34 patients diagnosed with lNFPA and gNFPA were included (median follow-up time 47.6 months) in this study. A total of twenty-three (23/34, 67.6%) patients had P/R, and the median time to P/R is 25.2 months. Solid tumor diameter (STD), solid tumor volume (STV), and extent of resection are associated with P/R (p < 0.05). Multivariate analysis showed large STV is a risk factor for P/R (p < 0.05) with a hazard ratio of 30.79. The cutoff points of STD and STV for prediction of P/R are 26 mm and 7.6 cm3, with AUCs of 0.78 and 0.79 respectively. Kaplan-Meier analysis of tumor P/R trends showed that patients with larger STD and STV exhibited shorter progression-free survival (p < 0.05). For lNFPA and gNFPA, preoperative STD and STV are significant predictors of P/R. The results offer objective and valuable information for treatment planning in this subgroup.


Assuntos
Adenoma , Neoplasias Hipofisárias , Adenoma/diagnóstico por imagem , Adenoma/patologia , Adenoma/cirurgia , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/cirurgia , Procedimentos Neurocirúrgicos/métodos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
3.
Pain Rep ; 6(1): e922, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34585035

RESUMO

Transient receptor potential vanilloid subtype 1 (TRPV1) is a polymodal nociceptor that monitors noxious thermal sensations. Few studies have addressed the role of TRPV1 in mechanical allodynia in small-fiber neuropathy (SFN) caused by sensory nerve damage. Accordingly, this article reviews the putative mechanisms of TRPV1 depletion that mediates mechanical allodynia in SFN. The intraepidermal nerve fibers (IENFs) degeneration and sensory neuronal injury are the primary characteristics of SFN. Intraepidermal nerve fibers are mainly C-polymodal nociceptors and Aδ-fibers, which mediated allodynic pain after neuronal sensitization. TRPV1 depletion by highly potent neurotoxins induces the upregulation of activating transcription factor 3 and IENFs degeneration which mimics SFN. TRPV1 is predominately expressed by the peptidergic than nonpeptidergic nociceptors, and these neurochemical discrepancies provided the basis of the distinct pathways of thermal analgesia and mechanical allodynia. The depletion of peptidergic nociceptors and their IENFs cause thermal analgesia and sensitized nonpeptidergic nociceptors respond to mechanical allodynia. These distinct pathways of noxious stimuli suggested determined by the neurochemical-dependent neurotrophin cognate receptors such as TrkA and Ret receptors. The neurogenic inflammation after TRPV1 depletion also sensitized Ret receptors which results in mechanical allodynia. The activation of spinal TRPV1(+) neurons may contribute to mechanical allodynia. Also, an imbalance in adenosinergic analgesic signaling in sensory neurons such as the downregulation of prostatic acid phosphatase and adenosine A1 receptors, which colocalized with TRPV1 as a membrane microdomain also correlated with the development of mechanical allodynia. Collectively, TRPV1 depletion-induced mechanical allodynia involves a complicated cascade of cellular signaling alterations.

4.
Lab Invest ; 101(10): 1341-1352, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34172832

RESUMO

We investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3-/- and clec5a-/-, respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a-/- mice. The DN and clec5a-/- groups also exhibited neuropathic behavior, but not in the aft3-/- group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation-regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α in the DN and clec5a-/- groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a-/- mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3-/- mice. Furthermore, the mRNA of reactive oxygen species-removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a-/- groups but were not changed in the aft3-/- group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy.


Assuntos
Fator 3 Ativador da Transcrição/genética , Neuropatias Diabéticas , Estresse do Retículo Endoplasmático/genética , Lectinas Tipo C/genética , Mutação com Perda de Função/genética , Receptores de Superfície Celular/genética , Animais , Citocinas/metabolismo , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
5.
PLoS One ; 15(5): e0233188, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413077

RESUMO

Glioblastoma (GBM) has the highest fatality rate among primary malignant brain tumors and typically tends to recur locally just adjacent to the original tumor site following surgical resection and adjuvant radiotherapy. We conducted a study to evaluate the survival outcomes between a standard dose (≤ 60 Gy) and moderate radiation dose escalation (>60 Gy), and to identify prognostic factors for GBM. We retrospectively reviewed the medical records of primary GBM patients diagnosed between 2005 and 2016 in two referral hospitals in Taiwan. They were identified from the cancer registry database and followed up from the date of diagnosis to October 2018. The progression-free survival (PFS) and overall survival (OS) were compared between the two dose groups, and independent factors for survival were analyzed through Cox proportional hazard model. We also affirmed the results using Cox regression with least absolute shrinkage and selection operator (LASSO) approach. From our cancer registry database, 142 GBM patients were identified, and 84 of them fit the inclusion criteria. Of the 84 patients, 52 (62%) were males. The radiation dose ranged from 50.0 Gy to 66.6 Gy, but their treatment volumes were similar to the others. Fifteen (18%) patients received an escalated dose boost >60.0 Gy. The escalated group had a longer median PFS (15.4 vs. 7.9 months, p = 0.01 for log-rank test), and a longer median OS was also longer in the escalation group (33.8 vs. 12.5 months, p <0.001) than the reference group. Following a multivariate analysis, the escalated dose was identified as a significant predictor for good prognosis (PFS: hazard ratio [HR] = 0.48, 95% confidence interval [95%CI]: 0.23-0.98; OS: HR = 0.40, 95%CI: 0.21-0.78). Using the LASSO approach, we found age > 70 (HR = 1.55), diagnosis after 2010 (HR = 1.42), and a larger radiation volume (≥ 250ml; HR = 0.81) were predictors of PFS. The escalated dose (HR = 0.47) and a larger radiation volume (HR = 0.76) were identified as predictors for better OS. Following detailed statistical analysis, a moderate radiation dose escalation (> 60 Gy) was found as an independent factor affecting OS in GBM patients. In conclusion, a moderate radiation dose escalation (> 60 Gy) was an independent predictor for longer OS in GBM patients. However, prospective studies including more patients with more information, such as molecular markers and completeness of resection, are needed to confirm our findings.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Doses de Radiação , Estudos Retrospectivos , Taxa de Sobrevida , Taiwan , Adulto Jovem
6.
Biol Open ; 8(1)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30578250

RESUMO

Specialized microdomains which have cholesterol-rich membrane regions contain transient receptor potential vanilloid subtype 1 (TRPV1) are involved in pain development. Our previous studies have demonstrated that the depletion of prostatic acid phosphatase (PAP) - a membrane-bound ectonucleotidase -- and disordered adenosine signaling reduce the antinociceptive effect. The role of membrane integrity in the PAP-mediated antinociceptive effect in small-fiber neuropathy remains unclear, especially with respect to whether TRPV1 and PAP are colocalized in the same microdomain which is responsible for PAP-mediated antinociception. Immunohistochemistry was conducted on the dorsal root ganglion to identify the membrane compositions, and pharmacological interventions were conducted using methyl-ß-cyclodextrin (MßC) - a membrane integrity disruptor that works by depleting cholesterol - in pure small-fiber neuropathy with resiniferatoxin (RTX). Immunohistochemical evidence indicated that TRPV1 and PAP were highly colocalized with flotillin 1 (66.7%±9.7%) and flotillin 2 (73.7%±6.0%), which reside in part in the microdomain. MßC mildly depleted PAP, which maintained the ability to hydrolyze phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and delayed the development of mechanical allodynia. MßC treatment had no role in thermal transduction and neuronal injury following RTX neuropathy. In summary, this study demonstrated the following: (1) membrane cholesterol depletion preserves PAP-mediated antinociception through PI(4,5)P2 hydrolysis and (2) pain hypersensitivity that develops after TRPV1(+) neuron depletion-mediated neurodegeneration following RTX neuropathy is attributable to the downregulation of PAP analgesic signaling.

7.
Pain ; 159(8): 1580-1591, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29672450

RESUMO

The neurochemical effects of adenosine signaling in small-fiber neuropathy leading to neuropathic pain are yet to be explored in a direct manner. This study examined this system at the level of ligand (through the ectonucleotidase activity of prostatic acid phosphatase [PAP]) and adenosine A1 receptors (A1Rs) in resiniferatoxin (RTX) neuropathy, a peripheral neurodegenerative disorder that specifically affects nociceptive nerves expressing transient receptor potential vanilloid type 1 (TRPV1). We conducted immunohistochemistry on dorsal root ganglion (DRG) neurons, high-performance liquid chromatography for functional assays, and pharmacological interventions to alter PAP and A1Rs in mice with RTX neuropathy. In DRG of RTX neuropathy, PAP(+) neurons were reduced compared with vehicle-treated mice (P = 0.002). Functionally, PAP ectonucleotidase activity was consequently reduced (ie, the content of adenosine in DRG, P = 0.012). PAP(+) neuronal density was correlated with the degree of mechanical allodynia, which was reversed by intrathecal (i.t.) lumbar puncture injection of recombinant PAP with a dose-dependent effect. Furthermore, A1Rs were downregulated (P = 0.002), and this downregulation was colocalized with the TRPV1 receptor (31.0% ± 2.8%). Mechanical allodynia was attenuated in a dose-dependent response by i.t. injection of the A1R ligand, adenosine; however, no analgesia was evident when an exogenous adenosine was blocked by A1R antagonist. This study demonstrated dual mechanisms of neuropathic pain in TRPV1-induced neuropathy, involving a reduced adenosine system at both the ligand (adenosine) and receptor (A1Rs) levels.


Assuntos
Adenosina/metabolismo , Diterpenos/toxicidade , Regulação para Baixo/efeitos dos fármacos , Neuralgia/metabolismo , Neurotoxinas/toxicidade , Receptor A1 de Adenosina/metabolismo , Neuropatia de Pequenas Fibras/induzido quimicamente , Animais , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Camundongos , Neuralgia/etiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Medição da Dor , Neuropatia de Pequenas Fibras/complicações , Neuropatia de Pequenas Fibras/metabolismo
8.
Biomed Pharmacother ; 101: 155-161, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29486333

RESUMO

Animal models are widely used to develop drugs for treating diabetes mellitus (DM). Insulin resistance (IR) is one of the main problems in type-2 DM (T2DM). Streptozotocin (STZ) is used to damage pancreatic cells for induction of DM. Many rat models were applied in research as T2DM. However, the degree of IR in each model is unknown. In the present study, IR and insulin signaling were compared in four models of type 2 diabetes: rats fed a fructose-rich chow for 8 weeks, rats feed high-fat chow for 4 weeks followed by injection with streptozotocin (35 mg/kg, i.p.), rats injected with a single low dose streptozotocin (45 mg/kg, i.p.), and rats injected with a single dose of nicotinamide followed by a single high dose of streptozotocin (60 mg/kg, i.p.). Values from these determinations in diabetic rats showing the order that insulin resistance is most marked in rats received fructose-rich chow followed by high-fat diet before STZ injection induced model (HFD/STZ rats), and rats injected with low dose of STZ but it is less marked in rats induced by nicotinamide and STZ. Additionally, insulin secretion was reduced in three rat models except the rats receiving fructose-rich chow. Western blots also showed the same changes in phosphorylation of IRS-1 or Akt using soleus muscle from each model. The obtained data suggest a lack of pronounced IR in the rats with acute diabetes induced by nicotinamide and STZ while IR is markedly identified in rats fed fructose-rich chow. However, the increase of plasma glucose levels in fructose-rich chow-fed rats was not so significant as other groups. Therefore, HFD/STZ rats is an appropriate and stable animal model which is analogous to the human T2DM through a combination of high-fat diet with multiple low-dose STZ injections.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Resistência à Insulina/fisiologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/toxicidade , Frutose/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina/toxicidade
9.
Low Urin Tract Symptoms ; 10(3): 315-319, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28681521

RESUMO

OBJECTIVES: To investigate the effect of high-fat diet (HFD) on bladder M1,3 muscarinic receptor expression and contractile function in the rat. METHODS: Eight-week-old male rats were divided into two groups including one with HFD for 8 weeks (short-term) and the other for 24 weeks (long-term). Each group was compared to age-matched rats fed with normal chow as controls. The body weight, food intake amount and blood biochemistry were monitored. Bladder muscle contractile responses to acetylcholine (0.1-10 µM), bethanechol (10 µM) and KCl (50 mM) were studied in an organ bath set-up. Bladder M1 and M3 muscarinic receptor protein expressions were measured by Western blotting analysis. RESULTS: Increase in body weight as well as blood triglyceride, cholesterol and sugar levels compared to controls were noted in both 8- and 24-week HFD rats. Eating appetite change with increased food and water intakes was noted in the HFD rats. Significantly decreased bladder contractile responses to acetylcholine and bethanechol were shown in both HFD groups. On the other hand, decreased bladder contractile response to KCl was demonstrated in the 24-week group but not the 8-week group. The expressions of bladder M1 and M3 muscarinic receptor proteins were significantly and progressively decreased by HFD feeding from 8 to 24 weeks. CONCLUSIONS: High-fat diet induces obesity and polyphagia in rats. Short-term and long-term HFD feeding decrease rat bladder M1 and M3 receptor expressions as well as contractile responses to the agonistic stimulation. In addition, bladder muscle dysfunction develops after long-term HFD feeding.


Assuntos
Gorduras na Dieta/administração & dosagem , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M3/metabolismo , Bexiga Urinária/metabolismo , Acetilcolina/farmacologia , Animais , Betanecol/farmacologia , Agonistas Colinérgicos/farmacologia , Comportamento Alimentar , Masculino , Agonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiopatologia , Ratos , Fatores de Tempo , Bexiga Urinária/fisiopatologia
10.
Drug Des Devel Ther ; 10: 2669-76, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27578964

RESUMO

BACKGROUND: G-protein-coupled bile acid receptor 1, also known as TGR5 is known to be involved in glucose homeostasis. In animal models, treatment with a TGR5 agonist induces incretin secretion to reduce hyperglycemia. Betulinic acid, a triterpenoid present in the leaves of white birch, has been introduced as a selective TGR5 agonist. However, direct activation of TGR5 by betulinic acid has not yet been reported. METHODS: Transfection of TGR5 into cultured Chinese hamster ovary (CHO-K1) cells was performed to establish the presence of TGR5. Additionally, TGR5-specific small interfering RNA was employed to silence TGR5 in cells (NCI-H716 cells) that secreted incretins. Uptake of glucose by CHO-K1 cells was evaluated using a fluorescent indicator. Amounts of cyclic adenosine monophosphate and glucagon-like peptide were quantified using enzyme-linked immunosorbent assay kits. RESULTS: Betulinic acid dose-dependently increases glucose uptake by CHO-K1 cells transfected with TGR5 only, which can be considered an alternative method instead of radioligand binding assay. Additionally, signals coupled to TGR5 activation are also increased by betulinic acid in cells transfected with TGR5. In NCI-H716 cells, which endogenously express TGR5, betulinic acid induces glucagon-like peptide secretion via increasing calcium levels. However, the actions of betulinic acid were markedly reduced in NCI-H716 cells that received TGR5-silencing treatment. Therefore, the present study demonstrates the activation of TGR5 by betulinic acid for the first time. CONCLUSION: Similar to the positive control lithocholic acid, which is the established agonist of TGR5, betulinic acid has been characterized as a useful agonist of TGR5 and can be used to activate TGR5 in the future.


Assuntos
Receptores Acoplados a Proteínas G/agonistas , Triterpenos/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Triterpenos Pentacíclicos , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química , Células Tumorais Cultivadas , Ácido Betulínico
11.
J Diabetes Complications ; 30(8): 1426-1433, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27481368

RESUMO

Increased evidence has shown that diabetes can be a risk factor for pulmonary fibrosis. The objective of this study was to use streptozotocin-induced diabetic rats (STZ rats) to assess the possible signals associated with lung damage in diabetic disorders. The expression levels of signal transducer and activator of transcription 3 (STAT3) and connective tissue growth factor (CTGF) in lung tissues were measured through Western blot analysis and real-time PCR. Additionally, the potential mechanisms were confirmed in cultured rat lung cell line (L2) incubated in high-glucose (HG) medium to mimic the in vivo changes. The pathological changes in the lung tissues of STZ rats were characterized using the bleomycin-treated tissues as reference. Moreover, the higher expression levels of STAT3 and CTGF in the lung tissues of STZ rats were reversed by treating the hyperglycemia. CTGF expression increased following the higher expression of STAT3 in the cultured L2 cells exposed to HG, and this change was reversed by siRNA treatment specific for STAT3. Stattic, at a dose sufficient to inhibit STAT3, reduced the CTGF levels in the lungs of STZ rats. In conclusion, STAT3 enhanced CTGF expression in a type-1 diabetes model associated with lung damage. Thus, STAT3 inhibitors may be developed to improve diabetes-induced lung damage in the future.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Hiperglicemia/fisiopatologia , Pulmão/patologia , Fibrose Pulmonar/patologia , Fator de Transcrição STAT3/metabolismo , Animais , Linhagem Celular , Masculino , Ratos , Ratos Wistar , Estreptozocina
12.
Drug Des Devel Ther ; 10: 1877-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27350742

RESUMO

BACKGROUND: Erythropoietin (EPO) is widely used in diabetic patients receiving hemodialysis. The role of EPO in glucose homeostasis remains unclear. Therefore, we investigated the effect of EPO on hyperglycemia in rats with type 1-like diabetes. METHODS: Rats with streptozotocin-induced type 1-like diabetes (STZ rats) were used to estimate the blood glucose-lowering effects of EPO, and changes in the expression levels of glucose transporter 4 (GLUT4) and the hepatic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were identified by Western blot analysis. RESULTS: EPO attenuated the hyperglycemia in the STZ rats in a dose-dependent manner without altering the hematopoietic parameters, including the hematocrit and number of red blood cells. The involvement of the EPO receptor (EPOR) was identified using EPOR-specific antibodies. In addition, injection of EPO enhanced the glucose utilization, which was assessed using an intravenous glucose tolerance test in rats. However, blood insulin was not changed by EPO in this assay, showing the insulinotropic action of EPO. Moreover, EPO treatment increased the insulin sensitivity. Western blots indicated that the phosphorylation of AMP-activated protein kinase was enhanced by EPO to support the signaling caused by EPOR activation. Furthermore, the decrease in the GLUT4 level in skeletal muscle was reversed by EPO, and the increase in the PEPCK expression in liver was reduced by EPO, as shown in STZ rats. CONCLUSION: Taken together, the results show that EPO injection may reduce hyperglycemia in diabetic rats through activation of EPO receptors. Therefore, EPO is useful for managing diabetic disorders, particularly hyperglycemia-associated changes. In addition, EPO receptor will be a good target for the development of antihyperglycemic agent(s) in the future.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Eritropoetina/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/induzido quimicamente , Modelos Animais de Doenças , Eritropoetina/administração & dosagem , Hiperglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Insulina/sangue , Masculino , Ratos , Ratos Wistar , Estreptozocina
13.
Chem Biol Interact ; 240: 304-9, 2015 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-26362499

RESUMO

Canavanine is a guanidinium derivative that has the basic structure of a ligand for the imidazoline receptor (I-R). Furthermore, canavanine is found in an herb that has been shown to improve diabetic disorders. Thus, the present study was designed to investigate the anti-hyperglycemic action of canavanine in rats with streptozotocin (STZ)-induced type 1-like diabetes. Canavanine decreased hyperglycemia in the STZ-induced diabetic rats, and this action was blocked by the antagonist specific to imidazoline I-2 receptors (I-2R), BU224, in a dose-dependent manner. Additionally, canavanine increased the plasma ß-endorphin level, as measured using enzyme-linked immunosorbent assay (ELISA), and this increase was also blocked by BU224 in the same manner. Moreover, amiloride at a dose sufficient to block I-2AR attenuated the actions of canavanine, including the increased ß-endorphin level and the antihyperglycemic effect. Otherwise, canavanine increased the radioactive glucose uptake into skeletal muscles isolated from the diabetic rats. Furthermore, canavanine increased the phosphorylation of AMPK measured using Western blot analysis in these isolated skeletal muscles in a dose-dependent manner. Additionally, the insulin sensitivity of the diabetic rats was markedly increased by canavanine, and this action was also blocked by BU224. Overall, canavanine is capable of activating imidazoline I-2R; I-2AR is linked to an increase in the plasma level of ß-endorphin, and I-2BR is related to effects on the glucose uptake by skeletal muscle that reduces hyperglycemia in type 1-like diabetic rats. Therefore, canavanine can be developed as effective agent to treat the diabetic disorders in the future.


Assuntos
Canavanina/farmacologia , Canavanina/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Receptores de Imidazolinas/metabolismo , Animais , Western Blotting , Masculino , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , beta-Endorfina/sangue
14.
Clin Exp Pharmacol Physiol ; 42(10): 1045-50, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26192192

RESUMO

Canavanine is a guanidinium derivative that contains the basic structure of the ligand(s) of imidazoline receptor (I-R). Canavanine has been reported to activate the imidazoline I-3 receptor (I-3R) both in vivo and in vitro. Additionally, the activation of the imidazoline I-2B receptor (I-2BR) by guanidinium derivatives may increase glucose uptake. Therefore, the effect of canavanine on the I-2BR was investigated in the present study. Glucose uptake into cultured C2 C12 cells was determined using the radio-ligated tracer 2-[(14) C]-deoxy-glucose. The changes in 5' AMP-activated protein kinase (AMPK) expression were also identified using Western blotting analysis. The canavanine-induced glucose uptake was inhibited in a dose-dependent manner by BU224 (0.01-1 µmol/L), which is a specific I-2BR antagonist, in the C2 C12 cells. Additionally, the canavanine-stimulated AMPK phosphorylation and glucose transporter (GLUT4) expression were also sensitive to BU224 inhibition in the C2 C12 cells. Moreover, both canavanine-stimulated glucose uptake and AMPK phosphorylation were attenuated by high concentrations of amiloride (1-2 µmol/L), which is another established I-2BR inhibitor, in a dose-dependent manner in C2 C12 cells. Additionally, compound C abolished the canavanine-induced glucose uptake and AMPK phosphorylation at a concentration (0.1 µmol/L) sufficient to inhibit AMPK. In conclusion, these data demonstrated that canavanine has an ability to activate I-2BR through the AMPK pathway to increase glucose uptake, which indicates I-2BR as a new target for diabetic therapy.


Assuntos
Canavanina/farmacologia , Glucose/metabolismo , Receptores de Imidazolinas/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos
15.
Inflamm Res ; 62(5): 527-35, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23525659

RESUMO

OBJECTIVE: We studied the effects of tetramethylpyrazine (TMP) on the fever, increased plasma levels of tumor necrosis factor-α (TNF-α) and increased hypothalamic levels of glutamate, hydroxyl radicals and prostaglandin-E2 (PGE2) induced by lipopolysaccharide (LPS). MATERIALS AND METHODS: The microdialysis probes were stereotaxically and chronically implanted into the hypothalamus of rabbit brain for determining extracellular levels of glutamate, hydroxyl radials, and PGE2. In addition, both the body core temperature and plasma levels of TNF-α were measured. RESULTS: All the body core temperature, plasma levels of TNF-α, and hypothalamic levels of glutamate, hydroxyl radicals, and PGE2 were up-graded by an intravenous dose of LPS (2 µg/kg). Pretreatment with intravenous TMP (10-40 mg/kg) or intracerebroventricular TMP (130 µg in 20 µl per animal) 1 h before LPS administration significantly attenuated the LPS-induced fever as well as the increased hypothalamic levels of glutamate, hydroxyl radicals, and PGE2. LPS-induced fever could also be attenuated by intravenous or intracerebroventricular TMP 1 h after LPS injection. CONCLUSION: TMP preconditioning may cause its antipyretic action by reducing plasma levels of TNF-α as well as hypothalamic levels of glutamate, hydroxyl radicals, and PGE2 in rabbits.


Assuntos
Antipiréticos/administração & dosagem , Hipotálamo/efeitos dos fármacos , Pirazinas/administração & dosagem , Animais , Temperatura Corporal/efeitos dos fármacos , Dinoprostona/metabolismo , Ácido Glutâmico/metabolismo , Radical Hidroxila/metabolismo , Hipotálamo/metabolismo , Lipopolissacarídeos , Masculino , Coelhos , Fator de Necrose Tumoral alfa/sangue
16.
BMC Neurosci ; 14: 33, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23496862

RESUMO

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is elevated early in injured brain after traumatic brain injury (TBI), in humans and in animals. Etanercept (a TNF-α antagonist with anti-inflammatory effects) attenuates TBI in rats by reducing both microglial and astrocytic activation and increased serum levels of TNF-α. However, it is not known whether etanercept improves outcomes of TBI by attenuating microglia-associated, astrocytes-associated, and/or neurons-associated TNF-α expression in ischemic brain. A well clinically relevant rat model, where a lateral fluid percussion is combined with systemic administration of etanercept immediately after TBI, was used. The neurological severity score and motor function was measured on all rats preinjury and on day 3 after etanercept administration. At the same time, the neuronal and glial production of TNF-α was measured by Immunofluorescence staining. In addition, TNFα contents of ischemic cerebral homogenates was measured using commercial enzyme-linked immunosorbent assay kits. RESULTS: In addition to inducing brain ischemia as well as neurological and motor deficits, TBI caused significantly higher numbers of microglia-TNF-α double positive cells, but not neurons-TNF-α or astrocytes-TNF-α double positive cells in the injured brain areas than did the sham operated controls, when evaluated 3 days after TBI. The TBI-induced cerebral ischemia, neurological motor deficits, and increased numbers of microglia-TNF-α double positive cells and increased TNF-α levels in the injured brain were all significantly attenuated by etanercept therapy. CONCLUSION: This finding indicates that early microglia overproduction of TNF-α in the injured brain region after TBI contributes to cerebral ischemia and neurological motor deficits, which can be attenuated by etanercept therapy. Studies in this model could provide insight into the mechanisms underlying neurological motor disturbance in brain-injured patients.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptores do Fator de Necrose Tumoral/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Lesões Encefálicas/complicações , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Etanercepte , Regulação da Expressão Gênica/efeitos dos fármacos , Imunoglobulina G/farmacologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/prevenção & controle , Ratos , Ratos Sprague-Dawley , Sais de Tetrazólio , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
17.
Childs Nerv Syst ; 28(3): 363-73, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22249380

RESUMO

INTRODUCTION: CD133 (PROM1) is a potential marker for cancer stem cells (CSCs), including those found in brain tumors. Recently, medulloblastoma (MB)-derived CD133-positive cells were found to have CSC-like properties and were proposed to be important contributors to tumorigenicity, cancer progression, and chemoradioresistance. However, the biomolecular pathways and therapeutic targets specific to MB-derived CSCs remain unresolved. MATERIALS AND METHODS: In the present study, we isolated CD133(+) cells from MB cell lines and determined that they showed increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared to CD133(-) cells. Bioinformatics analysis suggested that the STAT3 pathway might be important in MB and CD133(+) cells. To evaluate the effects of inhibiting the STAT3 pathway, MB-derived CD133(+/-) cells were treated with the potent STAT3 inhibitor, cucurbitacin I. Treatment with cucurbitacin I significantly suppressed the CSC-like properties and stemness gene signature of MB-derived CD133(+) cells. Furthermore, cucurbitacin I treatment increased the apoptotic sensitivity of MB-derived CD133(+) cells to radiation and chemotherapeutic drugs. Notably, cucurbitacin I demonstrated synergistic effects with ionizing radiation to inhibit tumorigenicity in MB-CD133(+)-inoculated mice. RESULTS: These results indicate that the STAT3 pathway plays a key role in mediating CSC properties in MB-derived CD133(+) cells. Targeting STAT3 with cucurbitacin I may therefore represent a novel therapeutic approach for treating malignant brain tumors.


Assuntos
Meduloblastoma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Triterpenos/farmacologia , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos da radiação , Biologia Computacional , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Glicoproteínas/metabolismo , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Camundongos , Análise em Microsséries , Células-Tronco Neoplásicas/efeitos da radiação , Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Raios Ultravioleta
18.
J Cell Physiol ; 227(3): 976-93, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21503893

RESUMO

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Patients diagnosed with GBM have a poor prognosis, and it has been reported that tumor malignancy and GBM recurrence are promoted by STAT3 signaling. As resveratrol (RV), a polyphenol in grapes, is reported to be a potent and non-toxic cancer-preventive compound, the aim of this study was to investigate the therapeutic effect and molecular mechanisms of RV on GBM-derived radioresistant tumor initiating cells (TIC). Firstly, our results showed that primary GBM-CD133(+) TIC presented high tumorigenic and radiochemoresistant properties as well as increased protein levels of phosphorylated STAT3. We consistently observed that treatment with shRNA-STAT3 (sh-STAT3) or AG490, a STAT3 inhibitor, significantly inhibited the cancer stem-like cell properties and radioresistance of GBM-CD133(+) in vitro and in vivo. Furthermore, treatment of GBM-CD133(+) with 100 µM RV induced apoptosis and enhanced radiosensitivity by suppressing STAT3 signaling. Microarray results suggested that RV or AG490 inhibited the stemness gene signatures of GBM-CD133(+) and facilitated the differentiation of GBM-CD133(+) into GBM-CD133(-) or astrocytoma cells. Finally, xenotransplant experiments indicated that RV or sh-STAT3 therapy could significantly improve the survival rate and synergistically enhance the radiosensitivity of radiation-treated GBM-TIC. In summary, RV can reduce in vivo tumorigenicity and enhance the sensitivity of GBM-TIC to radiotherapies through the STAT3 pathway.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Fator de Transcrição STAT3/antagonistas & inibidores , Estilbenos/farmacologia , Idoso , Animais , Antineoplásicos Fitogênicos/farmacologia , Astrocitoma/tratamento farmacológico , Astrocitoma/patologia , Astrocitoma/radioterapia , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , Feminino , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Resveratrol , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Neurooncol ; 106(3): 601-10, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21879395

RESUMO

Development of hypofractionated stereotactic radiosurgery (HSRS) has expanded the size of lesion that can be safely treated by focused radiation in a limited number of treatment sessions. However, clinical data regarding the efficacy and morbidity of HSRS in the treatment of cerebral metastasis is lacking. Here, we review our experience with CyberKnife(®) HSRS for this indication. From 2005 to 2010, we identified 37 patients with large (>3 cm in diameter) cerebral metastases resection cavity that was treated with HSRS. This constituted approximately 8% of all treated resection cavities. We reviewed dose regimens, local control, distal control, and treatment associated morbidities. Primary sites for the metastatic lesions included: lung (n = 10), melanoma (n = 12), breast (n = 9), kidney (n = 4), and colon (n = 2). All patients underwent resection of the cerebral metastasis and received 800 cGy × 3 daily fractions to the resection cavity. Of the 37 patients treated, one-year follow-up data was available for 35 patients. The median survival was 5.5 months. Actuarial local control rate at 6 months was 80%. Local failures did not correlate with prior WBRT, or tumor histology. Distant recurrence occurred in 7 of the 35 patients. Morbidities associated with HSRS totaled 9%, including radiation necrosis (n = 1, 2.9%), prolonged steroid use (n = 1, 2.9%), and new-onset seizures (n = 1, 2.9%). This study demonstrates the safety and efficacy of an 800 cGy × 3 daily fractions CyberKnife(®) HSRS regimen for irradiation of large resection cavity. The efficacy compares favorably to historical data derived from patients undergoing WBRT, SRS, or brachytherapy.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Recidiva Local de Neoplasia/secundário , Recidiva Local de Neoplasia/cirurgia , Radiocirurgia/métodos , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , Dosagem Radioterapêutica , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
20.
Int J Mol Sci ; 12(11): 7554-68, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22174616

RESUMO

Induced pluripotent stem cells formed by the introduction of only three factors, Oct4/Sox2/Klf4 (3-gene iPSCs), may provide a safer option for stem cell-based therapy than iPSCs conventionally introduced with four-gene iPSCs. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) plays an important role during brown fat development. However, the potential roles of PGC-1α in regulating mitochondrial biogenesis and the differentiation of iPSCs are still unclear. Here, we investigated the effects of adenovirus-mediated PGC-1α overexpression in 3-gene iPSCs. PGC-1α overexpression resulted in increased mitochondrial mass, reactive oxygen species production, and oxygen consumption. Microarray-based bioinformatics showed that the gene expression pattern of PGC-1α-overexpressing 3-gene iPSCs resembled the expression pattern observed in adipocytes. Furthermore, PGC-1α overexpression enhanced adipogenic differentiation and the expression of several brown fat markers, including uncoupling protein-1, cytochrome C, and nuclear respiratory factor-1, whereas it inhibited the expression of the white fat marker uncoupling protein-2. Furthermore, PGC-1α overexpression significantly suppressed osteogenic differentiation. These data demonstrate that PGC-1α directs the differentiation of 3-gene iPSCs into adipocyte-like cells with features of brown fat cells. This may provide a therapeutic strategy for the treatment of mitochondrial disorders and obesity.


Assuntos
Adipócitos/citologia , Diferenciação Celular/genética , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Transcrição/genética , Adenoviridae/genética , Animais , Citocromos c/genética , Citocromos c/metabolismo , Canais Iônicos/genética , Canais Iônicos/metabolismo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fator 1 Nuclear Respiratório/genética , Fator 1 Nuclear Respiratório/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Osteogênese/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Regulação para Cima
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