RESUMO
Gum arabic (GA) is widely used as an emulsion stabilizer and edible coating and consists of a complex carbohydrate moiety with a rhamnosyl-glucuronate group capping the non-reducing ends. Enzymes that can specifically cleave the glycosidic chains of GA and modify their properties are valuable for structural analysis and industrial application. Cryogenic X-ray crystal structure of GA-specific L-rhamnose-α-1,4-D-glucuronate lyase from Fusarium oxysporum (FoRham1), belonging to the polysaccharide lyase (PL) family 42, has been previously reported. To determine the specific reaction mechanism based on its hydrogen-containing enzyme structure, we performed joint X-ray/neutron crystallography of FoRham1. Large crystals were grown in the presence of L-rhamnose (a reaction product), and neutron and X-ray diffraction datasets were collected at room temperature at 1.80 and 1.25 Å resolutions, respectively. The active site contained L-rhamnose and acetate, the latter being a partial analog of glucuronate. Incomplete H/D exchange between Arg166 and acetate suggested that a strong salt-bridge interaction was maintained. Doubly deuterated His105 and deuterated Tyr150 supported the interaction between Arg166 and the acetate. The unique hydrogen-rich environment functions as a charge neutralizer for glucuronate and stabilizes the oxyanion intermediate. The NE2 atom of His85 was deprotonated and formed a hydrogen bond with the deuterated O1 hydroxy of L-rhamnose, indicating the function of His85 as the base/acid catalyst for bond cleavage via ß-elimination. Asp83 functions as a pivot between the two catalytic histidine residues by bridging them. This His-His-Asp structural motif is conserved in the PL 24, 25, and 42 families.
Assuntos
Fusarium , Polissacarídeo-Liases , Humanos , Acetatos , Cristalografia por Raios X , Ácido Glucurônico/química , Hidrogênio , Liases , Polissacarídeo-Liases/química , Ramnose/química , Fusarium/enzimologiaRESUMO
AMPK activation promotes glucose and lipid metabolism. Here, we found that our previously reported ADAM17 inhibitor SN-4 activates AMPK and promotes membrane translocation and sugar uptake of GLUT4. AMPK inhibitor dorsomorphin reversed this effect of SN-4, confirming that the effect is mediated by AMPK activation. In addition, SN-4 inhibited lipid accumulation in HepG2 under high glucose conditions by promoting lipid metabolism and inhibiting lipid synthesis. Although lactic acidosis is a serious side effect of biguanides such as metformin, SN-4 did not affect lactate production. Furthermore, SN-4 was confirmed to inhibit the release of TNF-α, a causative agent of insulin resistance, from adipocytes. In diabetes treatment, it is important to not only regulate blood sugar levels but also prevent complications. Our findings reveal the therapeutic potential of SN-4 as a new antidiabetic drug that can also help prevent future complications.
Assuntos
Proteínas Quinases Ativadas por AMP , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Hipoglicemiantes/farmacologia , Glucose/metabolismo , Metformina/farmacologia , Lipídeos , Transportador de Glucose Tipo 4RESUMO
BACKGROUND: Imaging examinations are crucial for diagnosing acute ischemic stroke, and knowledge of a patient's body weight is necessary for safe examination. To perform examinations safely and rapidly, estimating body weight using head computed tomography (CT) scout images can be useful. OBJECTIVE: This study aims to develop a new method for estimating body weight using head CT scout images for contrast-enhanced CT examinations in patients with acute ischemic stroke. METHODS: This study investigates three weight estimation techniques. The first utilizes total pixel values from head CT scout images. The second one employs the Xception model, which was trained using 216 images with leave-one-out cross-validation. The third one is an average of the first two estimates. Our primary focus is the weight estimated from this third new method. RESULTS: The third new method, an average of the first two weight estimation methods, demonstrates moderate accuracy with a 95% confidence interval of ±14.7âkg. The first method, using only total pixel values, has a wider interval of ±20.6âkg, while the second method, a deep learning approach, results in a 95% interval of ±16.3âkg. CONCLUSIONS: The presented new method is a potentially valuable support tool for medical staff, such as doctors and nurses, in estimating weight during emergency examinations for patients with acute conditions such as stroke when obtaining accurate weight measurements is not easily feasible.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Tomografia Computadorizada por Raios X/métodos , Cabeça/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Peso CorporalRESUMO
Gum arabic (GA) is widely used as an emulsion stabilizer and coating in several industrial applications, such as foods and pharmaceuticals. GA contains a complex carbohydrate moiety, and the nonreducing ends of the side chains are often capped with l-rhamnose; thus, enzymes that can remove these caps are promising tools for the structural analysis of the carbohydrates comprising GA. In this study, GA-specific l-rhamnose-α-1,4-d-glucuronate lyase from the fungus Fusarium oxysporum 12S (FoRham1) was cloned and characterized. FoRham1 showed the highest amino acid sequence similarity with enzymes belonging to the glycoside hydrolase family 145; however, the catalytic residue on the posterior pocket of the ß-propeller fold protein was not conserved. The catalytic residues of FoRham1 were instead conserved with ulvan lyases belonging to polysaccharide lyase family 24. Kinetic analysis showed that FoRham1 has the highest catalytic efficiency for the substrate α-l-rhamnose-(1â4)-d-glucuronic acid. The crystal structures of ligand-free and α-l-rhamnose-(1â4)-d-glucuronic acid -bound FoRham1 were determined, and the active site was identified on the anterior side of the ß-propeller. The three-dimensional structure of the active site and mutagenesis analysis revealed the detailed catalytic mechanism of FoRham1. Our findings offer a new enzymatic tool for the further analysis of the GA carbohydrate structure and for elucidating its physiological functions in plants. Based on these results, we renamed glycoside hydrolase family 145 as a new polysaccharide lyase family 42, in which FoRham1 is included.
Assuntos
Ácido Glucurônico/metabolismo , Goma Arábica/metabolismo , Polissacarídeo-Liases/metabolismo , Ramnose/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Cristalografia por Raios X , Fusarium/enzimologia , Filogenia , Polissacarídeo-Liases/química , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
BACKGROUND: Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were proposed in some similar cases. CASE PRESENTATION: We present here an 80-year-old man who had previously undergone surgery for a left adrenal PCC and newly developed severe hypertension, hypokalemia, and typical Cushingoid manifestations. Investigations revealed hyperglycemia, hypokalemia, and extremely high catecholamines and their metabolites, ACTH and cortisol. Imaging modalities showed a recurrent large left adrenal mass positively visualized with 123I-metaiodobenzylguanidine as well as somatostatin receptor scintigraphy. Surgical interventions were not indicated; thus, metyrapone, phentolamine, and doxazocin were initiated, which successfully controlled his symptoms and biochemical conditions. With the evidence that metyrapone administration decreased ACTH and catecholamine levels, the existence of positive feedback loops was speculated. During the terminal stages of the disease, additional metyrosine treatment successfully stabilized his physiological and biochemical conditions. Upon the patient's death, pathological autopsy was performed. Immunohistochemical analysis indicated that the tumor appeared to be co-positive with tyrosine hydroxylase (TH) as well as ACTH in most tumor cells in both PCC and liver metastasis. Most cells were clearly positive for somatostatin receptor 2 staining in the membrane compartment. The dense immunostaining of ACTH, TH, dopamine-ß-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation. CONCLUSIONS: We experienced a case of severe ectopic ACTH producing the largest reported recurrent malignant left PCC with liver metastases that presented positive feedback loops in the ACTH/cortisol and catecholamine/cortisol axes. Clinicians should be aware of the paradoxical response of ACTH on metyrapone treatment and possible steroid-induced catecholamine crisis.
Assuntos
Síndrome de ACTH Ectópico , Neoplasias das Glândulas Suprarrenais , Hipopotassemia , Tumores Neuroendócrinos , Feocromocitoma , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/etiologia , Neoplasias das Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Idoso de 80 Anos ou mais , Catecolaminas , Humanos , Hidrocortisona , Hipopotassemia/complicações , Masculino , Metirapona/uso terapêutico , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/complicações , Feocromocitoma/metabolismo , Feocromocitoma/cirurgiaRESUMO
BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to suppress atherosclerosis progression in atherosclerotic mouse models through unclear mechanisms. In this study, we investigated the effect of the DPP-4 inhibitor, linagliptin, on macrophage polarization in vitro and in vivo. METHODS: Mouse bone marrow macrophages (BMMs) were used in in vitro assays. High fat diet (HFD)-fed Apoe-/- mice were treated orally with linagliptin (10 mg/kg-1â¢day-1) or a vehicle (water) control. RESULTS: In in vitro assays using BMMs, treatment with LPS and IFNγ decreased the mRNA-expression levels of alternatively activated macrophage (M2) markers, and linagliptin treatment prevented these reductions. The mRNA levels of M2 markers and the number of M2 macrophages in the aorta were higher in linagliptin groups than in control groups. Linagliptin decreased the size of atherosclerotic lesions in HFD-fed Apoe-/- mice. Interestingly, inflammatory stimulation increased DPP-4 expression, and linagliptin suppressed these effects in BMMs. Treatment with DPP-4 small-interfering RNA (siRNA) reproduced linagliptin-mediated alteration of M2 polarization. CONCLUSIONS: Linagliptin increased M2 macrophage polarization by inhibiting DPP-4 expression and activity. These findings may indicate the beneficial effects of DPP-4 inhibitors on the progression of diabetic macrovascular complications.
Assuntos
Anti-Inflamatórios/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inflamação/tratamento farmacológico , Linagliptina/química , Animais , Anti-Inflamatórios/farmacologia , Aorta/metabolismo , Aterosclerose/tratamento farmacológico , Células da Medula Óssea/efeitos dos fármacos , Dieta Hiperlipídica , Dipeptidil Peptidase 4/genética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Linagliptina/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
MAIN CONCLUSION: TBG4 recognize multiple linkage types substrates due to having a spatially wide subsite + 1. This feature allows the degradation of AGI, AGII, and AGP leading to the fruit ripening. ß-galactosidase (EC 3. 2. 1. 23) catalyzes the hydrolysis of ß-galactan and release of D-galactose. Tomato has at least 17 ß-galactosidases (TBGs), of which, TBG 4 is responsible for fruit ripening. TBG4 hydrolyzes not only ß-1,4-bound galactans, but also ß-1,3- and ß-1,6-galactans. In this study, we compared each enzyme-substrate complex using X-ray crystallography, ensemble refinement, and docking simulation to understand the broad substrate-specificity of TBG4. In subsite - 1, most interactions were conserved across each linkage type of galactobioses; however, some differences were seen in subsite + 1, owing to the huge volume of catalytic pocket. In addition to this, docking simulation indicated TBG4 to possibly have more positive subsites to recognize and hydrolyze longer galactans. Taken together, our results indicated that during tomato fruit ripening, TBG4 plays an important role by degrading arabinogalactan I (AGI), arabinogalactan II (AGII), and the carbohydrate moiety of arabinogalactan protein (AGP).
Assuntos
Simulação por Computador , Cristalografia por Raios X , Solanum lycopersicum , beta-Galactosidase , Galactanos/química , Solanum lycopersicum/química , Solanum lycopersicum/enzimologia , Especificidade por Substrato , beta-Galactosidase/química , beta-Galactosidase/metabolismoRESUMO
Three recombinant ß-galactosidases (BGALs; PcBGAL35A, PcBGAL35B, and PcGALX35C) belonging to the glycoside hydrolase (GH) family 35 derived from Penicillium chrysogenum 31B were expressed using Pichia pastoris and characterized. PcBGAL35A showed a unique substrate specificity that has not been reported so far. Based on the results of enzymological tests and 1H-nuclear magnetic resonance, PcBGAL35A was found to hydrolyze ß-1,4-galactosyl residues linked to L-rhamnose in rhamnogalacturonan-I (RG-I) of pectin, as well as p-nitrophenyl-ß-D-galactopyranoside and ß-D-galactosyl oligosaccharides. PcBGAL35B was determined to be a common BGAL through molecular phylogenetic tree and substrate specificity analysis. PcGALX35C was found to have similar catalytic capacities for the ß-1,4-galactosyl oligomer and polymer. Furthermore, PcGALX35C hydrolyzed RG-I-linked ß-1,4-galactosyl oligosaccharide side chains with a degree of polymerization of 2 or higher in pectin. The amino acid sequence similarity of PcBGAL35A was approximately 30% with most GH35 BGALs, whose enzymatic properties have been characterized. The amino acid sequence of PcBGAL35B was approximately 80% identical to those of BGALs from Penicillium sp. The amino acid sequence of PcGALX35C was classified into the same phylogenetic group as PcBGAL35A. Pfam analysis revealed that the three BGALs had five domains including a catalytic domain. Our findings suggest that PcBGAL35A and PcGALX35C are enzymes involved in the degradation of galactosylated RG-I in pectin. The enzymes characterized in this study may be applied for products that require pectin processing and for the structural analysis of pectin.
Assuntos
Pectinas/metabolismo , Penicillium chrysogenum/enzimologia , beta-Galactosidase/metabolismo , Sequência de Aminoácidos , Hidrólise , Penicillium chrysogenum/genética , Filogenia , Pichia/genética , Especificidade por Substrato , beta-Galactosidase/genéticaRESUMO
Heat shock protein 72 (HSP72) is a major inducible molecule in the heat shock response that enhances intracellular stress tolerance. Decreased expression of HSP72 is observed in type 2 diabetes, which may contribute to the development of insulin resistance and chronic inflammation. We used HSP72 knockout (HSP72-KO) mice to investigate the impact of HSP72 on glucose metabolism and endoplasmic reticulum (ER) stress, particularly in the liver. Under a high-fat diet (HFD) condition, HSP72-KO mice showed glucose intolerance, insulin resistance, impaired insulin secretion, and enhanced hepatic gluconeogenic activity. Furthermore, activity of the c-Jun NH2-terminal kinase (JNK) was increased and insulin signaling suppressed in the liver. Liver-specific expression of HSP72 by lentivirus (lenti) in HFD-fed HSP72-KO mice ameliorated insulin resistance and hepatic gluconeogenic activity. Furthermore, increased adipocyte size and hepatic steatosis induced by the HFD were suppressed in HSP72-KO lenti-HSP72 mice. Increased JNK activity and ER stress upon HFD were suppressed in the liver as well as the white adipose tissue of HSP72-KO lenti-HSP72 mice. Thus, HSP72 KO caused a deterioration in glucose metabolism, hepatic gluconeogenic activity, and ß-cell function. Moreover, liver-specific recovery of HSP72 restored glucose homeostasis. Therefore, hepatic HSP72 may play a critical role in the pathogenesis of type 2 diabetes.
Assuntos
Tecido Adiposo Branco/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/genética , Proteínas de Choque Térmico HSP72/genética , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Animais , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático/genética , Glucose/metabolismo , Resistência à Insulina/genética , Secreção de Insulina/genética , Camundongos , Camundongos Knockout , Transdução de SinaisRESUMO
Although hyperemesis gravidarum (HG), an extreme form of morning sickness, is a common complication during pregnancy, HG associated simultaneous onset of rhabdomyolysis and diabetes insipidus due to electrolyte abnormalities are rare. A 34-year-old woman with severe HG at 17 weeks of gestation complicated with appetite loss, weight reduction by 17 kg, general fatigue, myalgia, weakness and polyuria was identified to have simultaneous hypophosphatemia (1.6 mg/dL) and hypokalemia (2.0 mEq/L). Appetite recovery and the improvement of the hypophosphatemia (3.2 mg/dL) were observed prior to the first visit to our department. At the admission, she presented polyuria around 7,000~8,000 mL/day with impaired concentrating activity (U-Osm 185 mOsm/L), and abnormal creatine kinase elevation (4,505 U/L). The electrolyte disturbances and physio-metabolic abnormalities in undernourished state due to HG let us diagnose this case as refeeding syndrome (RFS). In this case, abnormal loss by vomiting, insufficient intake and previous inappropriate fluid infusion as well as the development of RFS may accelerate the severity of hypokalemia due to HG. Thus, as her abnormalities were considered as results of rhabdomyolysis and diabetes insipidus due to severe HG associated hypokalemia based on RFS, oral supplementation of potassium chloride was initiated. After 6 days of potassium supplementation, her symptoms and biochemical abnormalities were completely resolved. Severe HG followed by RFS can be causes of electrolyte abnormalities and subsequent complications, including rhabdomyolysis and renal diabetes insipidus. Appropriate diagnosis and prompt interventions including adequate nutrition are necessary to prevent electrolyte imbalance induced cardiac, neuromuscular and/or renal complications.
Assuntos
Diabetes Insípido/etiologia , Hiperêmese Gravídica/complicações , Síndrome da Realimentação/complicações , Rabdomiólise/etiologia , Equilíbrio Hidroeletrolítico/fisiologia , Desequilíbrio Hidroeletrolítico/etiologia , Adulto , Diabetes Insípido/fisiopatologia , Feminino , Humanos , Hiperêmese Gravídica/fisiopatologia , Gravidez , Síndrome da Realimentação/fisiopatologia , Rabdomiólise/fisiopatologia , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
BACKGROUND: Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnancy that is associated with vasopressinase overproduction from the placenta. Although increased vasopressinase is associated with placental volume, the regulation of placental growth in the later stage of pregnancy is not well known. CASE PRESENTATION: A 16-year-old pregnant woman was urgently transferred to our hospital because of threatened premature labor when the Kumamoto earthquakes hit the area where she lived. During her hospitalization, she complained of gradually increasing symptoms of polyuria and polydipsia. The serum level of arginine vasopressin (AVP) was 1.7 pg/mL, which is inconsistent with central DI. The challenge of diagnostic treatment using oral 1-deamino-8-D-AVP (DDAVP) successfully controlled her urine and allowed for normal delivery. DDAVP tablets were not necessary to control her polyuria thereafter. Based on these observations, clinical diagnosis of GDI was confirmed. Pathophysiological analyses revealed that vasopressinase expression was more abundant in the GDI patient's syncytiotrophoblast in placenta compared with that in a control subject. Serum vasopressinase was also observed during gestation and disappeared soon after delivery. Vasopressinase is reportedly identical to oxytocinase or insulin regulated aminopeptidase (IRAP), which is an abundant cargo protein associated with the glucose transporter 4 (GLUT4) storage vesicle. Interestingly, the expression and subcellular localization of GLUT4 appeared to occur in a vasopressinase (IRAP)-dependent manner. CONCLUSION: Because placental volume may be associated with vasopressinase overproduction in GDI, vasopressinase (IRAP)/GLUT4 association appears to contribute to the growth of placenta in this case.
Assuntos
Antidiuréticos/uso terapêutico , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido/fisiopatologia , Neurofisinas/metabolismo , Complicações na Gravidez/prevenção & controle , Precursores de Proteínas/metabolismo , Vasopressinas/metabolismo , Adolescente , Diabetes Insípido/tratamento farmacológico , Diabetes Insípido/enzimologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/etiologia , PrognósticoRESUMO
The induction of beige adipogenesis within white adipose tissue, known as "browning", has received attention as a novel potential anti-obesity strategy. The expression of some characteristic genes including PR domain containing 16 is induced during the browning process. Although acetate has been reported to suppress weight gain in both rodents and humans, its potential effects on beige adipogenesis in white adipose tissue have not been fully characterized. We examined the effects of acetate treatment on 3T3-L1 cells and in obese diabetic KK-Ay mice. The mRNA expression levels of genes involved in beige adipocyte differentiation and genes selectively expressed in beige adipocytes were significantly elevated in both 3T3-L1 cells incubated with 1.0 mM acetate and the visceral white adipose tissue from mice treated with 0.6% acetate for 16 weeks. In KK-Ay mice, acetate reduced the food efficiency ratio and increased the whole-body oxygen consumption rate. Additionally, reduction of adipocyte size and uncoupling protein 1-positive adipocytes and interstitial areas with multilocular adipocytes appeared in the visceral white adipose tissue of acetate-treated mice, suggesting that acetate induced initial changes of "browning". In conclusion, acetate alters the expression of genes involved in beige adipogenesis and might represent a potential therapeutic agent to combat obesity.
RESUMO
The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe(-/-) mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe(-/-) mice. In conclusion, statins mediate anti-atherogenic effects through PPARγ activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis.
Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , PPAR gama/metabolismo , Animais , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/enzimologia , Aterosclerose/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Ácidos Graxos Monoinsaturados/farmacologia , Fluvastatina , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Indóis/farmacologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We report anesthetic management of total gastrectomy for gastric cancer under general anesthesia supplemented with a transversus abdominis plane (TAP) block. The patient was a 78-year-old man who had received coronary artery bypass grafting (CABG) with the right gastroepiploic artery (RGEA) 12 years before. Preoperative coronary angiography (CAG) showed that RCA was obstructed completely and RGEA was patent and the surgeons carried out gastrectomy with the utmost attention not to injure the RGEA. There were no signs of myocardial ischemia under monitoring by transesophageal echocardiography (TEE). The ultrasound-guided TAP block was effective. This case demonstrates that the ultrasound-guided TAP block is an alternative approach for providing analgesia and intraoperative TEE monitoring is useful in a patient with gastrectomy after CABG using the RGEA with coagulation abnormality.
Assuntos
Ponte de Artéria Coronária/métodos , Gastrectomia , Artéria Gastroepiploica/cirurgia , Bloqueio Nervoso/métodos , Idoso , Anestesia Geral/métodos , Humanos , MasculinoRESUMO
The Japan Diabetes Society (JDS) adopted a sweeping decision to release consensus statements on relevant issues in diabetes management that require updating from time to time and launched a "JDS Committee on Consensus Statement Development." In March 2020, the committee's first consensus statement on "Medical Nutrition Therapy and Dietary Counseling for People with Diabetes" was published. In September 2022, a second consensus "algorithm for pharmacotherapy in people with type 2 diabetes" was proposed. In developing an algorithm for diabetes pharmacotherapy in people with type 2 diabetes, the working concept was that priority should be given to selecting such medications as would appropriately address the diabetes pathology in each patient while simultaneously weighing the available evidence for these medications and the prescribing patterns in clinical practice in Japan. These consensus statements are intended to present the committee's take on diabetes management in Japan, based on the evidence currently available for each of the issues addressed. It is thus hoped that practicing diabetologists will not fail to consult these statements to provide the best available practice in their respective clinical settings. Given that the persistent dual GIP/GLP-1 receptor agonist tirzepatide was approved in April 2023, these consensus statements have been revised1). In this revision, specifically, tirzepatide was added to the end of [likely involving insulin resistance] of "Obese patients" in Step 1: "Select medications to address the diabetes pathology involved" in Fig. 2. While the sentence, "Insulin insufficiency and resistance can be assessed by referring to the various indices listed in the JDS 'Guide to Diabetes Management.' was mentioned in the previous edition as well, "While insulin resistance is analogized based on BMI, abdominal obesity, and visceral fat accumulation, an assessment of indicators (e.g., HOMA-IR) is desirable" was added as information in order to more accurately recognize the pathology. Regarding Step 2: "Give due consideration to safety," "For renal excretion" was added to the "Rule of thumb 2: Avoid glinides in patients with renal impairment." The order of the medications in "rule of thumb 3: Avoid thiazolidinediones and biguanides in patients with heart failure (in whom they are contraindicated)." to thiazolidinediones then biguanides. In the description of the lowest part of Fig. 2, for each patient failing to achieve his/her HbA1c control goal, "while reverting to step 1" was changed to "while reverting to the opening" and "including reassessment if the patient is indicated for insulin therapy" was added. In the separate table, the column for tirzepatides was added, while the two items, "Characteristic side effects" and "Persistence of effect" were added to the area of interest. The revision also carried additional descriptions of the figure and table such as tirzepatides and "Characteristic side effects" in the statement, and while not mentioned in the proposed algorithm figure, nonalcoholic fatty liver disease (NAFLD) is covered from this revision for patients with comorbidities calling for medical attention. Moreover, detailed information was added to the relative/absolute indication for insulin therapy, the Kumamoto Declaration 2013 for glycemic targets, and glycemic targets for older people with diabetes. Again, in this revision, it is hoped that the algorithm presented here will not only contribute to improved diabetes management in Japan, but will continue to evolve into a better algorithm over time, reflecting new evidence as it becomes available.
RESUMO
This algorithm was issued for the appropriate use of drugs for the treatment of type 2 diabetes mellitus in Japan. The revisions include safety considerations, fatty liver disease as a comorbidity to be taken into account and the position of tirzepatide.
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Craniopharyngiomas are difficult to resect completely, recurrence is frequent, and hypothalamic/pituitary function may be affected after surgery. Therefore, the ideal treatment for craniopharyngiomas is local control with preservation of hypothalamic and pituitary functions. The purpose of this study is to retrospectively evaluate the long-term efficacy and adverse events of stereotactic radiotherapy (SRT) with Novalis for craniopharyngioma. This study included 23 patients with craniopharyngiomas who underwent surgery between 2006 and 2021 and underwent SRT as their first irradiation after surgery. The median post-irradiation observation period was 88 months, with the overall survival rates of 100 % at 10 years and 85.7 % at 20 years. One patient died of adrenal insufficiency 12 years after irradiation. The local control rate of the cystic component was 91.3 % at 5 years, 83.0 % at 15 years, with no increase in the solid component. No delayed impairment of visual or pituitary function due to irradiation was observed. No new hypothalamic dysfunction was observed after radiation therapy. No delayed adverse events such as brain necrosis, cerebral artery stenosis, cerebral infarction, or secondary brain tumors were also observed. SRT was safe and effective over the long term in patients irradiated in childhood as well as adults, with no local recurrence or adverse events. We believe that surgical planning for craniopharyngioma with stereotactic radiotherapy in mind is effective in maintaining a good prognosis and quality of life.
Assuntos
Craniofaringioma , Neoplasias Hipofisárias , Adulto , Humanos , Craniofaringioma/radioterapia , Craniofaringioma/cirurgia , Craniofaringioma/patologia , Estudos Retrospectivos , Qualidade de Vida , Seguimentos , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Resultado do Tratamento , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/cirurgiaRESUMO
Insulin resistance is due to the reduced cellular response to insulin in peripheral tissues. The interaction of insulin with its receptor is the first step in insulin action and thus the identified target of insulin resistance. It has been well established that defects or mutations in the insulin receptor (IR) cause insulin resistance. Therefore, an IR activator might be a novel therapeutic approach for insulin resistance. Our previous report showed that mild electrical stress (MES) enhanced the insulin-induced signaling pathway. However, the molecular mechanism of the effect of MES remains unclear. We assessed the effect of MES, which is characterized by low-intensity direct current, on insulin signaling in vitro and in vivo. Here, we showed that MES activated the insulin signaling in an insulin-independent manner and improved insulin resistance in peripheral tissues of high fat-fed mice. Moreover, we found that MES increased the localization of IR in lipid rafts and enhanced the level of phosphorylated Akt in insulin-resistant hepatic cells. Ablation of lipid rafts disrupted the effect of MES on Akt activation. Our findings indicate that MES has potential as an activator of IR in an insulin-independent manner, and might be beneficial for insulin resistance in type 2 diabetes.
Assuntos
Estimulação Elétrica , Microdomínios da Membrana/metabolismo , Receptor de Insulina/metabolismo , Estresse Fisiológico , Animais , Dieta Hiperlipídica , Células Hep G2 , Humanos , Hiperglicemia/complicações , Insulina/farmacologia , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Microdomínios da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Production of reactive oxygen species (ROS) and other proinflammatory substances by macrophages plays an important role in atherogenesis. Apocynin (4-hydroxy-3-methoxy-acetophenone), which is well known as a NADPH oxidase inhibitor, has anti-inflammatory effects including suppression of the generation of ROS. However, the suppressive effects of apocynin on the progression of atherosclerosis are not clearly understood. Thus, we investigated anti-atherosclerotic effects of apocynin using apolipoprotein E-deficient (apoE(-/-)) mice in vivo and in mouse peritoneal macrophages in vitro. In atherosclerosis-prone apoE(-/-) mice, apocynin suppressed the progression of atherosclerosis, decreased 4-hydroxynonenal-positive area in atherosclerotic lesions, and mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) in aorta. In mouse peritoneal macrophages, apocynin suppressed the Ox-LDL-induced ROS generation, mRNA expression of MCP-1, IL-6 and granulocyte/macrophage colony-stimulating factor, and cell proliferation. Moreover, immunohistochemical studies revealed that apocynin decreased the number of proliferating cell nuclear antigen-positive macrophages in atherosclerotic lesions of apoE(-/-) mice. These results suggested that apocynin suppressed the formation of atherosclerotic lesions, at least in part, by inactivation of macrophages. Therefore, apocynin may be a potential therapeutic material to prevent the progression of atherosclerosis.
Assuntos
Acetofenonas/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Aterosclerose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Animais , Apolipoproteínas E/genética , Aterosclerose/patologia , Quimiocina CCL2/biossíntese , Fator Estimulador de Colônias de Granulócitos/biossíntese , Interleucina-6/biossíntese , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Mutantes , RNA Mensageiro/biossíntese , Espécies Reativas de Oxigênio/antagonistas & inibidoresRESUMO
Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine and one of the major mediators of obesity-induced insulin resistance. TNFα is generated through TNFα converting enzyme (TACE)-mediated cleavage of the transmembrane precursor pro-TNFα. Inhibition of TACE resulted in the improvement in glucose and insulin levels in diabetic animals, suggesting a crucial role of TACE activity in glucose metabolism. However, the regulation of TACE activity in insulin-sensitive tissues has not been fully determined. This study aimed to investigate the impact of TACE in insulin-sensitive tissues in the early stage of the development of obesity. C57BL6 mice were fed standard chow (B6-SC) or high-fat/high-sucrose diet (B6-HF/HS). KK-Ay mice were fed SC ad libitum (Ay-AL) or fed reduced amounts of SC (caloric restriction (CR); Ay-CR). As control for Ay-AL, KK mice fed SC ad libitum (KK-AL) were used. TACE activity in visceral adipose tissue (VAT), but not in liver or skeletal muscle, was significantly elevated in B6-HF/HS and Ay-AL compared with B6-SC and KK-AL, respectively. Phosphorylation of JNK and p38MAPK, but not ERK, in VATs from B6-HF/HS and Ay-AL was also significantly elevated. Ay-CR showed significantly lower TACE, JNK and p38MAPK activities in VAT and serum TNFα level compared with those of Ay-AL. In contrast, intraperitoneal injection of TNFα activated TACE, JNK and p38MAPK activities in VAT in KK mice. In conclusion, during the development of obesity, TACE activity is elevated only in VAT, and CR effectively reduced TACE activity and TACE-mediated pro-TNFα shedding in VAT.