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1.
PLoS One ; 16(10): e0258525, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644362

RESUMO

BACKGROUND: A substantial number of patients presenting with non-ST-elevation myocardial infarction (NSTEMI) and multivessel disease (MVD) have severe left ventricular systolic dysfunction (LVSD) (left ventricular ejection fraction (LVEF) less than 35%). But data are lacking regarding optimal percutaneous coronary intervention (PCI) strategy for these patients. The aim of this study was to compare the long-term outcomes of IRA (infarct-related artery)-only and multivessel PCI in patients with NSTEMI and MVD complicated by severe LVSD. METHODS: Among 13,104 patients enrolled in the PCI registry from November 2011 to December 2015, patients with NSTEMI and MVD with severe LVSD who underwent successful PCI were screened. The primary outcome was 3-year major adverse cardiovascular events (MACEs), defined as all-cause death, any myocardial infarction, stroke, and any revascularization. RESULTS: Overall, 228 patients were treated with IRA-only PCI (n = 104) or MV-PCI (n = 124). The MACE risk was significantly lower in the MV-PCI group than in the IRA-only PCI group (35.5% vs. 54.8%; hazard ratio [HR] 0.561; 95% confidence interval [CI] 0.378-0.832; p = 0.04). This result was mainly driven by a significantly lower risk of all-cause death (23.4% vs. 41.4%; hazard ratio [HR] 0.503; 95% confidence interval [CI] 0.314-0.806; p = 0.004). The results were consistent after multivariate regression, propensity-score matching, and inverse probability weighting to adjust for baseline differences. CONCLUSIONS: Among patients with NSTEMI and MVD complicated with severe LVSD, multivessel PCI was associated with a significantly lower MACE risk. The findings may provide valuable information to physicians who are involved in decision-making for these patients.

2.
J Gastrointest Surg ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506031

RESUMO

INTRODUCTION: The impact of adjuvant sequential chemoradiotherapy (CRT) on survival in resected pancreatic ductal adenocarcinoma (PDAC) remains unclear and warrants further investigation. METHODS: NCDB patients with R0/R1 resected PDAC who received adjuvant chemotherapy without CRT or followed by CRT per RTOG-0848 protocol were included. Cox regression for 5-year overall survival (OS) was performed and used to construct a pathologic nomogram in patients who did not receive CRT. A risk score was calculated and patients were divided into low-risk and high-risk groups. Patients from each risk stratum were matched for the receipt of CRT to assess the added benefit of CRT on survival. The Kaplan-Meier analysis was performed to compare OS. RESULTS: A total of 7146 patients were selected, 1308 (18.3%) received CRT per RTOG-0848. Cox regression concluded grade, T stage, N stage, node yield < 12, R1, and LVI as significant predictors of 5-year OS which were used to construct the risk score. Matched analysis in low-risk patients (score 0-79) showed no difference in OS between CRT vs. no CRT (47.6 ± 5.7 vs. 45.1 ± 3.9 months; p = 0.847). OS benefit was 3% at 1 year, - 4% at 2 years, and 4% at 5 years. In high-risk patients (score 80-100), median OS was higher in CRT vs. no CRT (24.8 ± 0.7 vs. 21.7 ± 0.8 months; p = 0.043). Absolute OS benefit was 13% at 1 year, 5% at 2 years, and - 1% at 5 years. CONCLUSION: CRT has a short-lived impact on OS in resected PDAC that is only evident in high-risk patients. In this subset, survival benefit peaks at 1 year and subsides at 3 to 5 years following PDAC resection.

3.
Int J Biol Macromol ; 190: 607-617, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508721

RESUMO

Bone morphogenic protein-2/4 (BMP-2/4) is an osteoinductive protein that accelerates osteogenesis when administered to bony defects. Sericin is produced by silkworms, and has a biological activity that differs depending on the degumming method used. Our results indicated that the high molecular weight fraction of silk sericin (MW > 30 kDa) obtained via sonication had a more abundant ß-sheet structure than the low molecular weight fraction. Administration of the ß-sheet structure silk sericin increased BMP-2/4 expression in a dose-dependent manner in RAW264.7 cells and human monocytes. This sericin increased the expression levels of toll-like receptor (TLR)-2, TLR-3, and TLR-4 in RAW264.7 cells. Application of a TLR-2 antibody or TLR pathway blocker decreased BMP-2/4 expression following sericin administration. In the animal model, the bone volume and BMP-2/4 expression were higher in rats treated with a sericin-incorporated gelatin sponge than in rats treated with a gelatin sponge alone or a sponge-incorporated with denatured sericin. In conclusion, sericin with a more abundant ß-sheet structure increased BMP-2/4 expression and bone formation better than sericin with a less abundant ß-sheet structure.

4.
Molecules ; 26(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34576901

RESUMO

Transient ischemia in brains causes neuronal damage, gliosis, and blood-brain barrier (BBB) breakdown, which is related to ischemia-induced brain dysfunction. Populus species have various pharmacological properties including antioxidant and anti-inflammatory activities. In this study, we found that phenolic compounds were rich in Populus tomentiglandulosa extract and examined the effects of Populus tomentiglandulosa extract on neuronal damage/death, astrogliosis, and BBB breakdown in the striatum, which is related to motor behavior, following 15-min transient ischemia in the forebrain in gerbils. The gerbils were pre-treated with 50, 100, and 200 mg/kg of the extract. The latter showed significant effects against ischemia-reperfusion injury. Ischemia-induced hyperactivity using spontaneous motor activity test was significantly attenuated by the treatment. Striatal cells (neurons) were dead at five days after the ischemia; however, pre-treatment with the extract protected the striatal cells from ischemia/reperfusion injury. Ischemia-induced reactive astrogliosis was significantly alleviated, in particular, astrocyte end feet, which are a component of BBB, were significantly preserved. Immunoglobulin G, which is not found in intact brain parenchyma, was apparently shown (an indicator of extravasation) in striatal parenchyma at five days after the ischemia, but IgG leakage was dramatically attenuated in the parenchyma by the pre-treatment. Based on these findings, we suggest that Populus tomentiglandulosa extract rich in phenolic compounds can be employed as a pharmaceutical composition to develop a preventive material against brain ischemic injury.

5.
Arch Microbiol ; 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34562146

RESUMO

A Gram-positive, aerobic, rod-shaped bacterium, designated as strain 1605-214T, was isolated from the blood sample of a patient with cholangitis. Based on its 16S rRNA gene sequence, the strain 1605-214T belonged to the genus Cohnella and exhibited 97.9% sequence identity with Cohnella luojiensis DSM 24270T (GQ214052). DNA-DNA hybridization, digital DNA-DNA hybridization, and average nucleotide identity values between the two species were 23% ± 1.9, 21.1%, and 77.2%, respectively. The cellular fatty acids of strain 1605-214T were mainly comprised of anteiso-C15:0 (36.1%), iso-C16:0 (16.5%), and C16:0 (15.1%). The predominant quinone was menaquinone-7; predominant polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, and aminophospholipid-1. The cell wall peptidoglycan of strain 1605-214T contained meso-diaminopimelic acid. DNA G + C content of strain 1605-214T was 50.6 mol%. 5187 genes out of a total of 5413 (94.6%) were assigned putative functions using eggNOG v5.0. Based on genotypic characteristics and genomic sequence analysis results, strain 1605-214T was confirmed to represent a novel species of genus Cohnella, for which the name Cohnella cholangitidis sp. nov., was proposed.

6.
Medicina (Kaunas) ; 57(7)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34356975

RESUMO

Background and Objectives: Data is still limited regarding clinical outcomes of rotational atherectomy (RA) after percutaneous coronary intervention. We sought to evaluate clinical outcomes of RA. Materials and Methods: This multi-center registry enrolled patients who underwent RA during PCI from nine tertiary centers in Korea between January 2010 and October 2019. The primary endpoint was target-vessel failure (TVF; the composite outcome of cardiac death, target-vessel spontaneous myocardial infarction, or target-vessel revascularization). Results: Of 540 patients (583 lesions), the mean patient age was 71.4 ± 0.4 years, 323 patients (59.8%) were men, and 305 patients (56.5%) had diabetes mellitus. Technical success rate was 96.4%. In-hospital major adverse cerebral and cardiac events occurred in 63 cases (10.8%). At 1.5 years, 72 (16.0%) of TVFs were occurred. We evaluated independent predictors of TVF, which included current smoker (hazard ratio (HR), 1.92; 95% confidence interval (CI), 1.17-3.16; p = 0.01), chronic renal disease (HR, 1.87; 95% CI, 1.14-3.08; p = 0.013), history of cerebrovascular attack (HR, 2.14; 95% CI, 1.24-3.68; p = 0.006), left ventricle ejection fraction (HR, 0.98; 95% CI, 0.97-0.999; p = 0.037), and left main disease (HR, 1.94; 95% CI, 1.11-3.37; p = 0.019). Conclusions: From this registry, we demonstrated acceptable success rates, in-hospital and mid-term clinical outcomes of RA in the DES era.


Assuntos
Aterectomia Coronária , Doença da Artéria Coronariana , Stents Farmacológicos , Intervenção Coronária Percutânea , Calcificação Vascular , Idoso , Doença da Artéria Coronariana/cirurgia , Humanos , Masculino , Sistema de Registros , República da Coreia/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
7.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445640

RESUMO

4-Hexylresorcinol (4HR) has been used as a food additive, however, it has been recently demonstrated as a Class I histone deacetylase inhibitor (HDACi). Unlike other HDACi, 4HR can be taken through foods. Unfortunately, some HDACi have an influence on craniofacial growth, therefore, the purpose of this study was to evaluate the effects of 4HR on craniofacial growth. Saos-2 cells (osteoblast-like cells) were used for the evaluation of HDACi and its associated activities after 4HR administration. For the evaluation of craniofacial growth, 12.8 mg/kg of 4HR was administered weekly to 4 week old rats (male: 10, female: 10) for 12 weeks. Ten rats were used for untreated control (males: 5, females: 5). Body weight was recorded every week. Serum and head samples were collected at 12 weeks after initial administration. Craniofacial growth was evaluated by micro-computerized tomography. Serum was used for ELISA (testosterone and estrogen) and immunoprecipitation high-performance liquid chromatography (IP-HPLC). The administration of 4HR (1-100 µM) showed significant HDACi activity (p < 0.05). Body weight was significantly different in male rats (p < 0.05), and mandibular size was significantly smaller in 4HR-treated male rats with reduced testosterone levels. However, the mandibular size was significantly higher in 4HR treated female rats with increased growth hormone levels. In conclusion, 4HR had HDACi activity in Saos-2 cells. The administration of 4HR on growing rats showed different responses in body weight and mandibular size between sexes.


Assuntos
Anti-Helmínticos/farmacologia , Osso e Ossos/citologia , Ossos Faciais/crescimento & desenvolvimento , Hexilresorcinol/farmacologia , Desenvolvimento Maxilofacial/efeitos dos fármacos , Osteoblastos/citologia , Animais , Osso e Ossos/efeitos dos fármacos , Ossos Faciais/efeitos dos fármacos , Feminino , Masculino , Osteoblastos/efeitos dos fármacos , Ratos
9.
Artigo em Inglês | MEDLINE | ID: mdl-34342422

RESUMO

Diamine-appended metal-organic frameworks (MOFs) exhibit exceptional CO2 adsorption capacities over a wide pressure range because of the strong interaction between basic amine groups and acidic CO2. Given that their high CO2 working capacity is governed by solvent used during amine functionalization, a systematic investigation on solvent effect is essential but not yet demonstrated. Herein, we report a facile one-step solvent exchange route for the diamine functionalization of MOFs with open metal sites, using an efficient method to maximize diamine loading. We employed an MOF, Mg2(dobpdc) (dobpdc4- = 4,4'-dioxido-3,3'-biphenyldicarboxylate), which contains high-density open metal sites. Indirect grafting with N-ethylethylenediamine (een) was performed with a minimal amount of methanol (MeOH) via multiple MeOH exchanges and diamine functionalization, resulting in a top-tier CO2 adsorption capacity of 16.5 wt %. We established the correlation between N,N-dimethylformamide (DMF) loading and infrared peaks, which provides a simple method for determining the amount of the remaining DMF in Mg2(dobpdc). All interactions among Mg, DMF, diamine, and solvent were analyzed by van der Waals (vdw)-corrected density functional theory (DFT) calculations to elucidate the effect of chemical potential on diamine grafting.

10.
Neurochem Res ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34403064

RESUMO

p27Kip1 (p27) regulates the cell cycle by inhibiting G1 progression in cells. Several studies have shown conflicting results on the effects of p27 against cell death in various insults. In the present study, we examined the neuroprotective effects of p27 against H2O2-induced oxidative stress in NSC34 cells and against spinal cord ischemia-induced neuronal damage in rabbits. To promote delivery into NSC34 cells and motor neurons in the spinal cord, Tat-p27 fusion protein and its control protein (Control-p27) were synthesized with or without Tat peptide, respectively. Tat-p27, but not Control-27, was efficiently introduced into NSC34 cells in a concentration- and time-dependent manner, and the protein was detected in the cytoplasm. Tat-p27 showed neuroprotective effects against oxidative stress induced by H2O2 treatment and reduced the formation of reactive oxygen species, DNA fragmentation, and lipid peroxidation in NSC34 cells. Tat-p27, but not Control-p27, ameliorated ischemia-induced neurological deficits and cell damage in the rabbit spinal cord. In addition, Tat-p27 treatment reduced the expression of α-synuclein, activation of microglia, and release of pro-inflammatory cytokines such as interleukin-1ß and tumor necrosis factor-α in the spinal cord. Taken together, these results suggest that Tat-p27 inhibits neuronal damage by decreasing oxidative stress, α-synuclein expression, and inflammatory responses after ischemia.

11.
World J Gastroenterol ; 27(27): 4322-4341, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34366607

RESUMO

Pancreatic cancer is a challenging malignancy with limited treatment options and poor life expectancy. The only curative option is surgical resection, but only 15%-20% of patients are resectable at presentation because more than 50% of patients has distant metastasis at diagnosis and the rest of them has locally advanced pancreatic cancer (LAPC). The standard of care first line treatment for LAPC patients is chemotherapy with or without radiation therapy. Recent developments in minimally invasive ablative techniques may add to the treatment armamentarium of LAPC. There are increasing number of studies evaluating these novel ablative techniques, including radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation. Most studies which included pancreatic tumor ablation, demonstrated improved overall survival in LAPC patients. However, the exact protocols are yet to set up to which stage of the treatment algorithm ablative techniques can be added and in what kind of treatment combinations. Patients with metastatic pancreatic cancer has dismal prognosis with 5-year survival is only 3%. The most common metastatic site is the liver as 90% of pancreatic cancer patients develop liver metastasis. Chemotherapy is the primary treatment option for patients with metastatic pancreatic cancer. However, when the tumor is not responding to chemotherapy or severe drug toxicity develops, locoregional liver-directed therapies can provide an opportunity to control intrahepatic disease progression and improve survival in selected patients. During the last decade new therapeutic options arose with the advancement of minimally invasive technologies to treat pancreatic cancer patients. These new therapies have been a topic of increasing interest due to the severe prognostic implications of locally advanced and metastatic pancreatic cancer and the low comorbid risk of these procedures. This review summarizes new ablative options for patients with LAPC and percutaneous liver-directed therapies for patients with liver-dominant metastatic disease.


Assuntos
Técnicas de Ablação , Criocirurgia , Neoplasias Hepáticas , Neoplasias Pancreáticas , Ablação por Radiofrequência , Técnicas de Ablação/efeitos adversos , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/terapia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/terapia
12.
Assay Drug Dev Technol ; 19(7): 442-452, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34415786

RESUMO

FK506-binding proteins (FKBPs) belong to the immunophilin family and are linked to various disease states, including the inflammatory response. The inhibition of cytokine and chemokine expression in addition to positive effects of FKBPs on corneal inflammation in animal models suggests that they may be used for ophthalmic delivery in the treatment of dry eye disease. To pass the effective barriers protecting eye tissues, testing the transduction domains of FKBPs is essential. However, monitoring their transduction efficiencies is not a simple task. The quantitative measurement of FKBP interactions was performed using a cell model with a specific G protein-coupled receptor, as FKBPs had been known to act at the inositol 1,4,5-trisphosphate receptor (IP3R) leading to the inhibition of intracellular calcium mobilization. Because of its luminescence amplitude and stability, human urotensin II receptor was expressed in aequorin parental cells to measure the action of selected FKBPs. This luminescence-based functional assay platform exhibited a high signal-to-background ratio of more than 100 and a Z' factor at 0.6204. As expected, changes in the sequence of the transduction domain affected the function of the FKBPs. The intracellular calcium mobilization assay with selected FKBPs represented a robust and reliable platform to screen initial candidates. Although the precise nature of the control that FKBPs exert on the IP3R is uncertain, this approach can be used to develop innovative anti-inflammatory treatments for dry eye disease by optimizing protein transduction domain sequences.

13.
Biochem Biophys Res Commun ; 571: 188-194, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34330063

RESUMO

Osteoarthritis (OA) is an incurable joint disease affecting 240 million elderly population, and major unmet medical needs exist for better therapeutic options for OA. During skeletal development, Nkx3.2 has been shown to promote chondrocyte differentiation and survival, but to suppress cartilage hypertrophy and blood vessel invasion. Here we show that Nkx3.2 plays a key role in osteoarthritis (OA) pathogenesis. Marked reduction of Nkx3.2 expression was observed in three different murine OA models. Consistent with these findings, analyses of surgery-induced and age-driven OA models revealed that cartilage-specific post-natal induction of Nkx3.2 can suppress OA progression in mice. These results suggest that Nkx3.2 may serve as a promising target for OA drug development.

14.
PLoS Genet ; 17(7): e1009678, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34260587

RESUMO

Animals can adapt to dynamic environmental conditions by modulating their developmental programs. Understanding the genetic architecture and molecular mechanisms underlying developmental plasticity in response to changing environments is an important and emerging area of research. Here, we show a novel role of cAMP response element binding protein (CREB)-encoding crh-1 gene in developmental polyphenism of C. elegans. Under conditions that promote normal development in wild-type animals, crh-1 mutants inappropriately form transient pre-dauer (L2d) larvae and express the L2d marker gene. L2d formation in crh-1 mutants is specifically induced by the ascaroside pheromone ascr#5 (asc-ωC3; C3), and crh-1 functions autonomously in the ascr#5-sensing ASI neurons to inhibit L2d formation. Moreover, we find that CRH-1 directly binds upstream of the daf-7 TGF-ß locus and promotes its expression in the ASI neurons. Taken together, these results provide new insight into how animals alter their developmental programs in response to environmental changes.

15.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206041

RESUMO

Parkinson's disease (PD) is characterized mainly by the loss of dopaminergic neurons in the substantia nigra (SN) mediated via oxidative stress. Although glutaredoxin-1 (GLRX1) is known as one of the antioxidants involved in cell survival, the effects of GLRX1 on PD are still unclear. In this study, we investigated whether cell-permeable PEP-1-GLRX1 inhibits dopaminergic neuronal cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We showed that PEP-1-GLRX1 protects cell death and DNA damage in MPP+-exposed SH-SY5Y cells via the inhibition of MAPK, Akt, and NF-κB activation and the regulation of apoptosis-related protein expression. Furthermore, we found that PEP-1-GLRX1 was delivered to the SN via the blood-brain barrier (BBB) and reduced the loss of dopaminergic neurons in the MPTP-induced PD model. These results indicate that PEP-1-GLRX1 markedly inhibited the loss of dopaminergic neurons in MPP+- and MPTP-induced cytotoxicity, suggesting that this fusion protein may represent a novel therapeutic agent against PD.


Assuntos
Cisteamina/análogos & derivados , Neurônios Dopaminérgicos/citologia , Glutarredoxinas/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Peptídeos/química , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , 1-Metil-4-fenilpiridínio/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Cisteamina/química , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutarredoxinas/química , Glutarredoxinas/farmacologia , Humanos , Masculino , Camundongos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Substância Negra/química
16.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34212986

RESUMO

Tumor necrosis factor (TNF)­α and TNF receptor 1 (TNF­R1) play diverse roles in modulating the neuronal damage induced by cerebral ischemia. The present study compared the time­dependent changes of TNF­α and TNF­R1 protein expression levels in the hippocampal subfield cornu ammonis 1 (CA1) between adult and young gerbils following transient forebrain ischemia (tFI), via western blot and immunohistochemistry analyses. In adult gerbils, delayed neuronal death of pyramidal neurons, the principal neurons in CA1, was recorded 4 days after tFI; however, in young gerbils, delayed neuronal death was recorded 7 days after tFI. TNF­α protein expression levels gradually increased in both groups following tFI; however, TNF­α expression was higher in young gerbils compared with adult gerbils. TNF­R1 protein expression levels markedly increased in both groups 1 day after tFI. Subsequently, TNF­R1 expression gradually decreased in young gerbils, whereas TNF­R1 expression levels were irregularly altered in adult gerbils following tFI. Notably, TNF­α immunoreactivity significantly increased in pyramidal neurons in both groups 1 day after tFI; however, the patterns altered between both groups. In adult gerbils, TNF­α immunoreactivity was rarely exhibited in pyramidal neurons 4 days after tFI due to neuronal death, suggesting that TNF­α immunoreactivity was newly expressed in astrocytes. In young gerbils, TNF­α immunoreactivity increased in pyramidal neurons 4 days after tFI, and TNF­α immunoreactivity was newly expressed in astrocytes. In addition, TNF­R1 immunoreactivity was exhibited in pyramidal cells of both sham groups, and significantly increased 1 day after tFI; however, the patterns altered between both groups. In adult gerbils, TNF­R1 immunoreactivity was rarely exhibited 4 days after tFI, and astrocytes newly expressed TNF­R1 immunoreactivity. In young gerbils, TNF­R1 immunoreactivity increased in pyramidal neurons 4 days after tFI; however, TNF­R1 immunoreactivity was not reported in pyramidal neurons and astrocytes thereafter. Taken together, the results of the present study suggest that different expression levels of TNF­α and TNF­R1 in ischemic CA1 between adult and young gerbils may be due to age­dependent differences of tFI­induced neuronal death.

17.
Free Radic Biol Med ; 172: 418-429, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34175438

RESUMO

Proline rich Akt substrate (PRAS40) is a component of mammalian target of rapamycin complex 1 (mTORC1) and activated mTORC1 plays important roles for cellular survival in response to oxidative stress. However, the roles of PRAS40 in dopaminergic neuronal cell death have not yet been examined. Here, we examined the roles of Tat-PRAS40 in MPP+- and MPTP-induced dopaminergic neuronal cell death. Our results showed that Tat-PRAS40 effectively transduced into SH-SY5Y cells and inhibited DNA damage, ROS generation, and apoptotic signaling in MPP+-induced SH-SY5Y cells. Further, these protective mechanisms of Tat-PRAS40 protein display through phosphorylation of Tat-PRAS40, Akt and direct interaction with 14-3-3σ protein, but not via the mTOR-dependent signaling pathway. In a Parkinson's disease animal model, Tat-PRAS40 transduced into dopaminergic neurons in mouse brain and significantly protected against dopaminergic cell death by phosphorylation of Tat-PRAS40, Akt and interaction with 14-3-3σ protein. In this study, we demonstrated for the first time that Tat-PRAS40 directly protects against dopaminergic neuronal cell death. These results indicate that Tat-PRAS40 may provide a useful therapeutic agent against oxidative stress-induced dopaminergic neuronal cell death, which causes diseases such as PD.


Assuntos
Neurônios Dopaminérgicos , Estresse Oxidativo , Animais , Apoptose , Morte Celular , Camundongos , Espécies Reativas de Oxigênio
18.
Korean J Ophthalmol ; 35(4): 261-271, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34162193

RESUMO

PURPOSE: The purpose of this study was to determine the efficacy and safety of selective intra-arterial thrombolysis in patients with central retinal artery occlusion (CRAO). METHODS: Medical records for 44 eyes of 44 patients diagnosed with acute non-arteritic CRAO and thrombolysis between October 2010 and February 2019 were analyzed retrospectively. Based on visual acuity, fundoscopic findings, and fluorescein angiography, the patients were classified into three stages: incomplete, subtotal, and total. The perfusion state using the best-corrected visual acuity (BCVA), arm to retina time, and arteriovenous passage times, after 1 month, 6 months, and at the final visit after the procedure, were compared with baseline readings. RESULTS: Improvement of visual acuity was confirmed in 31 out of 44 patients (70.45%). The mean BCVA of 44 patients changed from 1.65 ± 0.78 logarithmic minimum angle of resolution (logMAR) at the first visit to 1.18 ± 0.91 logMAR at the last visit (p = 0.114). The BCVA according to CRAO stage was 0.08 ± 0.11 logMAR for the incomplete stage at the first visit, 0.06 ± 0.05 logMAR (p = 0.933) 1 month after the procedure, and 0.05 ± 0.07 logMAR (p = 0.933) at the last visit. In the subtotal stage, the results were 1.81 ± 0.54 logMAR at the first visit, 1.63 ± 0.76 logMAR (p = 0.035) 1 month after the procedure, and 1.36 ± 0.85 logMAR (p = 0.014) at the last visit. For the total stage of BCVA, the result at the first visit was 2.36 ± 0.25 logMAR, and it was 2.30 ± 0.30 logMAR (p = 0.510) 1 month after the procedure, and 2.42 ± 0.30 logMAR (p = 0.642) at the last visit. Reperfusion was observed in 40 patients out of the 44 (90.91%). CONCLUSIONS: Selective intra-arterial thrombolysis can be helpful in patients with subtotal CRAO in terms of visual improvement and retinal arterial reperfusion.

19.
BMB Rep ; 54(9): 458-463, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34120676

RESUMO

Cytokines activate inflammatory signals and are major mediators in progressive ß-cell damage, which leads to type 1 diabetes mellitus. We recently showed that the cell-permeable Tat-CIAPIN1 fusion protein inhibits neuronal cell death induced by oxidative stress. However, how the Tat-CIAPIN1 protein affects cytokine-induced ß-cell damage has not been investigated yet. Thus, we assessed whether the Tat-CIAPIN1 protein can protect RINm5F ß-cells against cytokine-induced cytotoxicity. In cytokine-exposed RINm5F ß-cells, the transduced Tat-CIAPIN1 protein elevated cell survivals and reduced reactive oxygen species (ROS) and DNA fragmentation levels. The Tat-CIAPIN1 protein reduced mitogen-activated protein kinases (MAPKs) and NF-κB activation levels and elevated Bcl-2 protein, whereas Bax and cleaved Caspase-3 proteins were decreased by this fusion protein. Thus, the protection of RINm5F ß-cells by the Tat-CIAPIN1 protein against cytokine-induced cytotoxicity can suggest that the Tat-CIAPIN1 protein might be used as a therapeutic inhibitor against RINm5F ß-cell damage. [BMB Reports 2021; 54(9): 458-463].

20.
Neurochem Res ; 46(11): 2852-2866, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34050880

RESUMO

Transient ischemia in the brain causes blood-brain barrier (BBB) breakdown and dysfunction, which is related to ischemia-induced neuronal damage. Leakage of plasma proteins following transient ischemia is one of the indicators that is used to determine the extent of BBB dysfunction. In this study, neuronal damage/death, leakage of albumin and IgG, microgliosis, and inflammatory cytokine expression were examined in the hippocampal CA1 region, which is vulnerable to transient ischemia, following 5-min (mild) and 15-min (severe) ischemia in gerbils induced by transient common carotid arteries occlusion (tCCAo). tCCAo-induced neuronal damage/death occurred earlier and was more severe after 15-min tCCAo vs. after 5-min tCCAo. Significant albumin and IgG leakage (albumin and IgG immunoreactivity) took 1 or 2 days to begin, and immunoreactivity was markedly increased 5 days after 5-min tCCAo. While, albumin and IgG leakage began to increase 6 h after 15-min tCCAo and remained significantly higher over time than that seen in 5-min tCCAo. IgG immunoreactivity was observed in degenerating neurons and activated microglia after tCCAo, and microglia were activated to a greater extent after 15-min tCCAo than 5-min tCCAo. In addition, following 15-min tCCAo, pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß)] immunoreactivity was significantly higher than that seen following 5-min tCCAo, whereas immunoreactivity of anti-inflammatory cytokines (IL-4 and IL-13) was lower in 15-min than 5-min tCCAo. These results indicate that duration of tCCAo differentially affects the timing and degree of neuronal damage or loss, albumin and IgG leakage and inflammatory cytokine expression in brain tissue. In addition, more severe BBB leakage is closely related to acceleration of neuronal damage through increased microglial activation and pro-inflammatory cytokine expression in the ischemic hippocampal CA1 region.

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