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1.
Int J Mol Sci ; 21(5)2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143531

RESUMO

The goal of this study was to examine the effect of lipid emulsion on the vasodilation induced by ATP-sensitive potassium (KATP) channels in isolated rat aortae and the underlying mechanism. The effects of Intralipid, containing 100% long-chain fatty acids, and Lipofundin MCT/LCT, containing 50% long-chain fatty acids plus 50% medium-chain fatty acids, on the vasodilation induced by levcromakalim in endothelium-intact aorta with or without NW-nitro-L-arginine methyl ester (L-NAME) and in endothelium-denuded aorta were examined. The effects of L-arginine, L-NAME, glibenclamide, and Lipofundin MCT/LCT, alone or combined, on the levcromakalim-induced vasodilation were examined. Lipofundin MCT/LCT inhibited the levcromakalim-induced vasodilation of isolated endothelium-intact aortae, whereas Intralipid did not. In addition, Lipofundin MCT/LCT had no effect on the levcromakalim-induced vasodilation of endothelium-denuded rat aortae and endothelium-intact aortae with L-NAME. L-arginine and Lipofundin MCT/LCT produced more levcromakalim-induced vasodilation than Lipofundin MCT/LCT alone. Glibenclamide inhibited levcromakalim-induced vasodilation. Levcromakalim did not significantly alter endothelial nitric oxide synthase phosphorylation, whereas Lipofundin MCT/LCT decreased cyclic guanosine monophosphate. Lipofundin MCT/LCT did not significantly alter levcromakalim-induced membrane hyperpolarization. Taken together, these results suggest that Lipofundin MCT/LCT inhibits the vasodilation induced by levcromakalim by inhibiting basally released endothelial nitric oxide, which seems to occur through medium-chain fatty acids.

2.
Surg Endosc ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144557

RESUMO

BACKGROUND: Laparoscopic distal gastrectomy for early gastric cancer has been widely accepted, but laparoscopic total gastrectomy has still not gained popularity because of technical difficulty and unsolved safety issue. We conducted a single-arm multicenter phase II clinical trial to evaluate the safety and the feasibility of laparoscopic total gastrectomy for clinical stage I proximal gastric cancer in terms of postoperative morbidity and mortality in Korea. The secondary endpoint of this trial was comparison of surgical outcomes among the groups that received different methods of esophagojejunostomy (EJ). METHODS: The 160 patients of the full analysis set group were divided into three groups according to the method of EJ, the extracorporeal circular stapling group (EC; n = 45), the intracorporeal circular stapling group (IC; n = 64), and the intracorporeal linear stapling group (IL; n = 51). The clinicopathologic characteristics and the surgical outcomes were compared among these three groups. RESULTS: There were no significant differences in the early complication rates among the three groups (26.7% vs. 18.8% vs. 17.6%, EC vs. IC vs. IL; p = 0.516). The length of mini-laparotomy incision was significantly longer in the EC group than in the IC or IL group. The anastomosis time was significantly shorter in the EC group than in the IL group. The time to first flatus was significantly shorter in the IL group than in the EC group. The long-term complication rate was not significantly different among the three groups (4.4% vs. 12.7% vs. 7.8%; EC vs. IC vs. IL; p = 0.359), however, the long-term incidence of EJ stenosis in IC group (10.9%) was significantly higher than in EC (0%) and IL (2.0%) groups (p = 0.020). CONCLUSIONS: The extracorporeal circular stapling and the intracorporeal linear stapling were safe and feasible in laparoscopic total gastrectomy, however, intracorporeal circular stapling increased EJ stenosis.

3.
J Urol ; : 101097JU0000000000000794, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003614

RESUMO

PURPOSE: The clinicopathological features and treatment outcomes of plasmacytoid variant (PV)-urothelial carcinoma of the bladder (UCB) have not been fully understood. We aimed to evaluate the clinicopathologic characteristics and survival outcomes of PV-UCB as compared to conventional UCB (C-UCB). METHODS: A systematic review was performed following the PRISMA guideline. PubMed/Medline, Embase, and Cochrane Library were searched up to June 2019. The differences in the clinicopathological features (≥stage pT3, lymph node metastasis, ureteral margin-positive, and perivesical soft tissue margin-positive status) and survival outcomes [overall mortality (OM) and cancer-specific mortality (CSM)] between PV-UCB and C-UCB were compared. The GRADE approach was used for rating the certainty of evidence. RESULTS: A total of 8 studies were included. Patients with PV-UCB had a higher frequency of ≥stage pT3 (odds ratio [OR], 3.84; 95% confidence interval [CI], 1.63-9.03; p=0.002) and risk of lymph node metastasis (OR, 2.58; 95% CI, 1.15-5.76; p=0.02), ureteral margin-positive (OR 12.18; 95% CI, 4.62-32.13; p<0.00001), and perivesical soft tissue margin-positive (OR 12.31; 95% CI, 5.15-29.41; p<0.00001) status after radical cystectomy than those with C-UCB. Although there was no difference in CSM (hazard ratio [HR], 1.40; 95% CI, 0.82-2.40; p=0.22) between PV-UCB and C-UCB, PV-UCB had worse survival outcomes (OM) than C-UCB approaching the borderline of significance (HR, 1.62; 95% CI, 0.98-2.68; p=0.06) when adjusted for other clinicopathological characteristics. CONCLUSIONS: PV-UCB was strongly associated with adverse clinicopathological features and worse OM compared to C-UCB after adjusting other clinicopathological parameters, and PV histology of UCB is an independent prognostic factor for overall survival.

4.
Toxicol Mech Methods ; : 1-12, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32063085

RESUMO

Background/Aim: Acute liver injury (ALI) is a life-threatening clinical syndrome that is usually caused by toxic chemicals, drugs, or pathogen infections. Sirtuin2 (Sirt2), an NAD+-dependent deacetylase, appears to play detrimental roles in liver injury. Here, we evaluated the therapeutic application targeting Sirt2 in carbon tetrachloride (CCl4)-induced ALI, by using AK-1 (a Sirt2 inhibitor).Methods: For in vivo experiments, a single injection of CCl4 was used to induce ALI. One hour later, mice were intraperitoneally injected with AK-1 and were sacrificed 24 h after CCl4 administration. For in vitro experiments, primary mouse hepatocytes were used to determine the effects of AK-1 on oxidative stress and hepatocellular death induced by CCl4.Results: AK-1 alleviated CCl4-induced ALI as confirmed by histopathologic analysis, and decreased levels of serum biochemicals and inflammatory cytokines. Although it barely affected the expression of hepatic cytochrome P450 enzymes, AK-1 attenuated CCl4-induced oxidative stress and its related cell death. Mechanistically, Sirt2 inhibition significantly increased the nuclear protein level of nuclear factor erythroid 2-related factor 2 (Nrf2), and meanwhile decreased phosphorylation of c-Jun N-terminal kinases (JNK), in normal and injured livers. Similar results were observed in vitro. AK-1 significantly attenuated CCl4-induced cytotoxicity and oxidative stress by up-regulating the activity of Nrf2, and down-regulating JNK signaling in hepatocytes.Conclusions: Our results suggest that AK-1 treatment attenuated oxidative stress and cell death in the ALI model, at least partially, via activating Nrf2 and inhibiting JNK signaling, and that Sirt2 inhibition might be a potential approach to cure ALI.

5.
Am J Pathol ; 190(3): 614-629, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972159

RESUMO

Bacterial flagellin, recognized by cell surface of Toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin- and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of IL-1 receptor antagonist (IL1RN) and interferon (IFN)ß markedly increased in fibrotic livers on flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNß and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-α/ß receptor 1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibroinflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN had significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.

6.
Food Chem Toxicol ; 135: 110930, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678261

RESUMO

Cigarette smoke (CS) is a risk factor for the development of nonalcoholic fatty liver disease. However, the role of mainstream CS (MSCS) in the pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear. During the first (early exposure) or last (late exposure) three weeks of methionine-choline deficient with high fat diet feeding (6 weeks), each diet group was exposed to MSCS (300 or 600 µg/L). Hepatic or serum biochemical analysis showed that MSCS differentially modulated hepatic injury in NASH milieu, depending on exposure time points. Consistently, NASH-related hepatocellular apoptosis and fibrosis were increased in the early exposure group, but decreased in the late exposure group, except for steatosis. Ex vivo experiments showed that CS extract differentially regulated inflammatory responses in co-cultured hepatocytes and macrophages isolated from steatohepatitic livers after 10 days or 3 weeks of diet feeding. Furthermore, CS differentially up- and down-regulated the expression levels of M1/M2 polarization markers and peroxisome proliferator-activated receptor-gamma (PPARγ) in livers (29% and 38%, respectively) or co-cultured macrophages (2 and 2.5 fold, respectively). Collectively, our findings indicate that opposite effects of MSCS on NASH progression are mediated by differential modulation of PPARγ and its-associated M1/M2 polarization in hepatic macrophages, depending on exposure time points.


Assuntos
Fumar Cigarros/efeitos adversos , Inflamação/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Deficiência de Colina , Citocinas/metabolismo , Dieta Hiperlipídica , Progressão da Doença , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Macrófagos/efeitos dos fármacos , Masculino , Metionina/deficiência , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/patologia , Tamanho do Órgão/efeitos dos fármacos , PPAR gama/metabolismo , Fatores de Tempo
7.
Am J Pathol ; 190(1): 68-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31610178

RESUMO

Oxidative stress and its associated lipid peroxidation play a key role in nonalcoholic steatohepatitis (NASH). Ferroptosis is a recently recognized type of cell death characterized by an iron-dependent and lipid peroxidation-mediated nonapoptotic cell death. We demonstrate the impact of ferroptosis on the progression of NASH induced by methionine/choline-deficient diet (MCD) feeding for 10 days. RSL-3 (a ferroptosis inducer) treatment showed decreased hepatic expression of glutathione peroxidase 4 (GPX4) and conversely increased 12/15-lipoxygenase, and apoptosis-inducing factor, indicating that ferroptosis plays a key role in NASH-related lipid peroxidation and its associated cell death. Consistently, levels of serum biochemical, hepatic steatosis, inflammation, and apoptosis in MCD-fed mice were exacerbated with RSL-3 treatment. However, MCD-fed mice treated with sodium selenite (a GPX4 activator) showed increase of hepatic GPX4, accompanied by reduced NASH severity. To chelate iron, deferoxamine mesylate salt was used. Administration of deferoxamine mesylate salt significantly reduced NASH severity and abolished the harmful effects of RSL-3 in MCD-fed mice. Finally, treatment with liproxstatin-1 (a ferroptosis inhibitor) repressed hepatic lipid peroxidation and its associated cell death, resulting in decreased NASH severity. Consistent with the in vivo findings, modulation of ferroptosis/GPX4 affected hepatocellular death in palmitic acid-induced in vitro NASH milieu. We conclude that GPX4 and its related ferroptosis might play a major role in the development of NASH.

8.
J Cell Mol Med ; 24(2): 1383-1398, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31821710

RESUMO

Although numerous studies have suggested that canonical IκB kinases (IKK) play a key role in the progression of liver fibrosis, the role of non-canonical IKKε and TANK-binding kinase 1 (TBK1) on the development and progression of liver fibrosis remains unclear. To demonstrate such issue, repeated injection of CCl4 was used to induce hepatotoxin-mediated chronic liver injury and biliary fibrosis was induced by 0.1% diethoxycarbonyl-1, 4-dihydrocollidine diet feeding for 4 weeks. Mice were orally administered with amlexanox (25, 50, and 100 mg/kg) during experimental period. Significantly increased levels of TBK1 and IKKε were observed in fibrotic livers or hepatic stellate cells (HSCs) isolated from fibrotic livers. Interestingly, amlexanox treatment significantly inhibited the phosphorylation of TBK1 and IKKε accompanied by reduced liver injury as confirmed by histopathologic analysis, decreased serum biochemical levels and fibro-inflammatory responses. Additionally, treatment of amlexanox promoted the fibrosis resolution. In accordance with these findings, amlexanox treatment suppressed HSC activation and its related fibrogenic responses by partially inhibiting signal transducer and activator of transcription 3. Furthermore, amlexanox decreased the activation and inflammatory responses in Kupffer cells. Collectively, we found that inhibition of the TBK1 and IKKε by amlexanox is a promising therapeutic strategy to cure liver fibrosis.

9.
Int Immunopharmacol ; 78: 106071, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31835083

RESUMO

Nicotine, a potent parasympathomimetic alkaloid, manifests anti-inflammatory properties by activating nicotinic acetylcholine receptors (nAChRs). In this study, we evaluated the effects of nicotine on concanavalin A (ConA)-induced autoimmune hepatitis. Nicotine (0.5 and 1 mg/kg) was intraperitoneally administered to BALB/c mice and mice were intravenously injected with ConA (15 mg/kg) to induce hepatitis. The results showed that nicotine treatment ameliorated pathological lesions in livers and significantly suppressed the expression of pro-inflammatory cytokines in the livers. Such effects were mediated by inhibiting the nuclear factor-kappa B (NF-κB) signaling in livers. Interestingly, nicotine inhibited the ConA-induced inflammatory response in primary cultured Kupffer cells (KCs) but did not alter the proliferation of splenocytes. The protective effects of nicotine against ConA-induced hepatitis were abolished in KC-depleted mice, indicating the requirement of KCs in this process. Additionally, the expression of α7-nAChR on KCs was dramatically increased by nicotine treatment, and the protective effects of nicotine on ConA-induced liver injury were significantly suppressed by treatment with methyllycaconitine (MLA), a specific α7-nAChR antagonist. Consistently, in primary cultured KCs, the activation of NF-κB signaling was also regulated by nicotine treatment. This study suggests that nicotine increases α7-nAChR-mediated cholinergic activity in KCs resulting in decrease of ConA-induced autoimmune hepatitis through inhibiting NF-κB signaling.

10.
J Clin Lab Anal ; 34(2): e23064, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31692115

RESUMO

BACKGROUND: Atypical chronic myeloid leukemia (aCML) is a hematologic disorder characterized by leukocytosis with increased dysplastic neutrophils and their precursors. In CSF3R gene, the activation mutation including T618I is frequently reported in aCML but is rarely accompanied by truncation mutations. Herein, we report a unique aCML patient with two CSF3R mutations (T618I and Y779*) in the same DNA strand. METHODS: High-coverage next-generation sequencing for 40 genes related with myeloid leukemia was performed. Sanger sequencing was performed to confirm CSF3R mutations. To confirm whether two CSF3R mutations are in cis or not, TA cloning was used. Clinical information and bone marrow pathology were reviewed by two hematopathologists. RESULTS: In the patient diagnosed with aCML in bone marrow study, two CSF3R mutations, (T618I and Y779*) a SETBP1 mutation (G870S) and an U2AF1 mutation (Q157P), were identified by high-coverage next-generation sequencing. The two CSF3R mutations were confirmed to be located in the same DNA strand by TA cloning, indicating that the two mutations are harbored in one malignant clone. The SETBP1 mutation is known to be related with poor prognosis in aCML. Likewise, the patient was refractory to hydroxyurea and showed disease progression. Additionally, we discussed the potential therapeutic targets by reviewing the molecular profile of the patient. CONCLUSION: We believe that the accurate diagnosis and maximum therapeutic chance could be achieved by profiling the mutations and their characteristics.

11.
Ann Lab Med ; 40(3): 232-237, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31858763

RESUMO

BACKGROUND: Genetic counseling (GC) provides many benefits, including the identification of patients appropriate for testing, patient education, and medical management. We evaluated the current status of and challenges faced by GC practitioners in Korean hospitals. METHODS: An electronic survey was designed and conducted in 52 certified laboratory physicians belonging to the Korean Society of Laboratory Medicine, from August to September 2018. The questionnaires addressed three main categories of information: (1) current status of GC in hospitals; (2) essential qualifications of GC practitioners; and (3) challenges and perspectives for GC. Fisher's exact test was applied to analyze categorical data. RESULTS: Among a total of 52 participants who initially responded, 12 (23.1%) were performing GC either by direct or indirect care. GC clinics were opened regularly for one (33.3%) or more than three sessions (25.0%) per week; most respondents spent more time for pre-visit activities than in-person visits, both for a initial visit patient and for a follow-up visit patient. All laboratory physicians provided genetic information to their patients. Most recommended family genetic testing when indicated (91.7%), discussed disease management (75.0%), and/or ordered additional genetic testing (58.3%), and some referred patients to other specialists (8.3%). CONCLUSIONS: Both patients and laboratory physicians concede the advantage of GC performed by clinical geneticists; however, the practice of GC involves several challenges and raises some concerns. The cost and support required to implement GC need to be addressed in order to provide qualified GC in Korea.

12.
Am J Health Behav ; 44(1): 90-99, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783936

RESUMO

Objectives: Androgen-deprivation therapy (ADT) for prostate cancer (PCa) is associated with reduced physical function and quality of life (QoL). We investigated the impact of a structured lifestyle intervention on the promotion of physical activity (PA) and reduction of sedentary behavior (SB), and its effect on QoL in men on ADT. Methods: Patients with advanced PCa on long-term ADT were randomized to the intervention (N = 11) or a control arm (N = 10) between February 2018 and May 2019. The intervention group received a structured lifestyle intervention including motivational text messages for 8 weeks (maintenance visit at week 12). At each visit, self-report measures and accelerometer data were used to assess PA and SB, and questionnaires were used to measure QoL, life satisfaction, anxiety, and depression. Results: Significantly greater improvements in QoL and depression compared to baseline were reported in the intervention group compared to the control group. In addition, the intervention group also showed a significantly greater increase in self-reported light, as well as moderate-to-vigorous PA, and reduction in self-reported SB. Conclusions: Given its inherent advantage in improving QoL and reducing depression, a lifestyle intervention program should be offered to patients on ADT.

13.
Korean J Thorac Cardiovasc Surg ; 52(6): 392-399, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31832375

RESUMO

Background: The surgical strategies for carotid endarterectomy (CEA) vary in terms of the anesthesia method, neurological monitoring, shunt usage, and closure technique, and no gold-standard procedure has been established yet. We aimed to analyze the feasibility and benefits of CEA under regional anesthesia (RA) and CEA under general anesthesia (GA). Methods: Between June 2012 and December 2017, 65 patients who had undergone CEA were enrolled, and their medical records were prospectively collected and retrospectively reviewed. A total of 35 patients underwent CEA under RA with cervical plexus block, whereas 30 patients underwent CEA under GA. In the RA group, a carotid shunt was selectively used for patients who exhibited negative results on the awake test. In contrast, such a shunt was used for all patients in the GA group. Results: There were no cases of postoperative stroke, cardiovascular events, or mortality. Nerve injuries were noted in 4 patients (3 in the RA group and 1 in the GA group), but they fully recovered prior to discharge. Operative time and clamp time were shorter in the RA group than in the GA group (119.29±27.71 min vs. 161.43±20.79 min, p<0.001; 30.57±6.80 min vs. 51.77±13.38 min, p<0.001, respectively). The hospital stay was shorter in the RA group than in the GA group (14.6±5.05 days vs. 18.97±8.92 days, p=0.022). None of the patients experienced a stroke or restenosis during the 27.23±20.3-month follow-up period. Conclusion: RA with a reliable awake test reduces shunt use and decreases the clamp and operative times of CEA, eventually resulting in a reduced length of hospital stay.

14.
Dose Response ; 17(4): 1559325819894148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839761

RESUMO

This study aims to examine the effect of linolenic acid on the vasodilation or vasoconstriction induced by acetylcholine and bupivacaine in isolated rat aortae and its underlying mechanism. The effect of linolenic acid on the vasodilation induced by acetylcholine, the calcium ionophore A23187, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate sodium salt (bromo-cyclic guanosine monophosphate [bromo-cGMP]) in endothelium-intact and endothelium-denuded aortae was examined. Linolenic acid inhibited vasodilation induced by acetylcholine, calcium ionophore A23187, and sodium nitroprusside. However, this fatty acid increased bromo-cGMP-induced vasodilation in endothelium-denuded aortae. Linolenic acid increased bupivacaine-induced contraction in endothelium-intact aortae, whereas it decreased bupivacaine-induced contraction in endothelium-intact aortae with Nω-nitro-l-arginine methyl ester and endothelium-denuded aortae. Linolenic acid inhibited acetylcholine- and bupivacaine-induced phosphorylation of endothelial nitric oxide synthase. Sodium nitroprusside increased cGMP in endothelium-denuded aortic strips, whereas bupivacaine decreased cGMP in endothelium-intact aortic strips. Linolenic acid decreased cGMP levels produced by bupivacaine and sodium nitroprusside. Together, these results suggest that linolenic acid inhibits acetylcholine-induced relaxation by inhibiting a step just prior to nitric oxide-induced cGMP formation. In addition, linolenic acid-mediated inhibition of vasodilation induced by a toxic concentration (3 × 10-4 M) of bupivacaine seems to be partially associated with inhibition of the nitric oxide-cGMP pathway.

15.
Nutrients ; 11(12)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817227

RESUMO

The fermentation of Korean red ginseng (RG) increases the bioavailability and efficacy of RG, which has a protective role in various diseases. However, the ginsenoside-specific molecular mechanism of the fermented RG with Cordyceps militaris (CRG) has not been elucidated in non-alcoholic fatty liver disease (NAFLD). A mouse model of NAFLD was induced by a fast-food diet (FFD) and treated with CRG (100 or 300 mg/kg) for the last 8 weeks. CRG-mediated signaling was assessed in the liver cells isolated from mice. CRG administration significantly reduced the FFD-induced steatosis, liver injury, and inflammation, indicating that CRG confers protective effects against NAFLD. Of note, an extract of CRG contains a significantly increased amount of ginsenosides (Rd and Rg3) after bioconversion compared with that of conventional RG. Moreover, in vitro treatment with Rd or Rg3 produced anti-steatotic effects in primary hepatocytes. Mechanistically, CRG protected palmitate-induced activation of mTORC1 and subsequent inhibition of mitophagy and PPARα signaling. Similar to that noted in hepatocytes, CRG exerted anti-inflammatory activity through mTORC1 inhibition-mediated M2 polarization. In conclusion, CRG inhibits lipid-mediated pathologic activation of mTORC1 in hepatocytes and macrophages, which in turn prevents NAFLD development. Thus, the administration of CRG may be an alternative for the prevention of NAFLD.

16.
Toxicol Appl Pharmacol ; 385: 114767, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697998

RESUMO

Amlexanox, a clinically approved small-molecule therapeutic presently used to treat allergic rhinitis, ulcer, and asthma, is an inhibitor of the noncanonical IkB kinase-ε (IKKε) and TANK-binding kinase 1 (TBK1). This study was to investigate the protective mechanism of amlexanox in acetaminophen (APAP)-induced acute liver injury (ALI). Mice were intraperitoneally injected with APAP (300 mg/kg, 12 h) to induce ALI and were orally administrated with amlexanox (25, 50 and 100 mg/kg) one hour after APAP treatment. Inhibition of IKKε and TBK1 by treatment of amlexanox attenuated APAP-induced ALI as confirmed by decreased serum levels of aspartate aminotransferase and alanine aminotransferase. Furthermore, amlexanox significantly decreased hepatocellular apoptosis in injured livers of mice as evidenced by histopathologic observation. Consistently, reduced oxidative stress by amlexanox was observed by increased hepatic glutathione concomitant with decreased levels of malondialdehyde. Amlexanox also enhanced expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase in injured livers of mice. Mechanistic insights into the mode of action of amlexanox against APAP-induced hepatotoxicity were involved in increasing phosphorylation of AMP-activated protein kinase (AMPK) and nuclear translocation of Nrf2, both in vivo and in vitro. Furthermore, the protective effects of amlexanox on APAP-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. Taken together, our findings suggest that amlexanox exerts antioxidative activities against APAP-mediated hepatotoxicity via AMPK/Nrf2 pathway.

17.
Cancers (Basel) ; 11(12)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766332

RESUMO

Treatment-related adverse events (AEs) can obfuscate the maintenance of a conventional schedule of sunitinib in patients with metastatic renal cell carcinoma. Accordingly, alternative schedules seeking to improve the safety profile of sunitinib have been tested. Recently, two meta-analyses similarly described improved safety profiles favoring a two weeks on and one week off (2/1) schedule, but with conflicting results for survival outcomes. Therefore, we conducted an updated systematic review and meta-analysis, including all recently published studies and using complementary statistical methods. Endpoints included progression-free survival, overall survival, and AEs of 15 types. Eleven articles were included in this meta-analysis. Using adjusted findings, we noted statistically better results in progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.39-0.84; p = 0.005), but no difference in overall survival (hazard ratio, 0.66; 95% confidence interval, 0.42-1.04; p = 0.08). Moreover, the 2/1 schedule was beneficial for reducing the incidence of several AEs. Conclusively, our meta-analysis suggests that the 2/1 schedule holds promise as an alternative means of reducing AEs and maintaining patient quality of life. While the survival outcomes of the 2/1 schedule seem also to be favorable, the level of evidence for this was low, and the interpretation of these findings should warrant caution. Large scale randomized trials are needed to support these results.

18.
J Clin Med ; 8(12)2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31771310

RESUMO

This study aimed to evaluate the effect of bladder neck preservation (BNP) on long-term urinary continence after robot-assisted laparoscopic prostatectomy (RALP). We systematically searched the PubMed, Embase, and Cochrane Library databases to identify studies that assessed the difference in urinary continence and oncologic outcomes between patients who underwent RALP with BNP and those who underwent RALP without BNP. Four trials (1880 cases with BNP, 727 controls without BNP) were considered suitable for meta-analysis. BNP was associated with significantly better urinary continence outcomes at 3-4 months (odds ratio (OR), 2.88; 95% confidence interval (CI), 1.52-5.48; p = 0.001), 12 months (OR, 2.03; 95% CI, 1.10-3.74; p = 0.02), and 24 months (OR, 3.23; 95% CI, 1.13-9.20; p = 0.03) after RALP. There was no difference in the rate of overall positive surgical margin (PSM) (OR, 1.00; 95% CI, 0.72-1.39; p = 0.99) and that of PSM at the prostate base (OR, 0.49; 95% CI, 0.21-1.13; p = 0.09) between the two groups. The BNP technique during RALP leads to early return of urinary continence and long-term urinary continence without compromising the oncologic outcomes.

19.
J Clin Med ; 8(11)2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31717594

RESUMO

We attempted to visualize the periurethral stiffness of prostatic urethras using strain elastography in the midsagittal plane of transrectal ultrasonography (TRUS) and to evaluate periurethral stiffness patterns in relation to lower urinary tract symptoms (LUTS). A total of 250 men were enrolled. The stiffness patterns of the entire prostate and individual zones were evaluated using strain elastography during a TRUS examination. After excluding 69 men with inappropriate elastography images, subjects were divided according to periurethral stiffness into either group A (low periurethral stiffness, N = 80) or group B (high periurethral stiffness, N = 101). There were significant differences in patient age (p = 0.022), transitional zone volume (p = 0.001), transitional zone index (p = 0.33), total international prostate symptom score (IPSS) (p < 0.001), IPSS-voiding subscore (p < 0.001), IPSS-storage subscore (p < 0.001), and quality of life (QoL) score (p = 0.002) between groups A and B. After adjusting for relevant variables, significant differences in total IPSS, IPSS-voiding subscore, and QoL score were maintained. Men with high periurethral stiffness were associated with worse urinary symptoms than those with low periurethral stiffness, suggesting that periurethral stiffness might play an important role in the development of LUTS.

20.
Genomics Inform ; 17(3): e34, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31610630

RESUMO

Direct-to-consumer (DTC) genetic testing is a controversial issue although Korean Government is considering to expand DTC genetic testing. Preventing the exaggeration and abusing of DTC genetic testing is an important task considering the early history of DTC genetic testing in Korea. And the DTC genetic testing performance or method has been rarely reported to the scientific and/or medical community and reliability of DTC genetic testing needs to be assessed. Law enforcement needs to improve these issues. Also principle of transparency needs to be applied.

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