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1.
Artigo em Inglês | MEDLINE | ID: mdl-32084588

RESUMO

STUDY OBJECTIVE: To investigate the prognostic factors and impact of minimally invasive surgery (MIS) in surgically treated early-stage high-grade (HG) neuroendocrine cervical carcinoma (NECC). DESIGN: A retrospective cohort study SETTING: Asan Medical Center, Seoul, Korea PATIENTS: Patients with International Federation of Obstetrics and Gynecology (FIGO) (2009) stage IB1-IIA HG NECC INTERVENTIONS: All patients underwent radical hysterectomy (RH) with a laparotomy or an MIS approach. MEASUREMENTS AND MAIN RESULTS: Between 1993 and 2017, 47 patients with FIGO stage IB1-IIA1 HG NECC were initially treated with RH. Clinicopathological variables of patients were retrospectively reviewed from electronic medical records. The median follow-up period was 28.2 months (interquartile range, 17.1-42). Stage IB1 disease was the most common (70.2%). Twenty-nine patients (61.7%) underwent RH via MIS. The overall survival (OS) and disease-free survival (DFS) rates were 63.8% and 38.3%, respectively. Lymph-node (LN) metastasis and resection margin (RM) involvement were significant risk factors for DFS (hazard ratio [HR], 2.227; 95% confidence interval [CI], 1.018-4.871; P=0.045, and HR, 6.494; 95% CI, 1.415-29.809; P=0.016, respectively) and OS (HR, 3.236; 95% CI, 1.188-8.815; P=0.022, and HR, 12.710; 95% CI, 1.128-143.152; P=0.040, respectively). The Kaplan-Meier survival curves revealed no significant differences in OS and DFS between the laparotomy and MIS groups (50% vs. 72.4% log-rank P=0.196, 38.9% vs. 37.9% P=0.975). CONCLUSION: LN metastasis and RM involvement were poor prognostic factors of survival outcomes in initially surgically treated early-stage HG NECC. No difference was observed in the survival outcomes between the MIS and laparotomy approaches.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32014661

RESUMO

In this study, we performed the metabolism of endosulfan sulfate in human liver preparations (human liver microsomes, S9 fractions and hepatocytes) to identify new metabolites using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Endosulfan sulfate is a major oxidized metabolite of the organochlorine insecticide endosulfan, and it exhibits a similar toxicity to endosulfan. Six metabolites, including 5 novel metabolites of endosulfan sulfate, were identified in the three different human liver reaction mixtures and metabolic pathways of endosulfan sulfate were proposed. The phase I metabolites M1 and M2 were observed in human liver microsomes, S9 fractions and hepatocytes. M1 was suggested to be an endosulfan diol monosulfate and M2 was identified as (1,4,5,6,7,7-hexachloro-3-formylbicyclo[2,2,1]hept-5-en-2-yl)methyl hydrogen sulfate through the interpretation of the HRMS spectrum. The phase II metabolite M3 was produced as an endosulfan sulfate-GSH conjugate in those three liver preparations and transformed to M5 (dipeptide) in S9 fractions and hepatocytes. M3 was the most predominant metabolite identified in the three liver preparations. M4 was only detected in microsomes as an M2-GSH conjugate and was metabolized to M6 (monopeptide) in hepatocytes. These results are different from the metabolic pathway of endosulfan and suggest the possible detoxification metabolic reaction of endosulfan sulfate in living organisms.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31907970

RESUMO

BACKGROUND AND AIM: Exogenous 8-hydroxydeoxyguanosine (8-OHdG) was suggested as an inhibitor of Rac1 and NADPH oxidase (NOX). The aim of this study was to evaluate the effects of the exogenous 8-OHdG on hepatic fibrogenesis in vitro and in vivo model of liver fibrosis. METHODS: Adult Sprague-Dawley rats were allocated to sham-operated rats (n = 7), rats that underwent bile duct ligation (BDL) (n = 6), and BDL rats treated with 8-OHdG (60 mg/kg/day by gavage, n = 6). All rats were sacrificed on day 21. Double immunofluorescence staining between either NOX1 or NOX2 and α-smooth muscle actin (SMA) in liver was performed. Hepatic fibrotic contents were assessed by hydroxyproline assay and quantified by Sirius red staining. In vitro, hepatic stellate cell (HSC) line LX-2 and HHSteC cells were stimulated by angiotensin II (10 µM). The reactive oxygen species (ROS) production was measured by confocal microscopy. The expressions of NOX1, NOX2, α-SMA, transforming growth factor (TGF)-ß1, and collagen Iα were analyzed by quantitative real-time polymerase chain reaction or immunoblotting. RESULTS: The 8-OHdG treatment in BDL rats reduced the NOX1 and NOX2 protein expression, which overlapped with α-SMA compared with BDL rats. The 8-OHdG treatment in BDL rats significantly decreased the mRNA expression of NOX1, NOX2, α-SMA, TGF-ß1, and collagen Iα, and fibrotic contents. Increases of ROS production, Rac1 activation, NOX1, NOX2, and fibronectin expression induced by angiotensin II in HSCs were attenuated by 8-OHdG. CONCLUSIONS: Rac1 activation and NOX-derived ROS are implicated to liver fibrosis. The 8-OHdG ameliorates liver fibrosis through the inhibition of Rac1 activation and NOX-derived ROS.

4.
Xenobiotica ; 50(4): 380-388, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31233374

RESUMO

1. Glycyrol is a coumestan derivative that is isolated from roots of Glycyrrhiza uralensis. Glycyrol exhibits several biological effects, including anti-oxidative and anti-inflammatory effects.2. Herein, we characterized glycyrol metabolism by cytochrome P450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) using human liver microsomes (HLM), human liver cytosol, human intestinal microsomes, or human recombinant cDNA-expressed CYPs and UGTs. The analysis was conducted using high resolution mass spectroscopy (HR-MS) on a Q ExactiveTM HF Hybride Quadrupole-Orbitrap mass spectrometer.3. NADPH-supplemented HLM generated six glycyrol metabolites (M1-M6) via hydroxylation, oxidation, and hydration; both NADPH- and UDPGA-supplemented liver microsomes generated three glucuronides (M7-M9). Reaction phenotyping revealed that CYP1A2 is the primary enzyme responsible for phase I metabolism, with minor involvement of the CYP3A4/5, CYP2D6, and CYP2E1 enzymes. Glucuronidation of glycyrol was primarily mediated by UGT1A1, UGT1A3, UGT1A9, and UGT2B7.4. In conclusion, glycyrol undergoes the efficient metabolic hydroxylation and glucuronidation reactions in human liver microsomes, which are predominantly catalyzed by CYP1A2, UGT1A1/3/9, and UGT2B7.

5.
Eur Radiol ; 30(4): 2302-2311, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31858203

RESUMO

OBJECTIVE: To compare the diagnostic performance of abbreviated MRI (AMRI) combined with multiphasic CT (mCT) with that of full-sequence gadoxetic acid-enhanced MRI (EOB-MRI) in a hepatocellular carcinoma (HCC)-screening cohort METHODS: Consecutive patients at risk of HCC who underwent EOB-MRI and mCT within 3 months for evaluation of new 0.5-3-cm hepatic observations were retrospectively recruited from 3 centers. An AMRI protocol comprising hepatobiliary phase, T2- and diffusion-weighted imaging, and dual-echo sequence was reconstituted from EOB-MRI. Two radiologists independently reviewed each observation in AMRI plus mCT (set 1) and EOB-MRI (set 2) per LI-RADS v2018. Per-lesion sensitivity, accuracy, and positive predictive value (PPV) for HCC were calculated and compared between image sets. RESULTS: In 267 patients, 306 histologically confirmed observations (280 HCCs, 20 combined hepatocellular-cholangiocarcinomas, 1 cholangiocarcinoma, and 5 benignities) were assessed. Set 1 yielded higher sensitivity (96.4% vs. 92.9%, p = 0.013) and comparable accuracy (91.2% vs. 87.6%) and PPV (94.1% vs. 93.5%) to set 2 using LI-RADS category (LR)-4/5 criteria. The sets showed comparable sensitivity (66.4% vs. 70.4%), accuracy (67.7% vs. 70.6%), and PPV (97.4% vs. 96.6%) using LR-5 criteria. A similar substantial number of non-HCC malignancies were categorized as LR-4 or LR-5, as was the number of HCCs categorized as LR-M in both sets. CONCLUSIONS: AMRI combined with mCT showed diagnostic performance similar or superior to that of EOB-MRI for HCC diagnosis using LI-RADS. Therefore, mCT holds potential as a sequential examination for HCC diagnosis in AMRI-detected hepatic observation in patients at risk of HCC. KEY POINTS: • AMRI plus multiphasic CT showed comparable accuracy (91.2%) and PPV (94.1%) to full-sequence gadoxetic acid-enhanced MRI using LR-4/5 criteria. • AMRI plus multiphasic CT was significantly more sensitive than full-sequence gadoxetic acid-enhanced MRI (96.4% vs. 92.9%) using LR-4/5 criteria. • Multiphasic CT is a potential sequential modality for HCC diagnosis after AMRI.

6.
Org Lett ; 21(24): 10038-10042, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31794237

RESUMO

A Cp*Co(III)-catalyzed γ-selective C-H allylation/hydroamination cascade toward the synthesis of 3,4-dihydroisoquinolines (DHIQs) has been successfully developed, starting from NH ketimines and allyl carbonates. Notably, highly efficient and γ-selective C-H allylations were accomplished using γ-substituted allyl reagents, thus overcoming the issues of poor α/γ selectivity and low reactivity of previous transition metal-catalyzed C-H allylations. The stereochemistry of allyl carbonates was a crucial factor, and synthesis of the DHIQs was achieved using (Z)-allyl carbonates.

7.
Xenobiotica ; : 1-8, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31847686

RESUMO

Osthenol, a prenylated coumarin, is a C8-prenylated derivative of umbelliferone isolated from the root of Angelica koreana and Angelica dahurica, an intermediate and is known as a major metabolite of desmethyl-osthole.The various pharmacological effects of osthenol have been reported. In previous studies, we investigated five hydroxylated metabolites by cytochromes P450 (CYP) and glucuronide conjugates of osthenol by uridine diphosphate-glucuronosyltransferases (UGTs). However, osthenol have very few studies have been reported on its pharmacokinetic (PK) profiling, we reported the PK parameters in mouse of osthenol through this study.After oral (5 and 20 mg/kg) and intravenous (5 mg/kg) administration, the concentration of osthenol in plasma was determined by LC-MS/MS. The quantitative method was validated in terms of linearity, accuracy, and precision. When 5 and 20 mg/kg of osthenol were orally administered, the bioavailability (BA) was found to be very low at 0.43 and 0.02%, respectively.In fact, osthenol was mostly metabolized to a two-Phase II conjugates, a sulfonyl and glucuronyl-osthenol, in the blood, which was determined by LC-HR/MS analysis of the blood sample. Because osthenol is rapidly metabolized to two conjugates by first-pass effect the BA of osthenol is low after oral administration.

8.
Medicina (Kaunas) ; 56(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861707

RESUMO

Background and Objectives: For using appropriate goal-directed fluid therapy during the surgical conditions of pneumoperitoneum in the reverse Trendelenburg position, we investigated the predictability of various hemodynamic parameters for fluid responsiveness by using a mini-volume challenge test. Materials and Methods: 42 adult patients scheduled for laparoscopic cholecystectomy were enrolled. After general anesthesia was induced, CO2 pneumoperitoneum was applied and the patient was placed in the reverse Trendelenburg position. The mini-volume challenge test was carried out with crystalloid 4 mL/kg over 10 min. Hemodynamic parameters, including stroke volume variation (SVV), cardiac index (CI), stroke volume index (SVI), mean arterial pressure (MAP), and heart rate (HR), were measured before and after the mini-volume challenge test. The positive fluid responsiveness was defined as an increase in stroke volume index ≥10% after the mini-volume challenge. For statistical analysis, a Shapiro-Wilk test was used to test the normality of the data. Continuous variables were compared using an unpaired t-test or the Mann-Whitney rank-sum test. Categorical data were compared using the chi-square test. A receiver operating characteristic curve analysis was used to assess the predictability of fluid responsiveness after the mini-volume challenge. Results: 31 patients were fluid responders. Compared with the MAP and HR, the SVV, CI, and SVI showed good predictability for fluid responsiveness after the mini-volume challenge test (area under the curve was 0.900, 0.833, and 0.909, respectively; all p-values were <0.0001). Conclusions: SVV and SVI effectively predicted fluid responsiveness after the mini-volume challenge test in patients placed under pneumoperitoneum and in the reverse Trendelenburg position.

9.
Medicine (Baltimore) ; 98(46): e17959, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725656

RESUMO

Observational phantom study.This study aimed to evaluate the radiation exposure dose of practitioner's hands when performing C-arm guided procedures and to determine the usefulness of our newly designed radiation shielding device.C-arm guided procedures including lumbar transforaminal epidural steroid injections (TFESIs) are commonly used for pain control induced by lumbar radiculopathy. The practitioner's hands are vulnerable to radiation exposure because of the long exposure time and short distance from the radiation resource. No studies to date have reported the cumulative exposure of the physician's hands according to location and exposure time.Using a chest phantom irradiated with X-rays under lumbar TFESI conditions, cumulative scatter radiation dose was measured at 36 points using a dosimeter. The measurements were checked at 1, 3, 5, 10 minutes of radiation exposure. The experiment was repeated using our newly designed shielding device.Significant radiation accumulation was observed in the field where the practitioner's hands might be placed during C-arm guided procedures. The further the distance from the radiation resource and the shorter the exposure time, the smaller was the cumulative radiation expose dose. The new shielding device showed an excellent shielding rate (66.0%-99.9%) when the dosimeter was within the shielding range. However, at some points, increased accumulated radiation exposure dose was observed, although the dosimeter was within the range of the shielding device.To reduce radiation exposure of the practitioner's hands when performing C-arm-guided procedures, the radiation exposure time should be decreased and a greater distance from the radiation resource should be maintained. When using our shielding device, placing the hand close to the device surface and minimizing the time using fluoroscopy minimized the radiation exposure of the hand.


Assuntos
Fluoroscopia/métodos , Mãos/efeitos da radiação , Exposição Ocupacional/análise , Exposição à Radiação/análise , Tomografia Computadorizada por Raios X/métodos , Humanos , Imagens de Fantasmas , Doses de Radiação , Proteção Radiológica , Processo Xifoide/diagnóstico por imagem
10.
Medicine (Baltimore) ; 98(48): e18137, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770249

RESUMO

RATIONALE: Recently, commercial indoor trampoline parks have been opened around the globe, and both the number of venues and the park users are increasing. Academic literatures have largely focused on home trampoline related injuries, and less is known about the injuries associated with trampoline parks due to the limited number of studies or cases reported. In this report, we present a complete spinal cord injury sustained at a commercial indoor trampoline park. PATIENT CONCERNS: A 26-year old male developed tetraplegia after plainly jumping on the trampolines and diving into one of the foam pits head first. DIAGNOSIS: C-spine CT revealed bilateral interfacetal dislocation on C6-7, and his C-spine MRI showed anterior translational injury at C6-7 with severe cord encroachment and complete discoligamentous complex disruption. He was diagnosed with complete spinal cord injury. INTERVENTIONS: The patient underwent 30 minutes each of physical therapy and occupational therapy twice a day for a total of 25 days of in-patient rehabilitation. Interventions included tilt table, passive range of motion exercises, functional electrical stimulation, sitting balance training, upper extremity strengthening exercise, and hand manipulation exercises. OUTCOME: Despite intensive rehabilitation and the patient's good spirit, there was no functional change in all physical examinations between evaluations at initial and at discharge. LESSONS: In conclusion, we aim to alert the risks associated with improper use of trampolines, promote safer entertainment environment, and aid in developing mandatory safety measures. We hope to alert the risks associated with improper use of trampolines, promote safer entertainment environment, and aid in developing mandatory safety measures.


Assuntos
Traumatismos em Atletas/complicações , Segurança de Equipamentos/normas , Quadriplegia/etiologia , Traumatismos da Medula Espinal/etiologia , Adulto , Traumatismos em Atletas/prevenção & controle , Traumatismos em Atletas/reabilitação , Humanos , Masculino , Parques Recreativos , Quadriplegia/prevenção & controle , Quadriplegia/reabilitação , Traumatismos da Medula Espinal/prevenção & controle , Traumatismos da Medula Espinal/reabilitação
11.
J Control Release ; 315: 126-138, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31672625

RESUMO

In this study, dual drug-loaded nanoparticles were constructed to co-deliver low-dose doxorubicin (DOX) and miR-200c (DOX/miR-NPs) to inhibit programmed death-1 receptor (PD-L1) expression and trigger immunogenic cell death (ICD) in cancer cells. Two block copolymers, folic acid (FA)-conjugated PLGA-PEG (PLGA-PEG-FA) and PLGA-PEI, were formulated as folate-targeted NPs and loaded with DOX and miR-200c. The NPs, which were formed as nanosize objects (110.4 ± 2.1) with narrow size distribution (0.19 ± 0.02), effectively protected the miR-200c from degradation in serum. Modifying the NPs with FA increased not only their uptake by cancer cells in vitro but also their accumulation in tumor microenvironments in vivo, as compared with those properties of non-FA-modified NPs. The DOX/miR-NPs also exhibited efficacious inhibition of PD-L1 expression and robust induction of ICD in cancer cells in vitro and in vivo, resulting in increased dendritic cell maturation and CD8+ T cell response towards cancer cells. Furthermore, tumor growth was significantly inhibited by folate-targeted NPs loaded with the low-dose DOX/miR-200c combination, but not by treatments with free DOX, miR-NPs or DOX-NPs. Thus, our results suggest that simultaneous PD-L1 inhibition via microRNAs and the induction of an immunogenic tumor microenvironment via low-dose cytotoxic drugs may improve cancer therapy efficacy.

12.
Hepatology ; 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31654573

RESUMO

ARC-520, the first RNA interference (RNAi) therapeutic was designed to reduce all RNA transcripts derived from cccDNA, leading to a reduction in viral antigens and HBV DNA. We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC-520 compared to placebo (PBO) in two randomized, multi-center studies in nucleoside/nucleotide (NUC) experienced patients with hepatitis B e antigen negative (E-neg) or positive (E-pos) disease. A total of 58 E-neg and 32 E-pos patients were enrolled and received four monthly doses of PBO (n=20 E-neg, 11 E-pos), 1 mg/kg ARC-520 (n=17 E-neg, 10 E-pos) or 2 mg/kg ARC-520 (n=21 E-neg, 11 E-pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC-520 dose were compared to PBO. Both E-neg and E-pos high dose groups significantly reduced HBsAg compared to PBO with mean reductions of 0.38 and 0.54 Log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and > 85 days after the last dose in E-neg and E-pos patients respectively. The low dose groups did not reach statistical significance in either study. E-pos patients showed a dose dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 Log PEIU/mL in the low dose and high dose ARC-520 groups respectively. ARC-520 was well tolerated, with only two SAEs of pyrexia possibly related to study drug observed. In conclusion, ARC-520 was active in both E-neg and E-pos, NUC experienced HBV patients, but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin.

13.
J Korean Med Sci ; 34(41): e264, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31650719

RESUMO

BACKGROUND: The long-term data with direct acting antiviral agents were rare. This study investigated the durability of a sustained virologic response (SVR) and the improvement of fibrosis after daclatasvir and asunaprevir (DCV/ASV) treatment in genotype 1b (GT1b) hepatitis C virus (HCV)-infected patients. METHODS: A total of 288 HCV GT1b patients without baseline non-structural 5A (NS5A) resistance-associated substitution (RAS) treated with DCV/ASV were enrolled. Virologic response was measured at 12 weeks and 1 year after treatment completion. In cirrhotic patients, liver function, aspartate transaminase to platelet ratio index (APRI), FIB-4 index, fibrosis index (FI), and liver stiffness measurement (LSM) at baseline and 1 year after treatment completion were evaluated. RESULTS: SVR12 was obtained in 278 patients (96.5%). Six patients who checked NS5A RAS after treatment failure were RAS positive. Only one patient showed no durability of SVR. In cirrhotic patients who achieved SVR12 (n = 59), the changes of albumin (3.8 [2.2-4.7] to 4.3 [2.4-4.9] g/dL; P < 0.001), platelet count (99 [40-329] to 118 [40-399] × 10³/mm³; P < 0.001), APRI (1.8 [0.1-14.8] to 0.6 [0.1-4.8]; P < 0.001), FIB-4 index (5.45 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), FI (5.5 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), and LSM (17.2 [5.3-48.0] to 11.2 [3.7-28.1] kPa; P = 0.001) between baseline and 1 year after treatment completion were observed. CONCLUSION: DCV/ASV treatment for HCV GT1b infected patients without RAS achieved high SVR rates and showed durable SVR. Cirrhotic patients who achieved SVR12 showed the improvement of liver function and fibrosis markers.

15.
Pharmaceutics ; 11(9)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527544

RESUMO

Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor that is widely used for the treatment of pain and inflammation caused by chronic and transitory conditions. Its alcoholic metabolites are formed by carbonyl reductase (CR) and they consist of trans-LOX, which is active, and cis-LOX, which is inactive. In addition, LOX can also be converted into an inactive hydroxylated metabolite (OH-LOXs) by cytochrome P450 (CYP). In a previous study, we reported that CYP3A4 is primarily responsible for the formation of OH-LOX in human liver microsomes. Although metabolism by CYP3A4 does not produce active metabolites, it can affect the conversion of LOX into trans-/cis-LOX, since CYP3A4 activity modulates the substrate LOX concentration. Although the pharmacokinetics (PK) and metabolism of LOX have been well defined, its CYP-related interactions have not been fully characterized. Therefore, we investigated the metabolism of LOX after pretreatment with dexamethasone (DEX) and ketoconazole (KTC), which induce and inhibit the activities of CYP3A, respectively. We monitored their effects on the PK parameters of LOX, cis-LOX, and trans-LOX in mice, and demonstrated that their PK parameters significantly changed in the presence of DEX or KTC pretreatment. Specifically, DEX significantly decreased the concentration of the LOX active metabolite formed by CR, which corresponded to an increased concentration of OH-LOX formed by CYP3A4. The opposite result occurred with KTC (a CYP3A inhibitor) pretreatment. Thus, we conclude that concomitant use of LOX with CYP3A modulators may lead to drug-drug interactions and result in minor to severe toxicity even though there is no direct change in the metabolic pathway that forms the LOX active metabolite.

16.
Pharmaceutics ; 11(7)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336576

RESUMO

Catalposide, an active component of Veronica species such as Catalpa ovata and Pseudolysimachion lingifolium, exhibits anti-inflammatory, antinociceptic, anti-oxidant, hepatoprotective, and cytostatic activities. We characterized the in vitro metabolic pathways of catalposide to predict its pharmacokinetics. Catalposide was metabolized to catalposide sulfate (M1), 4-hydroxybenzoic acid (M2), 4-hydroxybenzoic acid glucuronide (M3), and catalposide glucuronide (M4) by human hepatocytes, liver S9 fractions, and intestinal microsomes. M1 formation from catalposide was catalyzed by sulfotransferases (SULTs) 1C4, SULT1A1*1, SULT1A1*2, and SULT1E1. Catalposide glucuronidation to M4 was catalyzed by gastrointestine-specific UDP-glucuronosyltransferases (UGTs) 1A8 and UGT1A10; M4 was not detected after incubation of catalposide with human liver preparations. Hydrolysis of catalposide to M2 was catalyzed by carboxylesterases (CESs) 1 and 2, and M2 was further metabolized to M3 by UGT1A6 and UGT1A9 enzymes. Catalposide was also metabolized in extrahepatic tissues; genetic polymorphisms of the carboxylesterase (CES), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for catalposide metabolism may cause inter-individual variability in terms of catalposide pharmacokinetics.

17.
Comput Struct Biotechnol J ; 17: 579-590, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073393

RESUMO

Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults. Cdk5/p25 abnormally phosphorylates tau protein, and induces tau-associated neurofibrillary tangles in neurological disorders. Therefore, the pharmacological inhibition of Cdk5/p25 alleviates tau-associated neurological disorders. Herein, computational simulations probed two candidate inhibitors of Cdk5/p25. Structure-based pharmacophore investigated the essential complementary chemical features of ATP-binding site of Cdk5 in complex with roscovitine. Resultant pharmacophore harbored polar interactions with Cys83 and Asp86 residues and non-polar interactions with Ile10, Phe80, and Lys133 residues of Cdk5. The chemical space of selected pharmacophore was comprised of two hydrogen bond donors, one hydrogen bond acceptor, and three hydrophobic features. Decoy test validation of pharmacophore obtained highest Guner-Henry score (0.88) and enrichment factor score (7.23). The screening of natural product drug-like databases by validated pharmacophore retrieved 1126 compounds as candidate inhibitors of Cdk5/p25. The docking of candidate inhibitors filtered 10 molecules with docking score >80.00 and established polar and non-polar interactions with the ATP-binding site residues of Cdk5/p25. Finally, molecular dynamics simulation and binding free energy analyses identified two candidate inhibitors of Cdk5/p25. During 30 ns simulation, the candidate inhibitors established <3.0 Šroot mean square deviation and stable hydrogen bond interactions with the ATP-binding site residues of Cdk5/p25. The final candidate inhibitors obtained lowest binding free energies of -122.18 kJ/mol and - 117.26 kJ/mol with Cdk5/p25. Overall, we recommend two natural product candidate inhibitors to target the pharmacological inhibition of Cdk5/p25 in tau-associated neurological disorders.

18.
J Gynecol Oncol ; 30(4): e65, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074247

RESUMO

OBJECTIVES: The aim of this study was to develop a new prognostic classification for epithelial ovarian cancer (EOC) patients using gradient boosting (GB) and to compare the accuracy of the prognostic model with the conventional statistical method. METHODS: Information of EOC patients from Samsung Medical Center (training cohort, n=1,128) was analyzed to optimize the prognostic model using GB. The performance of the final model was externally validated with patient information from Asan Medical Center (validation cohort, n=229). The area under the curve (AUC) by the GB model was compared to that of the conventional Cox proportional hazard regression analysis (CoxPHR) model. RESULTS: In the training cohort, the AUC of the GB model for predicting second year overall survival (OS), with the highest target value, was 0.830 (95% confidence interval [CI]=0.802-0.853). In the validation cohort, the GB model also showed high AUC of 0.843 (95% CI=0.833-0.853). In comparison, the conventional CoxPHR method showed lower AUC (0.668 (95% CI=0.617-0.719) for the training cohort and 0.597 (95% CI=0.474-0.719) for the validation cohort) compared to GB. New classification according to survival probability scores of the GB model identified four distinct prognostic subgroups that showed more discriminately classified prediction than the International Federation of Gynecology and Obstetrics staging system. CONCLUSION: Our novel GB-guided classification accurately identified the prognostic subgroups of patients with EOC and showed higher accuracy than the conventional method. This approach would be useful for accurate estimation of individual outcomes of EOC patients.

19.
BMC Cancer ; 19(1): 347, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975123

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) remains an important therapeutic option for many hematologic malignancies. Bone marrow harvesting from an appropriate donor must be conducted for hematopoietic stem cell transplantation (HSCT). Many previous studies show complications of the recipient after hematopoietic stem cell transplantation (HSCT). However, complications of the donor after bone marrow harvesting are rare. We here report a unique case of a patient who developed sacral nerve root injury after bone marrow harvesting. CASE PRESENTATION: A 26-year-old man was admitted to our medical center complaining of acute onset painful burning and tingling sensation at the left posterior thigh and calf. He was a bone marrow donor for his brother's bone marrow transplantation. He had underwent a bone marrow harvesting procedure two days before admission as a bone marrow donor, using both posterior superior iliac spine (PSIS) as the puncture site. Pelvic magnetic resonance image (MRI) showed enhancement around the left S2 nerve root in T1 and T2-weighted images. Nerve conduction studies (NCS) revealed normal conduction velocity and amplitude on both lower extremities. Electromyography (EMG) presented abnormal spontaneous activity and neurogenic motor unit potentials on the S2-innervated intrinsic foot muscle and gastrocnemius, soleus muscle on the left. The patient was treated with pregabalin for pain control. The patient was followed up after 3, 6, and 12 months. Neuropathic pain improved to Visual Analogue Scale (VAS) 1, and recovery state was confirmed by re-innervation patterns of motor unit potentials in electromyography. CONCLUSION: Bone marrow harvesting is a relatively safe procedure. However, variable complications may occur. Accurate anatomical knowledge and carefulness are required to avoid sacral nerve root injury when performing the bone marrow harvesting procedure.


Assuntos
Mononeuropatias/diagnóstico , Traumatismos dos Nervos Periféricos/diagnóstico , Coleta de Tecidos e Órgãos/efeitos adversos , Sítio Doador de Transplante , Adulto , Transplante de Medula Óssea , Eletromiografia , Neoplasias Hematológicas/cirurgia , Humanos , Imagem por Ressonância Magnética , Masculino , Mononeuropatias/tratamento farmacológico , Mononeuropatias/etiologia , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/etiologia , Pregabalina/uso terapêutico , Doadores de Tecidos , Resultado do Tratamento
20.
Metabolites ; 9(4)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965644

RESUMO

Alteration in the number and composition of intestinal microbiota affects the metabolism of several xenobiotics. Gastrodin, isolated from Gastrodia elata, is prone to be hydrolyzed by intestinal microbiota. In the present study, the role of intestinal microbiota in gastrodin metabolism was investigated in vitro and in vivo. Gastrodin was incubated in an anaerobic condition with intestinal contents prepared from vehicle- and antibiotics-treated rats and the disappearance of gastrodin and formation of 4-hydroxybenzyl alcohol (4-HBA) was measured by liquid chromatography coupled to mass spectroscopy (LC-MS/MS). The results showed that almost all gastrodin incubated with control intestinal contents was metabolized to its aglycone in time- and concentration-dependent manners. In contrast, much less formation of 4-HBA was detected in intestinal contents from antibiotics-treated rats. Subsequently, in vivo pharmacokinetic study revealed that the antibiotic pretreatment of rats significantly affected the metabolism of gastrodin to 4-HBA. When administered orally, gastrodin was rapidly absorbed rapidly into plasma, metabolized to 4-HBA, and disappeared from the body within six hours. Interestingly, the pharmacokinetic parameters of 4-HBA were changed remarkably in antibiotics-treated rats, compared to control rats. The results clearly indicated that the antibiotics treatment of rats suppressed the ability of intestinal microbiota to metabolize gastrodin to 4-HBA and that, thereby, the pharmacodynamic action was significantly modulated.

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