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1. Treatment periods of P-glycoprotein (P-gp) inhibitors have revealed different efficacies. We have previously reported dose-dependent inhibition of P-gp in single-treatment with LC478. However, whether repeated treatment with LC478 can inhibit P-gp even at its ineffective single-treatment dose remains unknown. 2. Therefore, the purpose of this study was to assess the effect of repeated treatment (i.e., 7-day treatment) with LC478 on P-gp known to affect docetaxel bioavailability in rats. Effects of LC478 on P-gp mediated efflux and expression in MDCK-MDR1 cells, P-gp ATPase activity, and binding site with P-gp were evaluated.3. The 7-day treatment with LC478 increased docetaxel absorption via intestinal P-gp inhibition in rats. Intestinal concentrations of LC478 were 8.31-10.3 μM in rats after 7-day treatment of LC478. These concentrations were close to 10 μM that reduced P-gp mediated docetaxel efflux and P-gp expression in MDCK-MDR1 cells. Considering that intestinal LC478 concentrations after 1-day treatment were 2.68-4.19 μM, higher LC478 concentrations after 7-day treatment might have driven P-gp inhibition and increased docetaxel absorption. LC478 might competitively inhibit P-gp considering its stimulated ATPase activity and its binding site with nucleotide binding domain of P-gp. 4. Therefore, repeated treatment with LC478 can determine its feasibility for P-gp inhibition and changing docetaxel bioavailability.

Adverse drug reactions (ADRs) constitute key factors in determining successful medication therapy in clinical situations. Integrative analysis of electronic medical record (EMR) data and use of proper analytical tools are requisite to conduct retrospective surveillance of clinical decisions on medications. Thus, we suggest that electronic medical recording and human genetic databases are considered together in future directions of pharmacovigilance. We analyzed EMR-based ADR studies indexed on PubMed during the period from 2005 to 2017 and retrospectively acquired 1161 (29.6%) articles describing drug-induced adverse reactions (e.g., liver, kidney, nervous system, immune system, and inflammatory responses). Of them, only 102 (8.79%) articles contained useful information to detect or predict ADRs in the context of clinical medication alerts. Since insufficiency of EMR datasets and their improper analyses may provide false warnings on clinical decision, efforts should be made to overcome possible problems on data-mining, analysis, statistics, and standardization. Thus, we address the characteristics and limitations on retrospective EMR database studies in hospital settings. Since gene expression and genetic variations among individuals impact ADRs, pharmacokinetics, and pharmacodynamics, appropriate paths for pharmacovigilance may be optimized using suitable databases available in public domain (e.g., genome-wide association studies (GWAS), non-coding RNAs, microRNAs, proteomics, and genetic variations), novel targets, and biomarkers. These efforts with new validated biomarker analyses would be of help to repurpose clinical and translational research infrastructure and ultimately future personalized therapy considering ADRs.

Phytochemical investigation on the dried fruits of

Seven new prenylated flavonoids (1-7) and one new prenylated phenylpropiophenone (8) were isolated from roots and rhizomes of Sophora tonkinensis, along with nine known compounds (9-17). The structures 1-8 were elucidated by spectroscopic data analysis and comparison with reported values. Compounds 8 and 12 (7-methoxyebenosin) showed inhibitory activities against nitric oxide production in lipopolysaccharide-induced RAW264.7 cells, with IC50 values of 8.1 and 6.2 μM, respectively. They also significantly lowered expression of CSF2, TNF, and IL-1β. Lonchocarpol A (10) and erybraedin D (16) at concentrations of 20 μM downregulated proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA expression in HepG2 cells. Moreover, erybraedin D (16) inhibited PCSK9 protein synthesis (IC50 7.8 μM), while simultaneously activating AMP-activated protein kinase and acetyl-CoA carboxylase.

Nonalcoholic fatty liver disease (NAFLD) arises from mitochondrial dysfunction under sustained imbalance between energy intake and expenditure, but the underlying mechanisms controlling mitochondrial respiration have not been entirely understood. Heterotrimeric G proteins converge with activated GPCRs to modulate cell-signaling pathways to maintain metabolic homeostasis. Here, we investigated the regulatory role of G protein α(12) (Gα(12)) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Gα(12) levels in mouse liver. Gα(12) ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the Gα(12)-signaling pathway regulated sirtuin 1 (SIRT1) and PPARα, which are responsible for mitochondrial respiration. Defective induction of SIRT1 upon fasting was observed in the liver of Gna12-KO mice, which was reversed by lentivirus-mediated Gα(12) overexpression in hepatocytes. Mechanistically, Gα(12) stabilized SIRT1 protein through transcriptional induction of ubiquitin-specific peptidase 22 (USP22) via HIF-1α increase. Gα(12) levels were markedly diminished in liver biopsies from NAFLD patients. Consistently, Gna12-KO mice fed a high-fat diet displayed greater susceptibility to diet-induced liver steatosis and obesity due to decrease in energy expenditure. Our results demonstrate that Gα(12) regulates SIRT1-dependent mitochondrial respiration through HIF-1α–dependent USP22 induction, identifying Gα(12) as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.

Ethnopharmacological relevance Penthorum chinense has been used in East Asia for the treatment of cholecystitis, infectious hepatitis, jaundice and to treat liver problems. Recent evidences provided the potential for the clinical use of P. chinense in the treatment of metabolic disease. Aim of the study: Based on the traditional use and recent evidences, we investigated the effects of constituents from P. chinense with modulation on proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) expression, and the effect of the most active substance on cholesterol uptake, and genes relevant to lipid metabolism. Materials and methods The isolation of compounds from the BuOH-soluble extract of 80% methanol extract of P. chinense was conducted using chromatographic methods and the structures were established by interpreting spectroscopic data. Quantitative real time-PCR, and Western blot analysis were performed to monitor the regulatory activity on PCSK9 and LDLR expression. PCSK9-LDLR binding interaction was also tested. The cholesterol uptake in hepatocyte was measured using 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI)-labeled LDL cholesterol. Additionally, gene network analysis of LDLR and responses of its target proteins were carried out to discover genes germane to the effect of active compound on HepG2 cells. Moreover, we performed protein-protein interaction analysis via String and constructed the compound target network using Cytoscape. Results Two new neolignans and 37 known compounds were characterized from P. chinense. Of the isolated compounds, (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3), penthorin A (4) and methyl gallate (25) were found to suppress PCSK9 mRNA expression with IC50 values of 5.13, 15.56 and 11.66 μM, respectively. However, all the isolated compounds were found to be inactive in PCSK9-LDLR interaction assay. Additionally, a dibenzoxepine-type lignan analog, (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3) demonstrated to upregulate LDLR mRNA and protein expression via transcriptional factor sterol regulatory element-binding protein 2 (SREBP2). Furthermore, (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3) increase the LDL-cholesterol uptake in DiI-LDL assay. Conclusion (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3) seemed to increase potentially cholesterol uptake via the downregulation of PCSK9 and the activation of LDLR in hepatocytes. Moreover, SREBP2 was found to play an important role in regulation of PCSK9 and LDLR by (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one.

Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool is expected to expedite the dereplication of secondary metabolites. In this study, using this tool, two new dilignans with a 2-phenyl-3-chromanol motif, obovatolins A (1) and B (2), were discovered from the stem barks of Magnolia obovata Thunb. along with six known compounds (3–8), expanding chemical diversity of lignan skeletons in this natural source. Their structures and configurations were elucidated using spectroscopic data. All isolates were evaluated for their PCSK9 mRNA expression inhibitory activity. Obovatolins A (1) and B (2), and magnolol (3) showed potent lipid controlling activities. To identify transcriptionally controlled genes by 1 along with downregulation of PCSK9, using small set of genes (42 genes) related to lipid metabolism selected from the database, focused bioinformatic analysis was carried out. As a result, it showed the correlations between gene expression under presence of 1, which led to detailed insight of the lipid metabolism caused by 1.

Phytochemical investigation of the methanol extract of the aerial parts of

Background: Penthorum chinense has been used in East Asia for the treatment of cholecystitis, infectious hepatitis, and jaundice. So far there is no report regarding proprotein convertase subtilisin/kexin type 9 inhibitory constituents from this plant. The aim of the present study was to discover new active constituents with PCSK9 expression inhibitory activities from P. chinenseMethods: All structures were established by interpreting NMR spectroscopic data and MS data. Further experimental and calculated ECD data were used to determine the absolute configuration of the two new neolignans. To monitor the inhibitory activity on proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA expression and PCSK9-low density lipoprotein receptor (LDLR) interaction, quantitative real time-PCR, Western blot analysis, and an enzyme-linked immunosorbent assay (ELISA) method by a PCSK9-biotinylated-LDLR binding assay were performed.Results: 39 compounds were isolated and identified including two new oxepine-type neolignans, penthorinols A (1) and B (2) and a naturally occurring chalcone, 6'-hydroxy-2'-methoxychalcone-4'-O-β-D-glucopyranoside (20). Of all tested compounds, penthorin A (4) and methyl gallate (25) were found to suppress PCSK9 mRNA expression with IC50 values of 15.56 and 11.66 µM, respectively. Furthermore, penthorin A (4) and methyl gallate (25) downregulated PCSK9 protein expression. However, all compounds seemed to be inactive in PCSK9-LDLR interaction.Conclusion: In the present study, two new compounds was discovered from this plant and active constituents with PCSK9 expression inhibitory activities were suggested.

Postsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism. Two postsurgical hypoparathyroidism rat models were made by hemi-parathyroidectomy or total parathyroidectomy with autotransplantation in 10-week-old female Wistar rats. AXT914 or vehicle was administered orally for 2 to 3 weeks. Serum PTH, calcium, and phosphorus levels, and the urinary excretion of calcium were measured. Autotransplanted parathyroid tissues were collected and examined histologically. In the hemi-parathyroidectomy model, the oral administration of the calcilytic AXT914 (5 and 10 mg/kg) for 2 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels and urinary calcium excretion. In the total parathyroidectomy with autotransplantation model, the oral administration of AXT914 (10 mg/kg) for 3 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels. The serum PTH and calcium levels increased by AXT914 were maintained for 1 week, even after discontinuation of the drug. In conclusion, AXT914 increased PTH secretion in rat models of postsurgical hypoparathyroidism, thereby correcting abnormal calcium and phosphorus homeostasis. Furthermore, AXT914 improved the functional recovery of autotransplanted parathyroid tissues.

The purpose of this study was to investigate the effect of photothermal treatment (PTT) with gold nanoshell (ANS) using a macrophage-mediated delivery system in a head and neck squamous cell carcinoma (HNSCC) cell line. To achieve this, ANS-loaded rat macrophages (ANS-MAs) were prepared via the coculture method with ANS. The human HNSCC (FaDu cell) and macrophage (rat macrophage; NR8383 cell) hybrid spheroid models were generated by the centrifugation method to determine the possibility of using ANS-MAs as a cancer therapy. These ANS-MAs were set into the tumor and macrophage hybrid spheroid model to measure PTT efficacy. Kinetic analysis of the spheroid growth pattern revealed that this PTT process caused a decreasing pattern in the volume of the hybrid model containing ANS-MAs (p<0.001). Comparison with empty macrophages showed harmony between ANS and laser irradiation for the generation of PTT. An annexin V/dead cell marker assay indicated that the PTT-treated hybrid model induced increasing apoptosis and dead cells. Further studies on the toxicity of ANS-MAs are needed to reveal whether it can be considered biocompatible. In summary, the ANS was prepared with a macrophage as the delivery method and protective carrier. The ANS was successfully localized to the macrophages, and their photoabsorption property was stationary. This strategy showed significant growth inhibition of the tumor and macrophage spheroid model under NIR laser irradiation. In vivo toxicology results suggest that ANS-MA is a promising candidate for a biocompatible strategy to overcome the limitations of fabricated nanomaterials. This ANS-MA delivery and PTT strategy may potentially lead to improvements in the quality of life of patients with HNSCC by providing a biocompatible, minimally invasive modality for cancer treatment.

Background Although several studies have shown the role of interleukin-31 (IL-31) and its receptors in inducing pruritus in certain skin disorders, knowledge of its role in post-burn hypertrophic scars is insufficient. Therefore, the histopathological expression levels of IL-31, IL-31 receptor alpha (IL-31RA), and oncostatin M receptor (OSMR) in post-burn hypertrophic scar tissues were investigated and compared with normal tissue expression levels. Methods Samples of hypertrophic scar tissue were obtained from 20 burn patients through punch biopsy. Normal samples were obtained from areas adjacent to the burn injury site of the same patients. Samples were placed in 10% neutral buffered formalin, embedded in paraplast, and processed into serial 5-μm sections. Immunohistochemistry results were semi-quantitatively evaluated for IL-31, IL-31RA, and OSMR. By hematoxylin and eosin staining, epidermal and dermal thickness were assessed with a microscope and digital camera. Intensities were rated on a scale of 1 to 4. Results Percentages for IL-31, IL-31RA, and OSMR in the epidermal basal layer cell cytoplasm were significantly greater in the burn scar tissue compared to normal skin, as well as the dermal and epidermal thickness (p < .05). There was a significant difference in IL-31 epidermal basal layer intensity in burn scar tissue compared to normal skin (p < .05). Besides the OSMR basal layer intensity, IL-31 and IL-31RA intensities between the burn scar and normal tissues were not significant. However, correlations were significant, indicating that the greater the infiltration percentage, the higher the intensity (p < .05). Conclusions IL-31, IL-31RA, and OSMR expression levels are increased in hypertrophic scars compared with normal tissue.

Ginseng berry extract contains plenty of ginsenosides showing anti-obesity and anti-hyperglycemic activities. Regarding that long-term intakes of herbal products to control metabolic disorders as popular alternatives have become popular, ginseng berry extract plus metformin is an attractive item for long-term glycemic control. Herein, we investigated the effect of ginseng berry extract (GBE) or its combination with metformin against obesity and hepatic steatosis in high-fat diet fed mice. GBE altered abnormal features (e.g. body weight, serum profiles, hepatic steatosis/inflammation and fat mass). Concomitantly, GBE increased mRNA levels of adiponectin and CCAAT/enhancer binding protein. All these changes were observed in metformin alone and GBE plus metformin. Moreover, in GBE plus metformin intake, GBE increased organic cation transporter-mediated metformin uptake in liver and mRNA of AMP-activated protein kinase together, which additively ameliorated obesity and hepatic steatosis. Therefore, GBE itself and GBE plus metformin could be useful to regulate metabolic disorders.

The synergistic activity of Houttuynia cordata ethanol extract (HCT) and metformin combination in diabetic rats has been previously reported, but the fundamental causes remain unsolved. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) transport metformin to the liver and kidneys. Therefore, pharmacological activity and systemic exposure of metformin in HCT-metformin combination were determined from pharmacokinetic change and glucose-lowering activity using in vitro HEK-293 cells expressing human OCTs or human MATEs and in vivo rats. HCT inhibited human OCT2 and human MATE1-mediated metformin transports in vitro. In in vivo rats, treatment with HCT and metformin for 28 days in rats (28MH rats) reduced the rat Oct2-mediated renal excretion of metformin and thereby the increased systemic exposure of metformin compared with only metformin-treated rats for 28 days (28M rats). In 28MH rats, rat Oct1-mediated metformin uptake into the liver was enhanced, leading to an improved glucose-lowering effect without hypoglycaemia compared with 28M rats. There was no impairment of renal function in HCT and metformin treatments. These results suggest that HCT-metformin combination therapy is applicable in terms of efficacy and safety.

목적: 본 연구에서는 물리적 박피기법인 스피큘이 포함된 제품과 화학적 박피기법인 글리콜릭산 40% (pH3)를 이용하여 여드름 피부의 모공과 피부상태의 변화를 비교 연구하여 피부장벽 손상을 최소화할 수 있는 안전하고 효과적인 필링관리 방법에 대한 기준을제시하고자 한다. 방법: 여드름 피부로 고민하고 있는 20–30대 여성 15명을 대상으로 물리적 박피인 스피큘 관리와 화학적 박피인글리콜릭산 관리를 실험군으로 설계하였다. 실험은 4주 동안 2주에 1회 총 2번의 필링관리를 진행하였다. 실험 전과 후에 눈에 띄는 모공수, 크게 열린 모공수, 블랙헤드 모공수, 경피수분손실량(transepidermal water loss, TEWL), 피부톤을 측정하였다. 결과: 눈에 띄는 모공수와 크게 열린 모공수에서 두 실험군 모두 감소하였고, 스피큘 그룹에서 더 큰 감소 효과를 보였으나 모두 유의미한차이는 아니였다. 블랙헤드 모공수에서도 두 그룹 모두 감소하는 효과를 보였으나, 스피큘 그룹만 유의미하게 감소하였다. 경피수분손실량의 변화는 스피큘 그룹에서 유의미하게 감소하였고, 글리콜릭산 그룹에서 감소는 하였으나 유의미하지는 않았다. 피부톤변화는 스피큘 그룹에서 피부밝기(L*), 홍반상태(a*), 피부병변(b*) 모두 유의미하게 효과가 개선되었고, 글리콜릭산 그룹에서는 L*, a*, b* 모두 효과가 개선되었으나, 피부밝기(L*)에서만 유의미한 차이를 보였다. 결론: 이상의 실험을 통해 스피큘이 포함된 물리적박피 제품은 여드름 피부의 문제점 개선 효과가 우수하고, 피부장벽 손상을 최소화한 필링 제품임을 검증하였다. 따라서 모공이 넓고, 홍반과 여드름 자국이 있는 색소침착 피부의 문제점을 해결하면서도 피부장벽 손상을 최소화 할 수 있는 화장품 소재로서의 가능성이 있을 것으로 사료된다.

FMS-like receptor tyrosine kinase-3 (FLT3) belongs to the family of receptor tyrosine kinase (RTK), and the FLT3 mutation is observed in 1/3 of all acute myeloid leukemia (AML) patients. Potential FLT3 inhibitors have been investigated as potential therapeutic agents of AML. In this study, we identified a potent FLT3 inhibitor LDD1937 containing an indirubin skeleton. The potent inhibitory activity of LDD1937 against FLT3 was shown with an in vitro kinase assay (IC50 = 3 nM). The LDD1937 compound selectively inhibited the growth of MV-4-11 cells (GI50 = 1 nM) and induced apoptotic cell death. LDD1937 caused cell cycle arrest at the G2/M phase and increased the cell population at the sub-G1 phase. Phosphorylation of STAT5, which is the downstream signaling of FLT3, was significantly reduced by LDD1937 in a dose-dependent manner. The pharmacokinetic properties of LDD1937 were investigated in mice. Then, the in vivo anti-tumor effect was investigated using a MV-4-11 xenograft. With the intravenous administration of 5 and 10 mg/kg in nu/nu mice, the tumor volume and weight were significantly reduced compared to the control. LDD1937 is a promising therapeutic candidate to treat AML patients because of its ability to suppress tumor cell growth in vitro and in vivo.

Nanomedicines have evolved into various forms including dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles since their first launch in the market. Widely highlighted benefits of nanomedicines over conventional medicines include superior efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profiles of pharmaceutical ingredients. Especially, various kinetic characteristics of nanomedicines in body are further influenced by their formulations. This review provides an updated understanding of nanomedicines with respect to delivery and pharmacokinetics. It describes the process and advantages of the nanomedicines approved by FDA and EMA. New FDA and EMA guidelines will also be discussed. Based on the analysis of recent guidelines and approved nanomedicines, key issues in the future development of nanomedicines will be addressed.

Lamivudine belongs to the set of antiviral agents effective against hepatitis B virus infection. Given case reports on liver injuries after certain antiviral agent treatments, this study examined the effects of lamivudine on alanine aminotransferase (ALT) and total bilirubin (TB) using a medical system database. A total of 1,321 patients taking lamivudine alone or with others were evaluated using laboratory hits in an electronic medical system at Seoul National University Hospital from 2005 through 2011. The patients were grouped according to prior ALT results: G#1, ALT lt; 40 IU/L; G#2, 40 IU/L ≤ ALT lt; 120 IU/L; G#3, 120 IU/L ≤ ALT lt; 240 IU/L; and G#4, ALT ≥ 240 IU/L. In G#1 and G#2 patients, lamivudine or adefovir treatment decreased ALT and TB compared to prior values. In G#3 and G#4 patients with three times the upper limit of normal (ULN) ≤ ALT lt; 15 times the ULN, both ALT and TB were decreased after treatment with lamivudine alone, or adefovir following lamivudine therapy, indicating that lamivudine therapy ameliorated liver functions. However, in G#4 patients who experienced severely advanced hepatitis (ALT ≥ 15 times the ULN, or ≥ 600 IU/L), lamivudine augmented TBmax (6.3 → 13.3 mg/dL) despite a slight improvement in ALT (839 → 783 IU/L), indicative of exacerbation of bilirubinemia. Patients who used adefovir after lamivudine also showed a high incidence of hyperbilirubinemia when they experienced severely advanced hepatitis. Treatment with adefovir alone did not show the effect. In conclusion, lamivudine may increase the risk of hyperbilirubinemia in patients with severely advanced hepatitis, implying that caution should be exercised when using lamivudine therapy in certain patient populations.

The pharmacokinetic (PK) change in a drug by co-administered herbal products can alter the efficacy and toxicity. In the circumstances that herb–drug combinations have been increasingly attempted to alleviate Alzheimer’s disease (AD), the PK evaluation of herb–drug interaction (HDI) is necessary. The change in systemic exposure as well as target tissue distribution of the drug have been issued in HDIs. Recently, the memory-enhancing effects of water extract of mangosteen pericarp (WMP) has been reported, suggesting a potential for the combination of WMP and donepezil (DNP) for AD treatment. Thus, it was evaluated how WMP affects the PK change of donepezil, including systemic exposure and tissue distribution in mice after simultaneous oral administration of DNP with WMP. Firstly, co-treatment of WMP and donepezil showed a stronger inhibitory effect (by 23.0%) on the neurotoxicity induced by Aβ(25–35) in SH-SY5Y neuroblastoma cells than donepezil alone, suggesting that the combination of WMP and donepezil may be more effective in moderating neurotoxicity than donepezil alone. In PK interaction, WMP increased donepezil concentration in the brain at 4 h (by 63.6%) after administration without affecting systemic exposure of donepezil. Taken together, our results suggest that WMP might be used in combination with DNP as a therapy for AD.

The histologic responses to varied parameters of 1,927-nm fractional thulium fiber laser treatment have not yet been sufficiently elucidated.This study sought to evaluate histologic changes immediately after 1,927-nm fractional thulium fiber laser session at various parameters.The dorsal skin of Yucatan mini-pig was treated with 1,927-nm fractional thulium fiber laser at varied parameters, with or without skin drying. The immediate histologic changes were evaluated to determine the effects of varying laser parameters on the width and the depth of treated zones.The increase in the level of pulse energy widened the area of epidermal changes in the low power level, but increased the dermal penetration depth in the high power level. As the pulse energy level increased, the increase in the power level under the given pulse energy level more evidently made dermal penetration deeper and the treatment area smaller. Skin drying did not show significant effects on epidermal changes, but evidently increased the depth of dermal denaturation under both high and low levels of pulse energy.These results may provide important information to establish treatment parameters of the 1,927-nm fractional thulium fiber laser for various skin conditions.

Acute extensive ischemic gastritis is an extremely rare disease because the stomach has an abundant submucosal vascular plexus with a dual blood supply from the pancreaticoduodenal and gastroduodenal arteries. Smoking, hypertension, and atherosclerotic vascular diseases can be major risk factors for ischemic gastritis. Acute gastric ischemia presents as an acute abdomen with diarrhea or hematemesis that rapidly progresses to acute peritonitis, irreversible septic shock, and death if untreated. We report a case of acute extensive ischemic gastritis combined with tetraplegia due to cervical myelopathy and extensive atherosclerotic changes of the celiac trunk and abdominal aorta.

In this study, inductively coupled plasma-mass spectrometry (ICP-MS) was used to determine the concentration of 15 elements (Mg, Al, K, Ca, Cr, Mn, Co, Ni, Cu, Zn, Rb, Sr, Cd, Ba, and Pb) of sesame seeds. Multivariate analysis was then performed to discriminate the origin of sesame seeds. Korean (48), Chinese (44), and Indian (21) samples were used to develop the calibration model. Another 10 samples were used to validate this model. All elements were significantly different (p

With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

Background:The collagen ultrastructure of the discoid lateral meniscus (DLM) has not been precisely defined.Purpose:To investigate the ultrastructure of the DLM, focusing on its collagen fibers, and to compare the collagen net architecture between intact and torn DLMs using the Collagen Meniscal Architecture (CMA) scoring system.Study Design:Descriptive laboratory study.Methods:Thirty specimens were taken from 30 patients with a diagnosis of a complete DLM using a 1-piece technique. The collagen ultrastructure of the DLMs was assessed with transmission electron microscopy. To evaluate the meniscal ultrastructure, the degree of collagen disruption, intrafibrillar edema, loss of banding, degree of collagen packing, and fibril size variability were assessed and graded from 1 (normal) to 3 (severe disarray) according to the CMA scoring system. The DLM specimens were divided into 3 groups according to the intrasubstance tear: the intact group (group I) had no tear; the simple tear group (group S) had a radial, longitudinal, or horizontal tear; and the complicated tear group (group C) had a complicated horizontal tear. Intact normal meniscus specimens (group N) were used as the control group.Results:There were 10 specimens in group I, 8 in group S, 12 in group C, and 13 in group N. In group I, there were 5 grade 1 and 5 grade 2 menisci; group S had 2 grade 1, 3 grade 2, and 3 grade 3 menisci; group C had 1 grade 1, 4 grade 2, and 7 grade 3 menisci; and group N had 4 grade 1, 7 grade 2, and 2 grade 3 menisci. A significant difference in the CMA score was observed between the 4 groups ( P = .009). The median CMA score was significantly lower in group I (2; range, 1-4) than in group S (4; range, 2-7) ( P = .041) and group C (4.25; range, 1.5-7) ( P = .018). No significant difference was found between groups S, C, and N.Conclusion:Variability existed in the collagen ultrastructure of the DLM, and some DLMs showed a nearly normal ultrastructural pattern. The degree of density and disorganization of the collagen architecture in the DLM was related to the tear.Clinical Relevance:The study results might provide a histological background for partial meniscectomy in the treatment of a symptomatic DLM.

Ulmus pumila L. bark underwent distilled water extraction under three temperature condition (4°C, room temperature, or 80°C) and two extraction times (1, or 5 min) in order to develop a functional beverage products. Changes in yield, pH, color, total phenolic (TP) content, tannin content and antioxidant activity of the aqueous extracts were evaluated for each extraction temperature and duration. Extraction conditions did not affect yield or pH value of the extracts; however CIE b* values were high in extracts prepared under high extraction temperature (80°C) and long extraction duration (5 min) conditions. Both extraction temperature and duration affected the TP and tannin contents of the extracts; however, all extraction conditions resulted in ≥450 mg GAE/g TP content and ≥80 mg CE/g tannin content. All extracts exhibited ABTS and DPPH radical scavenging ability similar to that of vitamin C. Nitric oxide inhibition activity was lower in the 5 min duration sample than in the 1 min sample. The 4°C extraction temperature produced an extract with the highest reducing power and hydrogen peroxide values. Extraction temperature also affected sensory evaluation results with the 80°C extraction temperature producing significantly higher flavor, bitterness, and color score, than those obtained under 4°C and room temperature extraction conditions.

Purpose: Metformin and Houttuynia cordata are representative anti-diabetic therapeutic agents in western and oriental medicinal fields, respectively. The present study examined the therapeutic effects of houttuynia cordata extract (HCE) and metformin in combination in a dysmetabolic mouse model. Methods: Metabolic disorders were induced in C57BL/6J mice by high fat diet (HFD) for 14 weeks. Results: Combination of metformin and HCE significantly lowered body weight, abdominal fat, perirenal fat, liver and kidney weights, but did not change epididymal fat in HFD-fed animals. Metformin + HCE treatment markedly attenuated the elevated serum levels of TG, TC, AST, ALT, and endotoxin and restored the depleted HDL level. Both HCE and metformin + HCE treatment ameliorated glucose tolerance and high level of fasting blood glucose in association with AMPK activation. Moreover, treatment with HCE + metformin dramatically suppressed inflammation in HFD-fed animals via inhibition of proinflammatory cytokines (MCP-1 and IL-6) and LPS receptor (TLR4). Histopathological findings showed that exposure of HFD-treated animals to metformin + HCE ameliorated fatty liver, shrinkage of intestinal villi and adipocytes enlargement. Furthermore, HCE and metformin + HCE treatments markedly modulated the abundance of gut Gram-negative bacteria, including Escherichia coli and Bacteriodetes fragilis, but not universal Gram-positive bacteria. Conclusions: Overall, HCE and metformin cooperatively exert their therapeutic effects via modulation of gut microbiota, especially reduction of Gram-negative bacteria, resulting in alleviation of endotoxemia.

Mast cells and their mediators play important roles in chronic spontaneous urticaria (CSU) pathogenesis. Transglutaminase 2 (TG2) is expressed in activated mast cells and contributes to airway inflammation in allergic asthma.To investigate the role of TG2 in CSU.Patients with CSU (n = 72) and healthy controls (n = 51) were evaluated. Skin biopsy specimens were obtained from 5 patients with CSU and 2 healthy controls. Cord blood-derived human mast cells and peripheral blood-derived human mast cells were activated with IgE. TG2 activity and inflammatory mediators, such as histamine, leukotriene C4, and cytokines, were measured in serum or supernatant from cultured mast cells by enzyme-linked immunosorbent assay. Colocalization of mast cells and TG2 was determined in skin tissues by immunofluorescence.TG2 activity was significantly higher in serum samples from patients with CSU than in serum samples from healthy controls (P.001). Colocalization of mast cell surface marker c-kit and TG2 was significantly increased in the lesional skin of patients with CSU compared with that in healthy controls. The levels of histamine, leukotriene C4, tumor necrosis factor α, transforming growth factor β, and interleukins 4, 5, and 6 were significantly higher in patients with CSU than in healthy controls (P.001). Serum TG2 levels had positive correlations with each inflammatory mediator (P.001). TG2 activity was increased in cord blood-derived human mast cells (CBMCs) and peripheral blood-derived human mast cells activated with IgE compared with those without activation (P.05).Our findings suggest that TG2 expressed in and released from mast cells plays an important role in CSU pathogenesis.

An energy dispersive X-ray fluorescence (ED-XRF) spectrometer and a near infrared (NIR) spectrometer combined with chemometrics were applied for origin discrimination of 48 Korean, 44 Chinese, and 21 Indian sesame seed samples used for development of a discriminant calibration model. Multi-elemental ED-XRF analysis based on Mg, Al, Si, P, S, Cl, K, Ca, Mn, Fe, and Cu was used for comparisons among origins. All elements, except for Fe, showed differences and 96.5% of seed samples were assigned to the correct origin using discriminant analysis based on chemical analytical results. NIR measurements were performed for spectral scanning. Classification of seeds using NIR discriminant analysis achieved 89.4% of seed samples assigned to the correct origin. Both ED-XRF and NIR are useful as nondestructive tools for discrimination of sesame seed origins.

Isoliquiritigenin (isoLQ), a chalcone found in licorice, has shown a variety of biological activity including anti-inflammatory and antioxidative effects, and the distribution of isoLQ in gastrointestinal tract was higher than any other tissues. Thus, we evaluated whether or not isoLQ attenuated the dextran sulfate sodium (DSS)-induced colitis by observing the physiological changes (body weight loss, diarrhea, bleeding stool, overall disease activity index (DAI) scores, colon length), histopathological analysis and myeloperoxidase (MPO) activities of esophagus and colon. Also, the MAPK pathways including phosphorylation of ERK1/2, p38, and AKT, and the activation of NK-κB were evaluated in colon tissue. Interestingly, the reduction of body weight and colon length, increase of diarrhea, bloody stool, DAI scores and MPO activity, and histologic disturbances in DSS-induced colitis were recovered by isoLQ treatment. Also, isoLQ treatment suppressed the phosphorylation of ERK1/2 and p38, and the activation of NK-κB compared to those in DSS-induced colitis mice. In addition, the distributions of isoLQ in colon were relatively higher in DSS-induced colitis models. All of these results suggested that isoLQ has potential activity to ameliorate the DSS-induced colitis through the inhibition of MAPK pathway.