Randomized, Double-blind, Active-controlled Phase 3 Study to Evaluate Efficacy and Safety of Zastaprazan compared to Esomeprazole in Erosive Esophagitis.

INTRODUCTION: Zastaprazan is a potent potassium-competitive acid blocker (P-CAB) developed to treat gastroesophageal reflux disease. This study aims to evaluate the efficacy and safety of zastaprazan compared to esomeprazole in patient with erosive esophagitis (EE). METHODS: A phase III, multicenter, randomized, double-blind, non-inferiority clinical study was conducted with 300 subjects with confirmed EE. Subjects were randomized to receive zastaprazan 20 mg or esomeprazole 40 mg once daily up to 8 weeks. The primary endpoint was the cumulative proportion of subject with healed EE confirmed by endoscopy at week 8. The secondary endpoints included the healing rate at week 4, symptom response and quality of life assessment. Safety profiles and serum gastrin levels were also assessed. RESULTS: In the full analysis set, the cumulative healing rate at week 8 were 97.92% (141/144) for zastaprazan and 94.93% (131/138) (P = 0.178) for esomeprazole. The healing rate at week 4 in the zastaprazan group was higher than esomeprazole group (95.14% (137/144) vs. 87.68% (121/138); P = 0.026). There was no significant difference between groups in healing rates (the per-protocol set) at week 8 and week 4, symptom responses, quality of life assessments and safety profiles. In addition, serum gastrin levels increased during treatment in both groups, with a significant difference between the two groups (P = 0.047), but both decreased after treatment. DISCUSSION: An 8-week therapy of zastaprazan 20 mg is non-inferior to esomeprazole 40 mg in subjects with predominantly low-grade EE. The healing rate at week 4 appears to be higher for zastaprazan than esomeprazole.

Gastroparesis might not be uncommon in patients with diabetes mellitus in a real-world clinical setting: a cohort study.

BACKGROUND: This study investigated the frequency of diabetic gastroparesis and associated risk factors in a real-world clinical setting. METHODS: This retrospective cross-sectional study included patients who underwent assessments of solid gastric emptying time (GET) by technetium-99 m scintigraphy between May 2019 and December 2020. We categorized patients into three groups according to gastric retention of technetium-99 m: rapid (< 65% at 1 h or < 20% at 2 h), normal (≤60% at 2 h and/or ≤ 10% at 4 h), and delayed (> 60% at 2 h and/or > 10% at 4 h). RESULTS: Patients with diabetes mellitus (DM) were more likely to show abnormal GET than those without DM (119 [70.8%] vs. 16 [44.4%]). The mean glycated A1c was 10.3% in DM patients. DM patients with normal GET were significantly younger (57.2 years, P = 0.044) than those with delayed (65.0 years) or rapid GET (60.2 years). Fasting glucose levels were the lowest in the normal GET group and the highest in the rapid GET group (delayed: 176.3 mg/dL, normal: 151.2 mg/dL, rapid: 181.0 mg/dL, P = 0.030). However, glycated A1c was not significantly different among the delayed, normal, and rapid GET groups in patients with DM. Patients with delayed and rapid GET showed a higher frequency of retinopathy (6.0 vs. 15.5%, P = 0.001) and peripheral neuropathy (11.3 vs. 24.4%, P = 0.001) than those with normal GET. In the multinomial logistic regression analysis, retinopathy demonstrated a positive association with delayed GET, while nephropathy showed a significant negative correlation. CONCLUSION: DM gastroparesis in the clinical setting was not uncommon. Abnormal GET, including delayed and rapid GET, was associated with DM retinopathy or peripheral neuropathy.

Inhibitory Effects of Sesquiterpenoids Isolated from Artemisia scoparia on Adipogenic Differentiation of 3T3-L1 Preadipocytes.

Obesity and related complications are significant health issues in modern society, largely attributed to a sedentary lifestyle and a carbohydrate-rich diet. Since anti-obesity drugs often come with severe side effects, preventative measures are being sought globally, including dietary changes and functional foods that can counteract weight gain. In this context, plant-based metabolites are extensively studied for their advantageous biological effects against obesity. Several plants within the Artemisia genus have been reported to possess anti-adipogenic properties, preventing adipocytes from maturing and accumulating lipids. The present study investigated the anti-adipogenic potential of two sesquiterpenoids, reynosin and santamarine, isolated from A. scoparia in adipose-induced 3T3-L1 preadipocytes. Differentiating 3T3-L1 adipocytes treated with these isolated compounds displayed fewer adipogenic characteristics compared to untreated mature adipocytes. The results indicated that cells treated with reynosin and santamarine accumulated 55.0% and 52.5% fewer intracellular lipids compared to untreated control adipocytes, respectively. Additionally, the mRNA expression of the key adipogenic marker, transcription factor PPARγ, was suppressed by 87.2% and 91.7% following 60 µM reynosin and santamarine treatment, respectively, in differentiated adipocytes. Protein expression was also suppressed in a similar manner, at 92.7% and 82.5% by 60 µM reynosin and santamarine treatment, respectively. Likewise, SERBP1c and C/EBPα were also downregulated at both gene and protein levels in adipocytes treated with samples during differentiation. Further analysis suggested that the anti-adipogenic effect of the compounds might be a result of AMPK activation and the subsequent suppression of MAPK phosphorylation. Overall, the present study suggested that sesquiterpenoids, reynosin, and santamarine were two potential bioactive compounds with anti-adipogenic properties. Further research is needed to explore other bioactive agents within A. scoparia and elucidate the in vivo action mechanisms of reynosin and santamarine.

Quercetin 3-O-Galactoside Isolated from Limonium tetragonum Inhibits Melanogenesis by Regulating PKA/MITF Signaling and ERK Activation.

Quercetin 3-O-galactoside (Q3G) is a common dietary flavanol that has been shown to possess several bioactivities, including anti-melanogenesis. However, how Q3G exerts its anti-melanogenic effect has not been studied. The current study, therefore aimed to investigate the anti-melanogenesis potential of Q3G and elucidate the underlying action mechanism in α-melanocyte-stimulating hormone (α-MSH)-induced hyperpigmentation model of B16F10 murine melanoma cells. Results showed that α-MSH stimulation significantly increased tyrosinase (TYR) and melanin production, which were significantly downregulated by Q3G treatment. The treatment with Q3G suppressed the transcriptional and protein expressions of melanogenesis-related enzymes TYR, tyrosinase related protein-1 (TRP-1), and TRP-2, along with the melanogenic transcription factor microphthalmia-associated transcription factor (MITF) in B16F10 cells. It was shown that Q3G downregulated MITF expression and suppressed its transcriptional activity by inhibiting the cAMP-dependent protein kinase A (PKA)-mediated activation of CREB and GSK3ß. In addition, MAPK-regulated MITF activation signaling was also involved in the inhibition of melanin production by Q3G. The results suggest that the anti-melanogenic properties of Q3G rationalize further studies in vivo to confirm its action mechanism and consequent utilization as a cosmetic ingredient against hyperpigmentation.

Oleracone C from Portulaca oleracea attenuates UVB-induced changes in matrix metalloproteinase and type I procollagen production via MAPK and TGF-ß/Smad pathways in human keratinocytes.

BACKGROUND: Chronic exposure to ultraviolet (UV) radiation induces photo-oxidation, which in turn causes the overproduction of matrix metalloproteinases (MMPs) and collagen degradation. These symptoms are referred to as photoaging, which is characterized by skin thickness, irregular pigmentation, elastosis and coarse wrinkles. In this study, the protective effects of oleracone C isolated from Portulaca olerace against UVB-induced changes in MMPs and type I procollagen production were investigated in human keratinocytes. METHODS: Human immortalized keratinocytes have been used as an in vitro cell model to study the abnormal skin barrier development such as in photoaging. The effects of the compound on cell viability were determined by colorimetric MTT assay. This study also measured ROS production using DCFH-DA assay. Releases of MMPs and type Iα1 procollagen were analysed by ELISA. RT-PCR and Western blot were carried out to test the expressions of mRNA and proteins related to MMPs and type I procollagen biosynthesis. RESULT: Effect of oleracone C against UVB-mediated oxidative stress was evaluated measuring its ability to eliminate UVB-induced activation of reactive oxygen species (ROS). Treatment of oleracone C hindered the production of intracellular ROS. UVB exposure increased MMPs (MMP-1, MMP-2 and MMP-9) release from keratinocytes and decreased the release of type I procollagen. Treatment with oleracone C reversed these effects of UVB exposure. Oleracone C treatment also diminished the intracellular expression of MMP-1, MMP-2 and MMP-9 and elevated the type I procollagen. Oleracone C suppressed the UVB irradiation-dependent upregulation phosphorylation of p38 and ERK1/2 in the mitogen-activated protein kinase (MAPK) pathway. Furthermore, oleracone C stimulated collagen production through the TGF-ß signalling pathway, which activates collagen synthesis in UVB-irradiated keratinocytes. CONCLUSION: These findings reasonably suggest ameliorating the potential of oleracone C against the UVB-induced photoaging of the human keratinocytes.

RÉSUMÉ: CONTEXTE: L'exposition chronique aux rayons ultraviolets (UV) induit la photo-oxydation, qui à son tour entraîne la surproduction de métalloprotéases matricielles (MMP) et la dégradation du collagène. Ces symptômes sont appelés photovieillissement, qui se caractérise par une épaisseur de la peau, une pigmentation irrégulière, une élastose et des rides grossières. Dans cette étude, les effets protecteurs de l'oléracone C isolée à partir du pourpier potager contre les changements induits par les UVB dans les MMP et la production de procollagène de type I ont été étudiés dans les kératinocytes humains. MÉTHODES: Les kératinocytes humains immortalisés ont été utilisés comme modèle cellulaire in vitro pour étudier le développement anormal de la barrière cutanée, comme c'est le cas dans le photovieillissement. Les effets du composé sur la viabilité cellulaire ont été déterminés par test colorimétrique au MTT. Cette étude a également mesuré la production de DRO à l'aide du dosage DCFH-DA. Les productions de MMP et de procollagène de type Iα1 ont été analysées par la méthode ELISA. La RT-PCR et le Western blot ont été réalisés pour tester les expressions de l'ARNm, et des protéines liées aux MMP et à la biosynthèse du procollagène de type I. RÉSULTAT: L'effet de l'oléracone C contre le stress oxydatif médié par les UVB a été évalué en mesurant sa capacité à éliminer l'activation induite par les UVB des dérivés réactifs de l'oxygène (DRO). Le traitement par oléracone C a empêché la production de DRO intracellulaires. L'exposition aux UVB a augmenté la production de MMP (MMP-1, MMP-2 et MMP-9) par les kératinocytes et a diminué la production de procollagène de type I. Le traitement par oléracone C a inversé ces effets de l'exposition aux UVB. Le traitement par oléracone C a également diminué l'expression intracellulaire de MMP-1, MMP-2 et MMP-9, et a augmenté le taux de procollagène de type I. L'oléracone C a supprimé la phosphorylation de régulation à la hausse dépendante de l'exposition aux UVB de p38 et ERK1/2 dans la voie de la protéine kinase activée par des agents mitogènes (Mitogen-Activated Protein Kinase, MAPK). En outre, l'oléracone C a stimulé la production de collagène par la voie de signalisation de TGF-ß, qui active la synthèse du collagène dans les kératinocytes exposés aux UVB. CONCLUSION: Ces résultats indiquent raisonnablement une amélioration du potentiel de l'oléracone C contre le photovieillissement induit par les UVB des kératinocytes humains.

Comparison of 2 L Polyethylene Glycol Plus Ascorbic Acid and 4 L Polyethylene Glycol in Elderly Patients Aged 60-79: A Prospective Randomized Study.

BACKGROUND: The bowel-cleansing efficacy and safety of 2 L polyethylene glycol (PEG) with ascorbic acid (2L PEG + Asc) has rarely been studied in the elderly population. In this randomized trial, we compared the bowel cleanliness, safety, and tolerability of 2L PEG + Asc with those of 4 L PEG in an elderly population aged 60-79. METHODS: Study participants were randomized either to 2L PEG + Asc or 4L PEG. The primary endpoint was the success rate of bowel preparation, using the Boston Bowel Preparation Scale. Before colonoscopy, all participants were questioned about adverse events and tolerability regarding purgative ingestion. RESULTS: A total of 347 individuals were enrolled (2L PEG + Asc, 174; 4L PEG, 173). Mean age in the 2L PEG + Asc and the 4L PEG was 69.3 ± 5.6 and 69.3 ± 5.0, respectively (P = 0.917). The rate for successful bowel cleansing was comparable between the 2L PEG + Asc (92%) and the 4L PEG (96%, P = 0.118). Total ingested liquid including purgative and water was lower in the 2L PEG + Asc group (2.9 L) than in the 4L PEG group (4.2 L, P < 0.001). The tolerability of purgative was superior in the 2L PEG + Asc (overall satisfaction, P < 0.001; willingness to reuse, P < 0.001). There were no serious adverse events during the trial. CONCLUSIONS: The bowel-cleansing efficacy of 2L PEG + Asc was comparable to that of 4L PEG. Tolerability was superior in the 2L PEG + Asc group. For older people, 2L PEG + Asc is an efficacious and safe bowel cleanser. (Clinical trial registration number: KCT0004123).

Libanoridin Isolated from Corydalis heterocarpa Inhibits Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells.

Bone marrow adiposity is a complication in osteoporotic patients. It is a result of the imbalance between adipogenic and osteogenic differentiation of bone marrow cells. Phytochemicals can alleviate osteoporotic complications by hindering bone loss and decreasing bone marrow adiposity. Corydalis heterocarpa is a biennial halophyte with reported bioactivities, and it is a source of different coumarin derivatives. Libanoridin is a coumarin isolated from C. heterocarpa, and the effect of libanoridin on adipogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) was evaluated in the present study. Cells were induced to undergo adipogenesis, and their intracellular lipid accumulation and expression of adipogenic markers were observed under libanoridin treatment. Results showed that 10 µM libanoridin-treated adipocytes accumulated 44.94% less lipid compared to untreated adipocytes. In addition, mRNA levels of PPARγ, C/EBPα, and SREBP1c were dose-dependently suppressed with libanoridin treatment, whereas only protein levels of PPARγ were decreased in the presence of libanoridin. Fluorescence staining of adipocytes also revealed that cells treated with 10 µM libanoridin expressed less PPARγ compared to untreated adipocytes. Protein levels of perilipin and leptin, markers of mature adipocytes, were also suppressed in adipocytes treated with 10 µM libanoridin. Analysis of MAPK phosphorylation levels showed that treatment with libanoridin inhibited the activation of p38 and JNK MAPKs observed by decreased levels of phosphorylated p38 and JNK protein. It was suggested that libanoridin inhibited adipogenic differentiation of hBM-MSCs via suppressing MAPK-mediated PPARγ signaling. Future studies revealing the anti-adipogenic effects of libanoridin in vivo and elucidating its action mechanism will pave the way for libanoridin to be utilized as a nutraceutical with anti-osteoporotic properties.

Dracunculin Inhibits Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells by Activating AMPK and Wnt/ß-Catenin Signaling.

Increased bone marrow adiposity is widely observed in patients with obesity and osteoporosis and reported to have deleterious effects on bone formation. Dracunculin (DCC) is a coumarin isolated from Artemisia spp. but, until now, has not been studied for its bioactive potential except antitrypanosomal activity. In this context, current study has reported the anti-adipogenic effect of DCC in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). DCC dose-dependently inhibited the lipid accumulation and expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) in hBM-MSCs induced to undergo adipogenesis. To elucidate its action mechanism, the effect of DCC on Wnt/ß-catenin and AMPK pathways was examined. Results showed that DCC treatment activated Wnt/ß-catenin signaling pathway via AMPK evidenced by increased levels of AMPK phosphorylation and Wnt10b expression after DCC treatment. In addition, DCC treated adipo-induced hBM-MSCs exhibited significantly increased nuclear levels of ß-catenin compared with diminished nuclear PPARγ levels. In conclusion, DCC was shown to be able to hinder adipogenesis by activating the ß-catenin via AMPK, providing potential utilization of DCC as a nutraceutical against bone marrow adiposity.

Sleep disorders in patients with functional dyspepsia: A multicenter study from the Korean Society of Neurogastroenterology and Motility.

BACKGROUND AND AIM: The few studies concerning the association between sleep disorders and functional dyspepsia (FD) have yielded inconsistent results. We compared the prevalence of sleep disorders in patients with FD and healthy controls, and evaluated whether FD was independently associated with sleep disorders, and the risk factors for sleep disorders in patients with FD. METHODS: This prospective, multicenter, cross-sectional study was conducted from August 2014 to December 2017 at 12 hospitals in South Korea. The inclusion criterion was the presence of FD (for ≥18 years) according to the Rome III criteria. Healthy controls were recruited from among patients who visited the Health Examination Center for check-ups. RESULTS: In total, 526 subjects were prospectively enrolled in this study (201 with FD and 325 healthy controls). The prevalence of sleep disorders was significantly higher among the patients with FD than among the healthy controls (41.8% vs 18.8%, P = 0.000). In a multivariate analysis, FD (odds ratio [OR] = 1.851; 95% confidence interval [CI] 1.194-2.870; P = 0.006), female sex (OR = 1.672; 95% CI 1.063-2.628; P = 0.026), and anxiety (OR = 3.325; 95% CI 2.140-5.166; P = 0.000) were independent risk factors for sleep disorders in the overall cohorts. In patients with FD only, low body mass index, heartburn, and anxiety were independent risk factors for sleep disorders in a further multivariate analysis. CONCLUSION: Sleep disorders were common in patients with FD. FD was significantly associated with sleep disorders in our patient population, irrespective of the presence of heartburn or psychiatric disorders.

Serial Screening for SARS-CoV-2 in Rectal Swabs of Symptomatic COVID-19 Patients.

We used serial rectal swabs to investigate the amount and duration of virus secretion through the gastrointestinal tract and assessed the association between fecal shedding and gastrointestinal symptoms and to clarify the clinical usefulness testing rectal swabs. We enrolled ten adult patients hospitalized with symptomatic coronavirus disease 2019 (COVID-19). Respiratory and stool specimens were collected by physicians. The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed using real-time reverse-transcription polymerase chain reaction. All ten patients had respiratory symptoms, six had diarrhea, and seven were positive for SARS-CoV-2 on rectal swabs. The viral loads in the respiratory specimens was higher than those in the rectal specimens, and no rectal specimens were positive after the respiratory specimens became negative. There was no association between gastrointestinal symptoms, pneumonia, severity, and rectal viral load. Rectal swabs may play a role in detecting SARS-CoV-2 in individuals with suspected COVID-19, regardless of gastrointestinal symptoms.

Santamarine Shows Anti-Photoaging Properties via Inhibition of MAPK/AP-1 and Stimulation of TGF-ß/Smad Signaling in UVA-Irradiated HDFs.

Chronic UVA exposure results in elevated reactive oxygen species in skin which leads to photoaging characterized as upregulated matrix metalloproteinase (MMP)-1 and loss of collagen. Therefore, natural antioxidants are hailed as promising agents to be utilized against photoaging. In the current study, reynosin and santamarine, two known sesquiterpene lactones isolated from Artemisia scoparia, were analyzed for their anti-photoaging properties in UVA-irradiated human dermal fibroblasts (HDFs). Results showed that UVA irradiation (8 J/cm2) upregulated the MMP-1 secretion and expression, and suppressed collagen production, which were significantly reverted by santamarine treatment (10 µM). Although both reynosin and santamarine exhibited ROS scavenging abilities, reynosin failed to significantly diminish UVA-stimulated MMP-1 release. UVA-irradiated HDFs showed increased collagen production when treated with santamarine. As a mechanism to suppress MMP-1, santamarine significantly suppressed the UVA-induced phosphorylation of p38 and JNK and nuclear translocation of p-c-Fos and p-c-Jun. Santamarine promoted collagen I production via relieving the UVA-induced suppression on TGF-ß and its downstream activator Smad2/3 complex. Antioxidant properties of santamarine were also shown to arise from stimulating Nrf2-dependent expression of antioxidant enzymes SOD-1 and HO-1 in UVA-irradiated HDFs. In conclusion, santamarine was found to be a promising natural antioxidant with anti-photoaging properties against UVA-induced damages in HDFs.

Comparison of 7- and 14-Day Eradication Therapy for Helicobacter pylori with First- and Second-Line Regimen: Randomized Clinical Trial.

BACKGROUND: Although Helicobacter pylori is a key cause of gastric cancer development, its eradication rate has been decreasing by standard regimens. For successful eradication, duration of treatment has been issued for overcoming antibiotics resistance. We were to compare the eradication rate of 7-day vs. 14-day treatment in first- and second-line regimens. METHODS: This study was an open-label randomized controlled trial. A total of 369 H. pylori-infected patients were enrolled and assigned either to 7-day or 14-day proton pump inhibitor (PPI)-based standard triple therapy (STT; PPI-clarithromycin-amoxicillin). Bismuth-containing quadruple therapy was used as second-line therapy. Eradication success was defined as a negative 13C-urea breath test. RESULTS: In first-line treatment, eradication rate was 78.5% (106/135) and 78.6% (114/143) in the 7-day and 14-day treatment in per-protocol (PP) analysis (P = 0.805). In intention-to-treat (ITT) analysis, eradication rate was 64.0% (114/178) and 66.0% (126/191), respectively (P = 0.924). There was no significant difference in drug compliance (81.5% vs. 84.3%, P = 0.320). In second-line therapy, eradication rate was not significantly different in both treatments of PP analysis (91.7% [33/36] vs. 100% [45/45], P = 0.084). In the ITT analysis, eradication rate was 79.6% (35/44) and 90.4% (47/52), respectively (P = 0.080). Drug compliances were not significantly different between the two groups (95.5% vs. 98.1%, P = 0.728). CONCLUSION: PPI-based STT for H. pylori is not efficient as a first-line therapy both in 7 days and 14 days in Korea. Although bismuth-containing quadruple therapy for 14 days as a second line therapy tend to show higher eradication rate compared to 7-day therapy, this should be elucidated by further larger scaled studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02487511.

Antiphotoaging Effect of 3,5-Dicaffeoyl-epi-quinic Acid against UVA-Induced Skin Damage by Protecting Human Dermal Fibroblasts In Vitro.

Cutaneous aging is divided into intrinsic and exogenous aging correspondingly contributing to the complex biological phenomenon in skin. Intrinsic aging is also termed chronological aging, which is the accumulation of inevitable changes over time and is largely genetically determined. Superimposed on this intrinsic process, exogenous aging is associated with environmental exposure, mainly to ultraviolet (UV) radiation and more commonly termed as photoaging. UV-induced skin aging induces increased expression of matrix metalloproteinases (MMPs) which in turn causes the collagen degradation. Therefore, MMP inhibitors of natural origin are regarded as a primary approach to prevent or treat photoaging. This study investigated the effects of 3,5-dicaffeoyl-epi-quinic acid (DEQA) on photoaging and elucidated its molecular mechanisms in UVA-irradiated human dermal fibroblasts (HDFs). The results show that treatment with DEQA decreases MMP-1 production and increases type I collagen production in UVA-damaged HDFs. In addition, treatment of UVA-irradiated HDFs with DEQA downregulates MMP-1, MMP-3 and MMP-9 expression via blocking MAPK-cascade-regulated AP-1 transcriptional activity in UVA-irradiated HDFs. Furthermore, DEQA relieves the UVA-mediated suppression of type I procollagen and collagen expression through stimulating TGF-ß/Smad signaling, leading to activation of the Smad 2/3 and Smad 4 nuclear translocation. These results suggest that DEQA could be a potential cosmetic agent for prevention and treatment of skin photoaging.

Effect of Quercetin 3-O-ß-D-Galactopyranoside on the Adipogenic and Osteoblastogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stromal Cells.

Natural products, especially phenols, are promising therapeutic agents with beneficial effects against aging-related complications such as osteoporosis. This study aimed to investigate the effect of quercetin 3-O-ß-D-galactopyranoside (Q3G), a glycoside of a common bioactive phytochemical quercetin, on osteogenic and adipogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). hBM-MSCs were induced to differentiate into osteoblasts and adipocytes in the presence or absence of Q3G and the differentiation markers were analyzed to observe the effect. Q3G treatment stimulated the osteoblastogenesis markers: cell proliferation, alkaline phosphatase (ALP) activity and extracellular mineralization. In addition, it upregulated the expression of RUNX2 and osteocalcin protein as osteoblastogenesis regulating transcription factors. Moreover, Q3G treatment increased the activation of osteoblastogenesis-related Wnt and bone morphogenetic protein (BMP) signaling displayed as elevated levels of phosphorylated ß-catenin and Smad1/5 in nuclear fractions of osteo-induced hBM-MSCs. The presence of quercetin in adipo-induced hBM-MSC culture inhibited the adipogenic differentiation depicted as suppressed lipid accumulation and expression of adipogenesis markers such as PPARγ, SREBP1c and C/EBPα. In conclusion, Q3G supplementation stimulated osteoblast differentiation and inhibited adipocyte differentiation in hBM-MSCs via Wnt/BMP and PPARγ pathways, respectively. This study provided useful information of the therapeutic potential of Q3G against osteoporosis mediated via regulation of MSC differentiation.

Syringaresinol Inhibits UVA-Induced MMP-1 Expression by Suppression of MAPK/AP-1 Signaling in HaCaT Keratinocytes and Human Dermal Fibroblasts.

Ultraviolet (UV) irradiation induces detrimental changes in human skin which result in photoaging. UV-induced intracellular changes cause degradation of extracellular matrix (ECM). UV-stimulated cleavage of collagen in ECM occurs via matrix metalloproteinases (MMPs). (±)-syringaresinol (SYR), a phytochemical which belongs to the lignan group of polyphenols, was investigated for its ability to reverse the UVA-induced changes in human HaCaT keratinocytes and dermal fibroblasts (HDFs) in vitro. Effect of SYR on UVA-induced changes was investigated by production and activation of MMPs and its transcriptional upstream effectors; mitogen-activated protein kinases (MAPKs) and pro-inflammatory mediators. Levels of expression were determined using ELISA, RT-PCR and immunoblotting. UVA irradiation stimulated the production of MMP-1 and inhibited collagen production. SYR treatment suppressed MMP-1 and enhanced collagen production in UVA-irradiated HaCaT keratinocytes and HDFs. SYR repressed the UV-induced phosphorylation of p38, ERK and JNK MAPKs in HaCaT keratinocytes while only suppressing JNK phosphorylation in HDFs. In addition, SYR was able to inhibit UVA-induced production of inflammatory cytokines; TNF-α, COX-2, IL-1ß and IL-6. Moreover, SYR suppressed the activator protein-1 (AP-1), a heterodimer of phosphorylated transcription factors c-Jun and c-Fos. SYR-treatment decreased nuclear levels of activated c-Fos and c-Jun as a mechanism to inhibit UVA-induced transcriptional activities leading to MMP-1 production. In conclusion, current results demonstrated that SYR could inhibit UVA-induced upregulation of MMP-1 by suppressing MAPK/AP-1 signaling in HaCaT keratinocytes and HDFs. Therefore, SYR was suggested as a potential compound with antiphotoaging properties against UVA-induced skin aging.

Anticatabolic and Anti-Inflammatory Effects of Myricetin 3-O-ß-d-Galactopyranoside in UVA-Irradiated Dermal Cells via Repression of MAPK/AP-1 and Activation of TGFß/Smad.

UV irradiation is one of the main causes of extrinsic skin aging. UV-mediated skin aging, also known as photoaging, causes excessive breakdown of extracellular matrix which leads skin to lose its elasticity and strength. Several phytochemicals are known to exert anti-photoaging effects via different mechanisms, partly due to their antioxidant properties. The current study has been carried out to determine the potential anti-photoaging properties of myricetin 3-O-ß-d-galacto-pyranoside (M3G), a flavonol glycoside isolated from L. tetragonum, in UVA-irradiated in vitro models; HaCaT keratinocytes and human dermal fibroblasts (HDFs). UVA-induced changes in MMP-1 and collagen production have been observed in HaCaT keratinocytes and HDFs. Further, UVA-induced activation of MAPK signaling, and pro-inflammatory cytokine production have been investigated. TGFß/Smad pathway has also been analyzed in UVA-irradiated HDFs. Treatment with M3G reversed the UVA-induced changes in MMP-1 and collagen production both in HaCaT keratinocytes and HDFs. UVA-mediated activation of p38, ERK and JNK MAPK activation was also inhibited by M3G treatment in HaCaT keratinocytes. In HDFs, M3G was able to upregulate the TGFß/Smad pathway activation. In addition, M3G downregulated the UVA-induced pro-inflammatory cytokines in keratinocytes and HDFs. It has been suggested that the M3G has exerted potential antiphotoaging properties in vitro, by attenuating UVA-induced changes in MMP-1 and collagen production in keratinocytes and dermal fibroblasts.

Phlorofucofuroeckol A from Edible Brown Alga Ecklonia Cava Enhances Osteoblastogenesis in Bone Marrow-Derived Human Mesenchymal Stem Cells.

The deterioration of bone formation is a leading cause of age-related bone disorders. Lack of bone formation is induced by decreased osteoblastogenesis. In this study, osteoblastogenesis promoting effects of algal phlorotannin, phlorofucofuroeckol A (PFF-A), were evaluated. PFF-A was isolated from brown alga Ecklonia cava. The ability of PFF-A to enhance osteoblast differentiation was observed in murine pre-osteoblast cell line MC3T3-E1 and human bone marrow-derived mesenchymal stem cells (huBM-MSCs). Proliferation and alkaline phosphatase (ALP) activity of osteoblasts during differentiation was assayed following PFF-A treatment along extracellular mineralization. In addition, effect of PFF-A on osteoblast maturation pathways such as Runx2 and Smads was analyzed. Treatment of PFF-A was able to enhance the proliferation of differentiating osteoblasts. Also, ALP activity was observed to be increased. Osteoblasts showed increased extracellular mineralization, observed by Alizarin Red staining, following PFF-A treatment. In addition, expression levels of critical proteins in osteoblastogenesis such as ALP, bone morphogenetic protein-2 (BMP-2), osteocalcin and ß-catenin were stimulated after the introduction of PFF-A. In conclusion, PFF-A was suggested to be a potential natural product with osteoblastogenesis enhancing effects which can be utilized against bone-remodeling imbalances and osteoporosis-related complications.

Species-specific role of gene-adjacent retroelements in human and mouse gastric carcinogenesis.

Helicobacter pylori (HP) infection promotes the recruitment of bone marrow stem cells into chronic gastritis lesions. Some of these marrow stem cells can differentiate into gastric epithelial cells and neoplastic cells. We propose that HP-associated methylation could stabilize trans-differentiation of marrow-derived stem cells and that an unstable methylation status is associated with a risk of gastric cancer. Pathobiologic behavior of experimental mouse gastric cancer is mild compared to invasive and metastatic human gastric cancer. Differences in epigenetic stabilization of adult cell phenotypes between humans and mice could provide a foundation to explore the development of invasive and metastatic gastric cancer. Retroelements are highly repetitive sequences that play an essential role in the generation of species diversity. In this review, we analyzed retroelements adjacent to human and mouse housekeeping genes and proposed a possible epigenetic mechanism for HP-associated carcinogenesis.

Analysis of factors influencing survival in patients with severe acute pancreatitis.

OBJECTIVE: Acute pancreatitis (AP) ranges from a mild and self-limiting disease to a fulminant illness with significant morbidity and mortality. Severe acute pancreatitis (SAP) is defined as persistent organ failure lasting for 48 h. We aimed to determine the factors that predict survival and mortality in patients with SAP. METHODS: We reviewed a consecutive series of patients who were admitted with acute pancreatitis between January 2003 and January 2013. A total of 1213 cases involving 660 patients were evaluated, and 68 cases with SAP were selected for the study. Patients were graded based on the Computer Tomography Severity Index (CTSI), the bedside index for severity (BISAP), and Ranson's criteria. RESULTS: The frequency of SAP was 5.6% (68/1213 cases). Among these patients, 17 died due to pancreatitis-induced causes. We compared several factors between the survivor (n = 51) and non-survivor (n = 17) groups. On multivariate analysis, there were significant differences in the incidence of diabetes mellitus (p = .04), Ranson score (p = .03), bacteremia (p = .05) and body mass index (BMI) (p = .02) between the survivor and non-survivor groups. CONCLUSIONS: Bacteremia, high Ranson score, DM, and lower BMI were closely associated with mortality in patients with SAP. When patients with SAP show evidence of bacteremia or diabetes, aggressive treatment is necessary. For the prediction of disease mortality, the Ranson score might be a useful tool in SAP.

Comparison of sequential therapy and amoxicillin/tetracycline containing bismuth quadruple therapy for the first-line eradication of Helicobacter pylori: a prospective, multi-center, randomized clinical trial.

BACKGROUND: The <80 % Helicobacter pylori eradication rate with sequential therapy is unsatisfactory. Modified bismuth quadruple therapy, replacing metronidazole with amoxicillin, could be promising because H. pylori resistance to tetracycline or to amoxicillin is relatively low. A 14-day modified bismuth quadruple protocol as first-line H. pylori treatment was compared with 10-day sequential therapy. METHODS: In total, 390 H. pylori-infected subjects participated in the randomized clinical trial: 10-day sequential therapy (40 mg pantoprazole plus 1 g amoxicillin twice a day for 5 days, then 40 mg pantoprazole and 500 mg clarithromycin twice a day and 500 mg metronidazole three times a day for 5 days) or 14-day modified bismuth quadruple therapy (40 mg pantoprazole, 600 mg bismuth subcitrate, 1 g tetracycline, and 1 g amoxicillin, twice a day). (13)C-urea breath test, rapid urease testing, or histology was performed to check for eradication. RESULTS: Intention-to-treat (ITT) eradication rates of 10-day sequential and 14-day quadruple therapy were 74.6 % and 68.7 %, respectively, and the per-protocol (PP) rates were 84.2 and 76.5 %, respectively. The eradication rate was higher in the sequential therapy group, but neither the ITT nor the PP analyses had a significant difference (P = 0.240 and P = 0.099, respectively). However, the adverse events were significantly lower in the modified bismuth quadruple therapy group than the sequential therapy group (36.9 vs. 47.7 %, P = 0.040). CONCLUSIONS: Ten-day sequential therapy appears to be more effective despite frequent adverse events. However, both 10-day SQT and 14-day PBAT did not reach the excellent eradication rates that exceed 90 %. Additional trials are needed to identify a more satisfactory first-line eradication therapy. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02159976 ); Registration date: 2014-06-03, CRIS ( KCT0001176 ); Registration date: 2014-07-23.