Masculinity, Rather Than Biological Sex, Is Associated With Psychological Comorbidities in Patients With Irritable Bowel Syndrome.

Background/Aims: Irritable bowel syndrome (IBS) generally shows sex differences, and psychiatric comorbidities play an important role in its pathogenesis. We aim to measure the levels of gender roles and investigate their relationship with psychiatric factors in patients with IBS versus healthy controls. Methods: Patients diagnosed with IBS by Rome III and whose colonoscopy findings were normal were enrolled at multiple sites in Korea. The participants completed the Korean Sex Role Inventory-Short Form (KSRI-SF) to assess masculinity and femininity, the stress questionnaire, the Hospital Anxiety Depression Scale (HADS), and the 36-item Short Form Health Survey questionnaire to assess the quality of life (QOL). Results: In total, 102 patients with IBS (male:female = 35:67; mean age 42.6 ± 16.7 years) and 55 controls (male:female = 20:35; mean age 42.4 ± 11.1 years) were recruited. IBS patients had higher stress (9.69 ± 8.23 vs 4.56 ± 8.31, P < 0.001) and HADS scores (16.12 ± 7.17 vs 10.22 ± 5.74, P < 0.001) than the control group, but showed no significant difference in KSRI-SF scores. No significant differences in HADS and KSRI-SF scores were found between males and females. However, IBS patients whose symptoms worsened due to stress and patients with anxiety or depression had significantly lower masculinity. QOL was poorer in IBS patients than in controls. In stepwise multivariate analyses, the anxiety score, depression score, and the degree of daily life disturbance, not masculinity, were associated with the QOL of IBS patients. Conclusions: IBS patients had higher stress, more psychiatric comorbidities, and lower QOL than controls. Low masculinity, rather than sex, was associated with stress and psychological comorbidities, which deteriorated the QOL in IBS patients.

Dietary flavonoid myricetin 3-O-galactoside suppresses α-melanocyte stimulating hormone-induced melanogenesis in B16F10 melanoma cells by regulating PKA and ERK1/2 activation.

Melanogenesis is the process where skin pigment melanin is produced through tyrosinase activity. Overproduction of melanin causes skin disorders such as freckles, spots, and hyperpigmentation. Myricetin 3-O-galactoside (M3G) is a dietary flavonoid with reported bioactivities. M3G was isolated from Limonium tetragonum and its anti-melanogenic properties were investigated in α-melanocyte stimulating hormone-stimulated B16F10 melanoma cells. The in vitro anti-melanogenic capacity of M3G was confirmed by inhibited tyrosinase and melanin production. M3G-mediated suppression of melanogenic proteins, tyrosinase, microphthalmia-associated transcription factor (MITF), and tyrosinase-related proteins (TRP)-1 and TRP-2, were confirmed by mRNA and protein levels, analyzed by RT-qPCR and Western blot, respectively. Furthermore, M3G suppressed Wnt signaling through the inhibition of PKA phosphorylation. M3G also suppressed the consequent phosphorylation of CREB and nuclear levels of MITF. Analysis of MAPK activation further revealed that M3G increased the activation of ERK1/2 while p38 and JNK activation remained unaffected. Results showed that M3G suppressed melanogenesis in B16F10 cells by decreasing tyrosinase production and therefore inhibiting melanin formation. A possible action mechanism was the suppression of CREB activation and upregulation of ERK phosphorylation which might cause the decreased nuclear levels of MITF. In conclusion, M3G was suggested to be a potential nutraceutical with anti-melanogenic properties.

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.

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).

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.

A case report of critical ischemic stroke in moyamoya-like vasculopathy accompanied by systemic lupus erythematosus.

Moyamoya-like vasculopathy (MMV) is a rare, chronic, progressive cerebrovascular disorder characterized by stenosis or occlusion of the terminal portion of the bilateral internal carotid arteries and development of abnormal collateral vessels at the base of the brain. This disorder develops in association with various systemic diseases and conditions, including neurofibromatosis type 1, Down syndrome, thyroid disease, radiation therapy, and autoimmune disease. We report a case of a 51-year-old female patient with low-activity systemic lupus erythematosus (SLE) who had a sudden onset of global aphasia and right hemiplegia. Three months previous, she had been on antiplatelet medication due to a single transient ischemic attack. Brain magnetic resonance imaging demonstrated a massive infarct of the left middle cerebral artery territory. Conventional angiography showed complete occlusion of the left middle cerebral artery with poor development of basal collateral vessels. This case demonstrates that a patient with underlying autoimmune disease such as SLE accompanied by MMV should be considered vulnerable to ischemic stroke.

Evaluation and Comparison of the Antimelanogenic Properties of Different Solvent Fractionated Cnidium japonicum Extracts in B16F10 Murine Melanoma Cells.

Cnidium japonicum is a biennial halophyte found in the salt marshes and shores of Korea and widely used in traditional Korean medicine as an ingredient. This study investigated and compared the antimelanogenic effect of solventpartitioned fractions of C. japonicum extract (CJEFs) in a B16F10 mouse melanoma cell model, focusing on tyrosinase activity and production. Melanogenesis is the process in which skin pigment melanin is produced through tyrosinase activity. Overproduction of melanin is the primary reason behind several skin disorders such as freckles, spots, and hyperpigmentation. The antimelanogenic capacity of CJEFs was initially screened by their tyrosinase inhibitory effects, prevention of dihydroxyphenylalanine (DOPA) oxidation, and suppression of melanin production. The inhibition of tyrosinase activity and DOPA oxidation by CJEFs was suggested to be related to the downregulation of microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2, which was confirmed using mRNA and protein expression levels. Moreover, the glycogen synthase kinase 3 beta- and cyclic adenosine monophosphate response element-binding protein-related signaling pathways were inhibited by treatment with CJEFs, indicating their action mechanism. All the tested CJEFs exerted similar effects on tyrosinase activity and production. However, among those, 85% aq. MeOH was the most active fraction to suppress the signaling pathway that produces tyrosinase. These results suggest that especially the MeOH fraction of C. japonicum extract serves as a potential source of bioactive substances, with effective antimelanogenesis properties.

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.

Myricetin 3-O-ß-D-Galactopyranoside Exhibits Potential Anti-Osteoporotic Properties in Human Bone Marrow-Derived Mesenchymal Stromal Cells via Stimulation of Osteoblastogenesis and Suppression of Adipogenesis.

Natural bioactive substances are promising lead compounds with beneficial effects on various health problems including osteoporosis. In this context, the goal of this study was to investigate the effect of myricetin 3-O-ß-D-galactopyranoside (M3G), a glycoside of a known bioactive phytochemical myricetin, on bone formation via osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). The hBM-MSCs were induced to differentiate into osteoblasts and adipocytes in the presence or absence of M3G and the differentiation markers were analyzed. Osteoblastogenesis-induced cells treated with M3G exhibited stimulated differentiation markers: cell proliferation, alkaline phosphatase (ALP) activity, and extracellular mineralization. In terms of intracellular signaling behind the stimulatory effect of M3G, the expression of RUNX2 and osteopontin transcription factors were upregulated. It has been shown that M3G treatment increased the activation of Wnt and BMP as a suggested mechanism of action for its effect. On the other hand, M3G treatment during adipogenesis-inducement of hBM-MSCs hindered the adipogenic differentiation shown as decreased lipid accumulation and expression of PPARγ, SREBP1c, and C/EBPα, adipogenic transcription factors. In conclusion, M3G treatment stimulated osteoblast differentiation and inhibited adipocyte differentiation in induced hBM-MSCs. Osteoblast formation was stimulated via Wnt/BMP and adipogenesis was inhibited via the PPARγ pathway. This study provided necessary data for further studies to utilize the therapeutic potential of M3G against osteoporosis via regulation of bone marrow stromal cell differentiation.

Second-Line Bismuth-Containing Quadruple Therapy for Helicobacterpylori Infection: A 12-Year Study of Annual Eradication Rates.

BACKGROUND: Bismuth-containing quadruple therapy (BQT) consisting of a proton-pump inhibitor (PPI), bismuth, metronidazole and tetracycline is recommended as a second-line treatment for Helicobacter pylori (H. pylori) infection when PPI-based standard triple therapy (STT) consisting of a PPI, amoxicillin and clarithromycin is unsuccessful. The purpose of this study was to analyze the long-term results of BQT as a second-line therapy to determine its effectiveness. METHODS: This study included 643 subjects who failed first-line STT and received 7 or 10-14 days of BQT as a second-line therapy. We retrospectively analyzed the annual H. pylori eradication rates, demographic factors and adverse events. RESULTS: The overall eradication rates by intention-to-treat (ITT) and per-protocol (PP) analyses were 80.7% (519/643) and 93.3% (519/556), respectively. By PP analysis, the eradication rates for 2008-2011, 2012-2015, and 2016-2019 were 93.3%, 91.0%, and 96.4%, respectively (p = 0.145). There were no significant differences between the 7-day group and the 10-14-day group in both the ITT (79.7% vs. 86.0%, p = 0.148) and the PP analyses (92.7% vs. 96.6%, p = 0.187). A multivariate analysis showed that current smoking was associated with eradication failure. Eighty-nine subjects (16.0%) suffered adverse events, mainly gastrointestinal symptoms, but only six cases were severe. CONCLUSIONS: BQT as a second-line therapy is an effective treatment for H. pylori. Treatment for 10-14 days showed a higher eradication rate compared with a 7-day regimen, but not significantly.

Reflux esophagitis in patients with chronic obstructive pulmonary disease.

ABSTRACT: The relationship between chronic obstructive pulmonary disease (COPD) and reflux esophagitis (RE) was controversial. We investigated the factors influencing RE development in patients with COPD and evaluated the association between RE and AECOPD.Patients with COPD who underwent esophagogastroduodenoscopy from January 2003 to December 2013 in St. Paul's Hospital, the Catholic University of Korea (Seoul, Korea) were enrolled retrospectively. The grade of RE was based on the Los Angeles classification and minimal change esophagitis. Body mass index, smoking history, medical history, AECOPD, pulmonary function test data, endoscopic findings, and comorbidities were reviewed.Of a total of 218 patients with COPD, 111 (50.9%) were diagnosed with RE. None of age, sex, smoking history, or the severity of airflow limitation was associated with RE. AECOPD was not related to either the presence or severity of RE. There was no significant correlation between RE grade by Los Angeles classification and severity of airflow limitation (P = .625). Those who had RE used theophylline (P = .003) and long-acting muscarinic antagonists (P = .026) significantly more often than did controls. The use of theophylline (OR 2.05; 95% CI, 1.16-3.65, P = .014) was associated with an increased incidence of RE.The use of theophylline might increase the risk of RE in COPD patients. RE may not be associated with airflow limitation or AECOPD.

Incomplete Removal of an Intrauterine Device Perforating the Sigmoid Colon.

Intrauterine devices (IUDs) are widely used for contraception in South Korea. However, several complications of IUDs have been reported, including inflammation, obstruction, perforation, and fistula. IUD perforation is the rarest of these complications but is also severe. Migrated IUDs can be retrieved through endoscopy, laparoscopy, or laparotomy. Presented below is an atypical case of an IUD perforating the sigmoid colon, which could not be removed endoscopically, and was subsequently incompletely removed through laparoscopic surgery. The present case underlines the importance of appropriate diagnosis and treatment approach in the management of IUD perforation.

Periodic Fluctuations in the Incidence of Gastrointestinal Cancer.

PURPOSE: Native stem cells can be periodically replaced during short and long epigenetic intervals. Cancer-prone new stem cells might bring about periodic (non-stochastic) carcinogenic events rather than stochastic events. We investigated the epigenetic non-stochastic carcinogenesis by analyzing regular fluctuations in lifelong cancer incidence. MATERIALS AND METHODS: Korean National Cancer Screening Program data were collected between 2009 and 2016. Non-linear and log-linear regression models were applied to comparatively evaluate non-stochastic and stochastic increases in cancer incidence. Prediction performances of regression models were measured by calculating the coefficient of determination, R2. RESULTS: The incidence of gastric and colorectal cancers fluctuated regularly during both short (8 years) and long (20 years) intervals in the non-linear regression model and increased stochastically in the log-linear regression model. In comparison between the 20-year interval fluctuation model and the stochastic model, R2 values were higher in the 20-year interval fluctuation model of men with gastric cancer (0.975 vs. 0.956), and in the stochastic model of men with colorectal cancer (0.862 vs. 0.877) and women with gastric cancer (0.837 vs. 0.890) and colorectal cancer (0.773 vs. 0.809). Men with gastric cancer showed a high R2 value (0.973) in the 8-year interval fluctuation model as well. CONCLUSION: Lifelong incidence of gastrointestinal cancer tended to fluctuate during short and long intervals, especially in men with gastric cancer, suggesting the influence of an epigenetic schedule.

Ligustrum japonicum Thunb. Fruits Exert Antiosteoporotic Properties in Bone Marrow-Derived Mesenchymal Stromal Cells via Regulation of Adipocyte and Osteoblast Differentiation.

Ligustrum japonicum fruits have been used as a part of traditional medicinal practices and supplements in Korea and Japan. It has been reported to possess various bioactivities, but its antiosteoporotic potential and active substances have not been reported yet. The present study followed an ALP activity and lipid accumulation-guided screening of L. japonicum fruits for antiosteoporotic compounds and isolated salidroside as an active compound. Antiosteoporotic effects of L. japonicum fruits and salidroside were examined in mesenchymal stromal cells by their ability to enhance osteoblast formation by increased ALP activity and osteogenic marker gene expression while suppressing adipogenesis by inhibition of lipid accumulation and adipocyte marker gene expressions. Results showed that salidroside was able to enhance osteoblast differentiation via Wnt/BMP signaling pathway overactivation and suppress the PPARγ-mediated adipocyte differentiation, both through the MAPK pathway. In conclusion, L. japonicum fruits were suggested to possess antiosteoporotic activities and to be a source of antiosteoporotic substances such as salidroside.

Effect and Comparison of Luteolin and Its Derivative Sodium Luteolin-4'-sulfonate on Adipogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells through AMPK-Mediated PPARγ Signaling.

Luteolin is a common phytochemical from the flavonoid family with a flavone structure. Studies reported several bioactivities for luteolin and similar flavones. Attenuating the increased adipogenesis of bone marrow cells (hBM-MSCs) has been regarded as a therapeutic target against osteoporotic bone disorders. In the present study, the potential roles of luteolin and its sulfonic acid derivative luteolin-OSO3Na in regulating adipogenic differentiation of hBM-MSCs were investigated. Adipo-induced cells were treated with or without compounds, and their effect on adipogenesis was evaluated by adipogenic marker levels such as lipid accumulation and PPARγ pathway activation. Luteolin hindered the adipogenic lipid accumulation in adipo-induced hBM-MSCs. Immunoblotting and reverse transcription-polymerase chain reaction analysis results indicated that luteolin downregulated PPARγ and downstream factors of C/EBPα and SREBP1c expression which resulted in inhibition of adipogenesis. Luteolin-OSO3Na showed similar effects; however, it was significantly less effective compared to luteolin. Investigating p38, JNK, and ERK MAPKs and AMPK activation indicated that luteolin suppressed the MAPK phosphorylation while stimulating AMPK phosphorylation. On the other hand, luteolin-OSO3Na was not able to notably affect the MAPK and AMPK activation. In conclusion, this study suggested that luteolin inhibited adipogenic differentiation of hBM-MSCs via upregulating AMPK activation. Replacing its 4'-hydroxyl group with sulfonic acid sodium salt diminished its antiadipogenic effect indicating its role in regulating AMPK activation. The general significance is that luteolin is a common phytochemical with various health-beneficial effects. The current study suggested that luteolin may serve as a lead compound for developing antiosteoporotic substances with antiadipogenic properties.

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.

3,5-dicaffeoyl­epi-quinic acid from Atriplex gmelinii enhances the osteoblast differentiation of bone marrow-derived human mesenchymal stromal cells via WnT/BMP signaling and suppresses adipocyte differentiation via AMPK activation.

BACKGROUND: Impaired bone formation is one of the reasons behind osteoporosis. Alterations in the patterns of mesenchymal stromal cell differentiation towards adipocytes instead of osteoblasts contribute to osteoporosis progression. Natural anti-osteoporotic agents are effective and safe alternatives for osteoporosis treatment. PURPOSE: In this context, 3,5-dicaffeoyl­epi-quinic acid (DCEQA) which is a derivative of chlorogenic acid with reported bioactivities was studied for its osteogenic differentiation enhancing potential in vitro. METHODS: Anti-osteoporotic effects of DCEQA were investigated in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) which were induced to differentiate into osteoblasts or adipocytes with or without DCEQA treatment. Changes in the osteogenic and adipogenic markers such as ALP activity and lipid accumulation, respectively, were observed along with differentiation-specific activation of mitogen activated protein kinase (MAPK) pathways. RESULTS: At 10 µM concentration, DCEQA increased the proliferation of bone marrow-derived human mesenchymal stromal cells (hBM-MSCs) during osteoblast differentiation. The expression of osteogenic markers ALP, osteocalcin, Runx2, BMP2 and Wnt 10a was upregulated by DCEQA treatment. The ALP activity and extracellular mineralization were also increased. DCEQA elevated the phosphorylation levels of p38 and JNK MAPKs as well as the activation of ß-catenin and Smad1/5. DCEQA suppressed the lipid accumulation and downregulated expression of adipogenic markers PPARγ, C/EBPα and SREBP1c in adipo-induced hBM-MSCs. DCEQA also decreased the phosphorylation of p38 and ERK MAPKs and stimulated the activation of AMPK in hBM-MSC adipocytes. CONCLUSION: DCEQA was suggested to enhance osteoblast differentiation via stimulating Wnt/BMP signaling. The adipocyte differentiation inhibitory effect of DCEQA was suggested to arise from its ability to increase AMPK phosphorylation. Overall, DCEQA was shown to possess osteogenesis enhancing and adipogenesis inhibitory properties which might facilitate its use against osteoporotic conditions.

6-Acetyl-2,2-Dimethylchroman-4-One Isolated from Artemisia princeps Suppresses Adipogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stromal Cells via Activation of AMPK.

Obesity is a world-wide health concern with increasing mortality and morbidity rates. Development of novel therapeutic agents for obesity from phytochemicals may lead to the effective prevention and control of obesity and obesity-related complications. 6-acetyl-2,2-dimethylchroman-4-one (1) was isolated from a dietary plant, Artemisia princeps. The antiobesity effect of compound 1 was determined in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) induced to differentiate into adipocytes. Treatment with compound 1 resulted in decreased lipid accumulation and expression of key adipogenic markers, proliferator-activated receptor-γ, CCAAT/enhancer-binding protein-α, and sterol regulatory element-binding transcription factor 1. It was also shown that compound 1 downregulated the adipogenesis-induced p38 and JNK MAPK activation, while upregulating adipogenesis inhibitory ß-catenin-dependent Wnt10b pathway. Compound 1 was also able to stimulate adenosine monophosphate-activated protein kinase phosphorylation, which was suggested to be the underlying mechanism that resulted in inhibition of adipogenesis in hBM-MSCs. In conclusion, 6-acetyl-2,2-dimethylchroman-4-one was identified as a bioactive constituent of A. princeps that exerts antiobesity properties via suppressing adipocyte formation.

3,5-Dicaffeoyl-epi-quinic acid inhibits the PMA-stimulated activation and expression of MMP-9 but not MMP-2 via downregulation of MAPK pathway.

Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are very important gelatinases that are overexpressed during tumor metastasis. Up to date, several MMP inhibitors have been developed from natural sources as well as organic synthesis. In the present study, the MMP-2 and MMP-9 inhibitory effects of 3,5-dicaffeoyl-epi-quinic acid (DCEQA), a caffeoylquinic acid derivative isolated from Atriplex gmelinii, were investigated in phorbol 12-myristate 13-acetate (PMA)-treated human HT1080 fibrosarcoma cells. Gelatin zymography and immunoblotting showed that DCEQA significantly inhibited the PMA-induced activation and expression of MMP-9 but was not able to show any effect against MMP-2. DCEQA treatment was also shown to upregulate the protein expression of tissue inhibitor of MMP-1 along with decreased MMP-9 protein levels. Moreover, the effect of DCEQA on phosphorylation of mitogen activated protein kinases (MAPKs), analyzed by immunoblotting, indicated the DCEQA inhibited the MMP-9 by downregulation of MAPK pathway. Collectively, current results suggested that DCEQA is a potent MMP-9 inhibitor and can be utilized as lead compound for treatment of pathological complications involving enhanced MMP activity such as cancer metastasis.