Gastric and colorectal cancer incidence attributable to dietary factors in Korea.

Background: Dietary factors play a role in the etiology of gastrointestinal cancer. We aimed to estimate the burden of gastric and colorectal cancer that can be attributable to dietary factors in adults aged 20 years and older in Korea in 2018. Methods: Dietary intakes in 2000 were estimated using data from the 2001, 2005, and 2007-2018 Korea National Health and Nutrition Examination Survey (KNHANES). For counterfactual scenarios, the optimal level of intake suggested by the Global Burden of Disease (GBD) study was used if it was available. Otherwise, the average intake values of reference groups among published studies globally were used. Relative risks (RRs) were pooled through dose-response meta-analyses of Korean studies. Results: In Korea in 2018, an estimated 18.6% of gastric cancer cases and 34.9% of colorectal cancer cases were attributed to the combined effect of evaluated dietary factors. High intake of salted vegetables accounted for 16.0% of gastric cancer cases, followed by salted fish at 2.4%. Low intakes of whole grains (16.6%) and milk (13.7%) were leading contributors to colorectal cancer cases, followed by high intakes of processed meat (3.1%) and red meat (5.9%), and a low intake of dietary fiber (0.5%). Conclusions: These results suggest that a considerable proportion of gastric and colorectal cancer incidence might be preventable by healthy dietary habits in Korea. However, further research is needed to confirm the associations between dietary factors and gastric and colorectal cancers in Korea and to formulate and apply effective cancer prevention strategies to Koreans.

The Efficacy and Tolerability of Radiosurgery in Treating Benign Meningiomas: A Dose Comparison Study from a Single-Center Analysis.

This retrospective study aimed to evaluate the impact of radiation dose on the outcomes of stereotactic radiosurgery (SRS) for benign meningiomas and determine an optimal dosing strategy for balancing tumor control and treatment-related toxicity. Clinical data of 147 patients with 164 lesions treated between 2014 and 2022 were reviewed. Primary outcomes included progression-free survival (PFS), local control rate (LCR), and radiation-induced toxicity, with secondary outcomes focusing on LCR and radiation-induced peritumoral edema (PTE) in two dose groups (≥14 Gy and <14 Gy). The results revealed a median follow-up duration of 47 months, with 1-year, 2-year, and 5-year PFS rates of 99.3%, 96.7%, and 93.8%, respectively, and an overall LCR of 95.1%. Radiation-induced toxicity was observed in 24.5% of patients, primarily presenting mild symptoms. Notably, no significant difference in LCR was found between the two dose groups (p = 0.628), while Group 2 (<14 Gy) exhibited significantly lower PTE (p = 0.039). This study concludes that SRS with a radiation dose < 14 Gy demonstrates comparable tumor control with reduced toxicity, advocating consideration of such dosing to achieve a balance between therapeutic efficacy and safety.

Pediatric Eosinophilic Granuloma Associated With Delayed Epidural Hematoma Following on Seizure: A Case Report.

Eosinophilic granuloma (EG), a subtype of Langerhans cell histiocytosis (LCH), the monostotic form, is a rare condition characterized by a solitary bone lesion. It is even more unusual for this condition to be accompanied by an epidural hematoma (EDH). This case is unique in that it is the first to involve delayed EDH following a seizure. We describe a remarkable example of EG accompanied by an EDH and consider the rarity of this comorbidity. A 32-month-old boy developed a rapidly growing skull mass following a minor head injury. During surgical preparation for a biopsy, the patient experienced a single convulsion. Imaging following the seizure revealed an EDH in the vicinity of the mass. The mass was excised and confirmed to be an EG, but with positive margins. The patient underwent chemotherapy after systemic skeletal evaluation, in accordance with the LCH III protocol established by the Histiocytosis Society. EG is a rare neoplasm that typically presents as a painless growth on the skull that gradually enlarges over time. The correlation between EG and EDH is exceedingly uncommon, with only a few documented cases. This case study underscores the significance of considering EG in the differential diagnosis of an expanding cranium mass, even when associated with EDH. Prompt diagnosis and treatment can prevent serious complications and improve patient outcomes.

Adherence to the American Cancer Society guidelines on nutrition and physical activity for cancer survivors and biomarkers of inflammation among breast cancer survivors.

OBJECTIVES: This study investigated whether adherence to the overall lifestyle recommendations in the American Cancer Society (ACS) guidelines on nutrition and physical activity for cancer survivors was associated with inflammation in breast cancer survivors. METHODS: The study included 409 women who had undergone breast cancer surgery at least 1 year before enrollment. A generalized linear model was used to estimate the least square means and 95% confidence intervals of plasma levels of inflammatory markers according to lifestyle factors defined in terms of adherence to the ACS guidelines. RESULTS: Higher overall adherence scores were associated with lower levels of high-sensitivity C-reactive protein (hs-CRP) (p for trend=0.015) and higher levels of adiponectin (p for trend=0.009). Similar significant associations of hs-CRP (p for trend= 0.004) and adiponectin (p for trend=0.010) levels were observed with the score for the body mass index (BMI) component of the adherence score. A higher diet component score was associated with a higher adiponectin level (p for trend=0.020), but there was no significant association for the physical activity component score. CONCLUSIONS: The present study's findings suggest that maintaining a healthy lifestyle according to the ACS guidelines was associated with beneficial effects on inflammatory marker levels, especially hs-CRP and adiponectin, among breast cancer survivors. Among the 3 components of lifestyle guidelines, the BMI component exhibited the most similar tendency to the overall adherence score in relation to inflammatory indicators. Further prospective and intervention studies are needed to investigate longitudinal associations between lifestyle factors and inflammatory markers among breast cancer survivors.

Associations of body mass index and weight change with circulating levels of high-sensitivity C-reactive protein, proinflammatory cytokines, and adiponectin among breast cancer survivors.

AIM: This study examined the associations of body mass index (BMI) and weight change with inflammatory markers among breast cancer survivors in Korea. METHODS: A total of 495 women were included who had been diagnosed with primary breast cancer and survived for at least 6 months since the surgery. Information on the body weight and height of the participants was collected both at the study enrollment and diagnosis. The plasma levels of inflammatory markers were measured, including high-sensitivity C-reactive protein, interleukin (IL)-6, IL-8, tumor necrosis factor-α, and adiponectin. A summary z-score was calculated by summing up the z-scores of each biomarker. The least-square means and 95% confidence intervals (CIs) were calculated using a generalized linear model and odds ratios (ORs) and 95% CIs for the elevated levels of inflammatory markers with a multivariate logistic regression model. RESULTS: Participants with a BMI ≥27.5 kg/m2 at the study enrollment and at diagnosis were significantly associated with elevated summary z-scores compared to those with a BMI < 23 kg/m2 ; the ORs (95% CIs) were 5.42 (2.15-13.71) for current BMI and 3.66 (1.68-7.98) for BMI at diagnosis, respectively. Additionally, a weight loss > 5% since diagnosis was associated with a lower prevalence of high summary z-scores; the OR (95% CI) was .20 (.08-.52) compared to a stable weight. CONCLUSIONS: A high BMI at diagnosis and current BMI with a greater degree were associated with unfavorable levels of inflammatory markers among breast cancer survivors. Additionally, weight loss since diagnosis was inversely associated with these markers.

Lower Dietary Calcium Intake is Associated with a Higher Risk of Mortality in Korean Adults.

BACKGROUND: Calcium, one of the most abundant minerals in the human body, has a pivotal role in human physiology. However, only a few studies have examined the association of dietary calcium intake with mortality in a population with low calcium intake. OBJECTIVE: The aim of this study was to examine the association of dietary calcium intake with risk of all-cause and cause-specific mortality among Korean adults with low calcium intake. DESIGN: This study was a prospective cohort study. PARTICIPANTS/SETTING: The analysis was conducted using data from 44,327 eligible Korean adults aged 19 years and older who participated in the Korea National Health and Nutrition Examination Survey 2007-2015. Dietary calcium intake was assessed using 1-day 24-hour recall data. MAIN OUTCOME MEASURES: The main outcomes of this study were mortality from all causes, cancer, cardiovascular disease, respiratory disease, and all other causes combined. The outcome was ascertained through linkage to the death registry compiled by Statistics Korea with the use of the resident registration number. STATISTICAL ANALYSES PERFORMED: Weighted Cox proportional hazard models were used to estimate the hazard ratios and 95% CIs of the all-cause and cause-specific mortality according to dietary calcium intake. RESULTS: During a mean follow-up of 7.28 person-years, 1,889 deaths were ascertained. After multivariable adjustment, the hazard ratios for all-cause mortality for the second quintile to the highest quintile of dietary calcium intake, respectively, compared with the first quintile were 0.86 (95% CI 0.73 to 1.00), 0.82 (95% CI 0.69 to 0.98), 0.85 (95% CI 0.69 to 1.03), and 0.78 (95% CI 0.64 to 0.96) (P for trend from the lowest to the highest quintile = .04). There were no statistically significant associations between dietary calcium intake and risk of mortality from cancer, cardiovascular, or respiratory disease. CONCLUSIONS: In this large prospective cohort study of Korean adults, lower dietary calcium intake was associated with a higher risk of all-cause mortality.

Association of coffee drinking with all-cause and cause-specific mortality in over 190,000 individuals: data from two prospective studies.

We examined the association of coffee drinking with all-cause and cause-specific mortality in a pooled analysis of two Korean prospective cohort studies: The Korea National Health and Nutrition Examination Survey and the Korean Genome and Epidemiology Study. We included 192,222 participants, and a total of 6057 deaths were documented. Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), and the HRs were combined using a random-effects model. Coffee drinking was associated with a lower risk of all-cause mortality [HR (95% CI) = 0.84 (0.77-0.92), for ≥3 cups/day of coffee drinking versus non-drinkers; p for trend = 0.004]. We observed the potential benefit of coffee drinking for mortality due to cardiovascular disease, respiratory disease, and diabetes, but not for cancer mortality. Overall, we found that moderate coffee drinking was associated with a lower risk of death in population-based cohort analysis of Korean adults.

Regulation of Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Activity of Advanced Cooling Composition (ACC) in UVB-Irradiated Human HaCaT Keratinocytes.

We recently demonstrated that advanced cooling composition (ACC) has effective ingredients that exhibit anti-inflammatory effects in RAW 264.7 cells stimulated with lipopolysaccharide (LPS) and exhibit strong antimicrobial effects on Pseudomonas aeruginosa, Staphylococcus aureus, MRSA (methicillin-resistant Staphylococcus aureus), Candida albicans, and Streptococcus mutans. To further investigate whether ACC has beneficial effects in ultraviolet B (UVB)-irradiated human keratinocytes (HaCaT cells), HaCaT cells were pretreated with ACC prior to UVB irradiation. Our data showed that ACC, which is effective at 100 µg/mL, is nontoxic and has an antioxidative effect against UVB-induced intracellular reactive oxygen species (ROS) in HaCaT cells. In addition, ACC exerts cytoprotective effects against UVB-induced cytotoxicity in HaCaT cells by inhibiting abnormal inflammation and apoptosis through the regulation of mitogen-activated protein kinase (MAPK) signals, such as jun-amino-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). Therefore, these results indicate that ACC is a potentially beneficial raw material that possesses antioxidative, anti-inflammatory, and antiapoptotic effects against UVB-induced keratinocytes and may have applications in skin health.

Pickled Vegetable and Salted Fish Intake and the Risk of Gastric Cancer: Two Prospective Cohort Studies and a Meta-Analysis.

An increased risk of gastric cancer for pickled vegetable and salted fish intake has been suggested, yet the lack of a dose-response association warrants a quantitative analysis. We conducted a meta-analysis, combining results from our analysis of two large Korean cohort studies and those from previous prospective cohort studies. We investigated the association of pickled vegetable and salted fish intake with gastric cancer in the Korean Genome Epidemiology Study and the Korean Multi-center Cancer Cohort Study using Cox proportional hazard models. We then searched for observational studies published until November 2019 and conducted both dose-response and categorical meta-analyses. The pooled relative risk (RR) of gastric cancer incidence was 1.15 (95% Confidence Interval (CI), 1.07-1.23) for 40 g/day increment in pickled vegetable intake in a dose-response manner (P for nonlinearity = 0.11). As for salted fish intake, the pooled risk of gastric cancer incidence was 1.17 (95% CI, 0.99-1.38) times higher, comparing the highest to the lowest intake. Our findings supported the evidence that high intake of pickled vegetable and salted fish is associated with elevated risk of gastric cancer incidence.

Vasodilator-stimulated phosphoprotein-phosphorylation by ginsenoside Ro inhibits fibrinogen binding to αIIb/ß3 in thrombin-induced human platelets.

BACKGROUND: Glycoprotein IIb/IIIa (αIIb/ß3) is involved in platelet adhesion, and triggers a series of intracellular signaling cascades, leading to platelet shape change, granule secretion, and clot retraction. In this study, we evaluated the effect of ginsenoside Ro (G-Ro) on the binding of fibrinogen to αIIb/ß3. METHODS: We investigated the effect of G-Ro on regulation of signaling molecules affecting the binding of fibrinogen to αIIb/ß3, and its final reaction, clot retraction. RESULTS: We found that G-Ro dose-dependently inhibited thrombin-induced platelet aggregation and attenuated the binding of fibrinogen to αIIb/ß3 by phosphorylating cyclic adenosine monophosphate (cAMP)-dependently vasodilator-stimulated phosphoprotein (VASP; Ser157). In addition, G-Ro strongly abrogated the clot retraction reflecting the intensification of thrombus. CONCLUSION: We demonstrate that G-Ro is a beneficial novel compound inhibiting αIIb/ß3-mediated fibrinogen binding, and may prevent platelet aggregation-mediated thrombotic disease.

Total saponin from Korean Red Ginseng inhibits binding of adhesive proteins to glycoprotein IIb/IIIa via phosphorylation of VASP (Ser(157)) and dephosphorylation of PI3K and Akt.

BACKGROUND: Binding of adhesive proteins (i.e., fibrinogen, fibronectin, vitronectin) to platelet integrin glycoprotein IIb/IIIa (αIIb/ß3) by various agonists (thrombin, collagen, adenosine diphosphate) involve in strength of thrombus. This study was carried out to evaluate the antiplatelet effect of total saponin from Korean Red Ginseng (KRG-TS) by investigating whether KRG-TS inhibits thrombin-induced binding of fibrinogen and fibronectin to αIIb/ß3. METHODS: We investigated the effect of KRG-TS on phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and dephosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt, affecting binding of fibrinogen and fibronectin to αIIb/ß3, and clot retraction. RESULTS: KRG-TS had an antiplatelet effect by inhibiting the binding of fibrinogen and fibronectin to αIIb/ß3 via phosphorylation of VASP (Ser(157)), and dephosphorylation of PI3K and Akt on thrombin-induced platelet aggregation. Moreover, A-kinase inhibitor Rp-8-Br-cyclic adenosine monophosphates (cAMPs) reduced KRG-TS-increased VASP (Ser(157)) phosphorylation, and increased KRG-TS-inhibited fibrinogen-, and fibronectin-binding to αIIb/ß3. These findings indicate that KRG-TS interferes with the binding of fibrinogen and fibronectin to αIIb/ß3 via cAMP-dependent phosphorylation of VASP (Ser(157)). In addition, KRG-TS decreased the rate of clot retraction, reflecting inhibition of αIIb/ß3 activation. In this study, we clarified ginsenoside Ro (G-Ro) in KRG-TS inhibited thrombin-induced platelet aggregation via both inhibition of [Ca(2+)]i mobilization and increase of cAMP production. CONCLUSION: These results strongly indicate that KRG-TS is a beneficial herbal substance inhibiting fibrinogen-, and fibronectin-binding to αIIb/ß3, and clot retraction, and may prevent platelet αIIb/ß3-mediated thrombotic disease. In addition, we demonstrate that G-Ro is a novel compound with antiplatelet characteristics of KRG-TS.

Onion (Allium cepa L.) peel extract has anti-platelet effects in rat platelets.

The effects of onion peel extract (OPE) in collagen (5 µg/mL)-stimulated washed rat platelet aggregation were investigated. OPE inhibited platelet aggregation via inhibition of aggregation-inducing molecules, intracellular Ca(2+) and thromboxane A2 (TXA2) by blocking cyclooxygenase-1 (COX-1) and TXA2 synthase (TXAS) activities in a dose-dependent manner. In addition, OPE elevated the formation of cyclic adenosine monophosphate (cAMP), aggregation-inhibiting molecule, but not cyclic guanosine monophosphate (cGMP). High performance liquid chromatography (HPLC) analysis of OPE revealed that OPE contains quercetin, one of the major flavonoids, which has anti-platelet effect. In conclusion, we suggest that OPE is an effective inhibitor of collagen-stimulated platelet aggregation in vitro. Therefore, it can be a promising and safe strategy for anti-cardiovascular diseases.

Inhibitory effects of total saponin from Korean Red Ginseng on [Ca(2+)]i mobilization through phosphorylation of cyclic adenosine monophosphate-dependent protein kinase catalytic subunit and inositol 1,4,5-trisphosphate receptor type I in human platelets.

BACKGROUND: Intracellular Ca(2+)([Ca(2+)]i) is a platelet aggregation-inducing molecule. Therefore, understanding the inhibitory mechanism of [Ca(2+)]i mobilization is very important to evaluate the antiplatelet effect of a substance. This study was carried out to understand the Ca(2+)-antagonistic effect of total saponin from Korean Red Ginseng (KRG-TS). METHODS: We investigated the Ca(2+)-antagonistic effect of KRG-TS on cyclic nucleotides-associated phosphorylation of inositol 1,4,5-trisphosphate receptor type I (IP3RI) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) in thrombin (0.05 U/mL)-stimulated human platelet aggregation. RESULTS: The inhibition of [Ca(2+)]i mobilization by KRG-TS was increased by a PKA inhibitor (Rp-8-Br-cAMPS), which was more stronger than the inhibition by a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) inhibitor (Rp-8-Br-cGMPS). In addition, Rp-8-Br-cAMPS inhibited phosphorylation of PKA catalytic subunit (PKAc) (Thr(197)) by KRG-TS. The phosphorylation of IP3RI (Ser(1756)) by KRG-TS was very strongly inhibited by Rp-8-Br-cAMPS compared with that by Rp-8-Br-cGMPS. These results suggest that the inhibitory effect of [Ca(2+)]i mobilization by KRG-TS is more strongly dependent on a cAMP/PKA pathway than a cGMP/PKG pathway. KRG-TS also inhibited the release of adenosine triphosphate and serotonin. In addition, only G-Rg3 of protopanaxadiol in KRG-TS inhibited thrombin-induced platelet aggregation. CONCLUSION: These results strongly indicate that KRG-TS is a potent beneficial compound that inhibits [Ca(2+)]i mobilization in thrombin-platelet interactions, which may result in the prevention of platelet aggregation-mediated thrombotic disease.

Antiplatelet effects of caffeic acid due to Ca(2＋) mobilizationinhibition via cAMP-dependent inositol-1, 4, 5-trisphosphate receptor phosphorylation.

AIM: In this study, we investigated the effects of caffeic acid (CAFA), a phenolic acid, on Ca(2＋)-antagonistic cyclic nucleotides associated with the phosphorylation of inositol 1,4,5-trisphosphate receptor (IP3R) and vasodilator-stimulated phosphoprotein (VASP) and the thromboxane A2 (TXA2)-associated microsomal cyclooxygenase-1 (COX-1) activity in collagen (10 µg/mL)-stimulated platelet aggregation. METHODS: Washed platelets (10(8)/mL) obtained from Sprague-Dawley rats (6-7 weeks old, male) were preincubated for 3 minutes at 37℃ in the presence of 2 mM exogenous CaCl2 with or without CAFA or other materials, stimulated with collagen (10 µg/mL) for 5 minutes, then used to determine the levels of intracellular cytosolic Ca(2＋) ([Ca(2＋)]i), TXA2, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), COX-1 activity, VASP and IP3R phosphorylation. RESULTS: CAFA dose-dependently inhibited collagen-induced platelet aggregation and suppressed the production of TXA2, an aggregation-inducing autacoid associated with the strong inhibition of COX-1 in platelet microsomes exhibiting cytochrome C reductase activity. CAFA dose-dependently inhibited collagen-elevated [Ca(2＋)]i mobilization, which was increased by a cAMP-dependent protein kinase (A-kinase) inhibitor, Rp-8-Br-cAMPS, but not a cGMP-dependent protein kinase (G-kinase) inhibitor, Rp-8-Br-cGMPS. In addition, CAFA significantly increased the formation of cAMP and cGMP, intracellular Ca(2＋)-antagonists that function as aggregation-inhibiting molecules. CAFA increased IP3R (320 kDa) phosphorylation, indicating the inhibition of IP3-mediated Ca(2＋) release from internal stores (i.e. the dense tubular system) via the IP3R on collagen-activated platelets. Furthermore, CAFA-induced IP3R phosphorylation was strongly inhibited by an A-kinase inhibitor, Rp-8-Br-cAMPS, but only mildly inhibited by a G-kinase inhibitor, Rp-8-Br-cGMPS. These results suggest that the inhibition of [Ca(2＋)]i mobilization by CAFA is resulted from the cAMP/A-kinase-dependent phosphorylation of IP3R. CAFA elevated the phosphorylation of VASP-Ser(157), an A-kinase substrate, but not the phosphorylation of VASP-Ser(239), a G-kinase substrate. We demonstrate that CAFA increases cAMP and subsequently phosphorylates both IP3R and VASP-Ser(157) through A-kinase activation to inhibit [Ca(2＋)]i mobilization and TXA2 production via the inhibition of the COX-1 activity. CONCLUSIONS: These results strongly indicate that CAFA is a potent beneficial compound that elevates the level of cAMP-dependent protein phosphorylation in collagen-platelet interactions, which may result in the prevention of platelet aggregation-mediated thrombotic diseases.

Inhibitory effects of total saponin from Korean red ginseng via vasodilator-stimulated phosphoprotein-Ser(157) phosphorylation on thrombin-induced platelet aggregation.

In this study, we have investigated the effects of total saponin from Korean red ginseng (TSKRG) on thrombin-induced platelet aggregation. TSKRG dose-dependently inhibited thrombin-induced platelet aggregation with IC50 value of about 81.1 µg/mL. In addition, TSKRG dose-dependently decreased thrombin-elevated the level of cytosolic-free Ca(2+) ([Ca(2+)]i), one of aggregation-inducing molecules. Of two Ca(2+)-antagonistic cyclic nucleotides as aggregation-inhibiting molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), TSKRG significantly dose-dependently elevated intracellular level of cAMP, but not cGMP. In addition, TSKRG dose-dependently inhibited thrombin-elevated adenosine triphosphate (ATP) release from platelets. These results suggest that the suppression of [Ca(2+)]i elevation, and of ATP release by TSKRG are associated with upregulation of cAMP. TSKRG elevated the phosphorylation of vasodilator-stimulated phosphoprotein (VASP)-Ser(157), a cAMP-dependent protein kinase (A-kinase) substrate, but not the phosphorylation of VASP-Ser(239), a cGMPdependent protein kinase substrate, in thrombin-activated platelets. We demonstrate that TSKRG involves in increase of cAMP level and subsequent elevation of VASP-Ser(157) phosphorylation through A-kinase activation to inhibit [Ca(2+)]i mobilization and ATP release in thrombin-induced platelet aggregation. These results strongly indicate that TSKRG is a beneficial herbal substance elevating cAMP level in thrombin-platelet interaction, which may result in preventing of platelet aggregation-mediated thrombotic diseases.

Urosodeoxycholic Acid Therapy in a Child with Trimethoprim-Sulfamethoxazole-induced Vanishing Bile Duct Syndrome.

We present a case of a 7-year-old boy who had cholestasis after trimethoprim-sulfamethoxazole combination therapy. Liver biopsy was performed 36 days after the onset of jaundice because of no evidence of improving cholestasis. Liver histology revealed portal inflammation, bile plug, and biliary stasis around the central vein with the loss of the interlobular bile ducts. Immunohistochemical stains for cytokeratin 7 and 19 were negative. These findings were consistent with those of vanishing bile duct syndrome (VBDS). Chlestasis was progressively improved with dose increment of urosodeoxycholic acid from conventional to high dose. This is the first case report of trimethoprime-sulfamethoxazole associated VBDS in Korean children. The case suggests that differential diagnosis of VBDS should be considered in case of progressive cholestatic hepatitis with elevation of alkaline phosphatase and gamma-glutamyl transpeptidase after or during taking medicine to treat nonhepatobiliary diseases illness.

Inhibition of platelet aggregation by chlorogenic acid via cAMP and cGMP-dependent manner.

In this study, we investigated the effect of chlorogenic acid, a phenolic acid, on collagen (10 µg/ml)-stimulated platelet aggregation. Chlorogenic acid dose-dependently inhibited collagen-induced platelet aggregation, and suppressed the production of thromboxane A2 (TXA2), an intracellular Ca-agonist as an aggregation-inducing autacoidal molecule, which was associated with the strong inhibition of cyclooxygenase (COX)-1 in platelet microsomes having cytochrome c reductase activity. In addition, chlorogenic acid increased significantly the formation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), intracellular Ca-antagonists as aggregation-inhibiting molecules. These results suggest that chlorogenic acid has antiplatelet activity through the reduction of TXA2 and the increase of cAMP and cGMP levels. Therefore, our data demonstrate that chlorogenic acid is a potent inhibitor of collagen-stimulated platelet aggregation, and may be a crucial tool for a negative regulator during platelet activation in thrombotic diseases.

Epigallocatechin-3-gallate has an anti-platelet effect in a cyclic AMP-dependent manner.

AIM: In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on cyclic nucleotide production and vasodilator-stimulated phosphoprotein (VASP) phosphorylation in collagen (10 µg/mL)-stimulated platelet aggregation. METHODS: Washed platelets (10(8)/mL) from Sprague-Dawley rats (6-7 weeks old, male) were preincubated for 3 min at 37°C in the presence of 2 mM exogenous CaCl(2) with or without EGCG or other materials, stimulated with collagen (10 µg/mL) for 5 min, and then used for the determination of intracellular cytosolic Ca(2+) ([Ca(2+)](i)), thromboxane A(2) (TXA(2)), adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and VASP phosphorylation. RESULTS: EGCG dose-dependently inhibited collagen-induced platelet aggregation by inhibiting both [Ca(2+)](i) mobilization and TXA(2) production. Of two aggregation-inhibiting molecules, cAMP and cGMP, EGCG significantly increased intracellular levels of cAMP, but not cGMP. EGCG-elevated cAMP level was decreased by SQ22536, an adenylate cyclase inhibitor, but not by etazolate, a cAMPspecific phosphodiesterase inhibitor. In addition, EGCG elevated the phosphorylation of VASP-Ser(157), a cAMP-dependent protein kinase (A-kinase) substrate, but not the phosphorylation of VASP-Ser(239), a cGMP-dependent protein kinase substrate, in intact platelets and collagen-induced platelets, and VASP-Ser(157) phosphorylation by EGCG was inhibited by both an adenylate cyclase inhibitor SQ22536 and an A-kinase inhibitor Rp-8-Br-cAMPS. We have demonstrated that EGCG increases cAMP via adenylate cyclase activation and subsequently phosphorylates VASP-Ser(157) through A-kinase activation to inhibit [Ca(2+)](i) mobilization and TXA(2) production on collagen-induced platelet aggregation. CONCLUSIONS: These results strongly indicate that EGCG is a beneficial compound elevating cAMP level in collagen-platelet interaction, which may result in the prevention of platelet aggregation-mediated thrombotic diseases.

Total saponin from korean red ginseng inhibits thromboxane A2 production associated microsomal enzyme activity in platelets.

Ginseng, the root of Panax ginseng Meyer, has been used frequently in traditional oriental medicine and is popular globally. Ginsenosides, which are the saponins in ginseng, are the major components having pharmacological and biological activities, including anti-diabetic and anti-tumor activities. In this study, we investigated the effects of total saponin from Korean red ginseng (TSKRG) on thrombin-produced thromboxane A2 (TXA2), an aggregating thrombogenic molecule, and its associated microsomal enzymes cyclooxygenase (COX)-1 and TXA2 synthase (TXAS). Thrombin (0.5 U/mL) increased TXA2 production up to 169 ng/10(8) platelets as compared with control (0.2 ng/10(8) platelets). However, TSKRG inhibited potently TXA2 production to the control level in a dose-dependent manner, which was associated with the strong inhibition of COX-1 and TXAS activities in platelet microsomes having cytochrome c reductase activity. The results demonstrate TSKRG is a beneficial traditional oriental medicine in platelet-mediated thrombotic diseases via suppression of COX-1 and TXAS to inhibit production of TXA2.

A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations.

Platelets, though anucleated, possess several transcription factors, including NF-kappaB, that exert non-genomic functions regulating platelet activation. Since platelets have not only been recognized as central players of homeostasis, but also participated in pathological conditions such as thrombosis, atherosclerosis, and inflammation, we examined rat platelet NF-kappaB expression and evaluated the effects of anti-inflammatory drug BAY 11-7082, an inhibitor of NF-kappaB activation, in platelet physiology. Western blotting revealed that rat platelets express NF-kappaB. BAY 11-7082, dose dependently, inhibited collagen- or thrombin-induced-platelet aggregation. ATP release, TXB(2) formation, P-selectin expression, and intercellular Ca(2+) concentration activated by collagen were reduced in BAY 11-7082-treated platelets. BAY 11-7082 elevated intracellular levels of cAMP, but not cGMP, and its co-incubation with cAMP-activating agent (forskolin) or its hydrolyzing enzyme inhibitor (3-isobutyl-1-methylxanthine, IBMX), synergistically inhibited collagen-induced-platelet aggregation. In addition, vasodilator-stimulated-phosphoprotein (VASP) phosphorylation was enhanced in BAY 11-7082-treated platelets, which was partially inhibited by a protein kinase A (PKA) inhibitor, H-89. Moreover, while p38 mitogen-activated protein kinase (MAPK) was not affected, BAY 11-7082 attenuated c-Jun N-terminal kinase 1 (JNK1) and extracellular-signal-regulated protein kinase 2 (ERK2) phosphorylations. In conclusion, BAY 11-7082 inhibits platelet activation, granule secretion, and aggregation, and that this effect is mediated by inhibition of JNK1 and ERK2 phosphorylations, and partially by stimulation of cAMP-dependent PKA VASP phosphorylation. The ability of BAY 11-7082 to inhibit platelet function might be relevant in cases involving aberrant platelet activation where the drug is considered as anti-atherothrombosis, and anti-inflammatory therapy.