An essential role of PI(4,5)P2 for maintaining the activity of the transient receptor potential canonical (TRPC)4β

The transient receptor potential canonical 4 (TRPC4) channel is a Ca²⁺-permeable nonselective cation channel in mammalian cells and mediates a number of cellular functions. Many studies show that TRPC channels are activated by stimulation of Gα_q-phospholipase C (PLC)-coupled receptors. However, our previous study showed that the TRPC4 current was inhibited by co-expression of a constitutively active form of Gα_q (Gα_q ^Q209L). A shortage of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] in Gα_q ^Q209L may be responsible for reduced TRPC4 activity. Here, we tested this hypothesis by using a rapamycin-inducible system that regulates PI(4,5)P₂ acutely and specifically. Our results showed that the TRPC4β current was reduced by inducible Gα_q ^Q209L, but not by the mutants with impaired binding ability to PLCβ. Depletion of PI(4,5)P₂ by inducing the inositol polyphosphate 5-phosphatase to HEK293 cells that express TRPC4β led to an irreversible inhibition of TRPC4β currents. In contrast, inducing phosphatidylinositol 4-phosphate 5-kinase or intracellular PI(4,5)P₂ application did not activate the TRPC4β current. Finally, we revealed that PI(4,5)P₂ is important in delaying the desensitization of TRPC4β. Taken together, we suggest that PI(4,5)P₂ is not the activator of TRPC4β activation, but it is still necessary for regulating TRPC4β activation.     

Serum growth arrest-specific protein 6 levels are elevated in adult-onset Still’s disease

We investigated the growth arrest-specific protein 6 in adult-onset Still’s disease. Serums were collected from 52 adult-onset Still’s disease patients with follow-up samples of 21 patients. The growth arrest-specific protein 6 levels in adult-onset Still’s disease were higher compared to those in the normal controls (25.37?±?7.71 vs. 19.86?±?5.01 ng/mL, p?<?0.001). However, growth arrest-specific protein 6 did not correlate with disease activity. Also, growth arrest-specific protein 6 was not decreased after activity was resolved in the follow-up. The growth arrest-specific protein 6 in adult-onset Still’s disease patients were higher than the normal controls. However, growth arrest-specific protein 6 was not correlated with disease activity.     

Protocatechuic acid extends lifespan and increases stress resistance in Caenorhabditis elegans

Veronica peregrina has a wide range of types of constituents with various pharmacological properties. Here in this study, we isolated protocatechuic acid (PCA) from V. peregrina and examined PCAs effects on the lifespan and stress tolerance using Caenorhabditis elegans model system. We found that lifespan of wild-type worms was significantly lengthened in the presence of PCA in a dose dependent manner. PCA also elevated tolerance of worms against osmotic, heat shock, and oxidative stress. We also demonstrated antioxidant capacity of PCA by checking intracellular reactive oxygen species level and antioxidant enzyme activities such as catalase and superoxide dismutase. We further investigated several factors including pharyngeal pumping rate and progeny production that might influence prolonged lifespan and enhanced stress tolerance by PCA. Interestingly, both factors were significantly reduced after PCA exposure, indicating PCA exerts longevity activity by shifting food intake and reproduction at least in part. In addition, PCA-treated aged worms showed increased body movement compared to untreated controls suggesting PCA could enhance healthspan as well as lifespan.     

Levofloxacin-azithromycin combined triple therapy for Helicobacter pylori eradication]

BACKGROUND/AIMS: Antibiotic resistance and poor compliance are the main causes of Helicobacter pylori (H. pylori) eradication failure. This study evaluated the eradication rate, tolerability, and compliance of levofloxacin- azithromycin combined triple therapy for H. pylori eradication. METHODS: 1) First-line eradication: A total of 78 H. pylori-positive patients were enrolled. Seventeen military men in Armed Forces Capital Hospital were treated with 7 days of levofloxacin-azithromycin combined triple therapy (omeprazole 20 mg bid, levofloxacin 500 mg od, and azithromycin 500 mg od), and 61 patients in Kangbuk Samsung Hospital were treated with standard PPI-based triple therapy (omeprazole 20 mg bid, amoxicillin 1.0 g bid, and clarithromycin 500 mg bid) for 7 days. 2) Second-line eradication: A consecutive series of 59 patients who failed H. pylori eradication with standard PPI-based triple therapy in Kangbuk Samsung Hospital were randomized to two groups. Thirty patients were retreated with 7 days of bismuth-based quadruple therapy (omeprazole 20 mg bid, bismuth 120 mg qid, metronidazole 500 mg tid, and tetracycline 500 mg qid), and remaining 29 patients were retreated with levofloxacin-azithromycin combined triple therapy. Patient's compliance and tolerability were evaluated at the end of treatment. The status of H. pylori infection was assessed 8 weeks later then. The successful eradication of H. pylori was defined as negative results from histology and CLO test, or 13C-urea breath test. RESULTS: First-line eradication rate of levofloxacin-azithromycin triple therapy was lower than that of standard PPI-based triple therapy, but there was no statistically significant difference (70.6% vs. 80.3%, p=0.390). Second-line eradication rate of levofloxacin-azithromycin combined triple therapy was significantly lower than that of bismuth-based quadruple therapy (ITT/PP 65.5%/73.1% vs. 90%/90%, p<0.0001). The compliances of all patients were more than 85%. Two of patients with levofloxacin-azithromycin combined triple therapy complained self-limiting side effects (mild dizziness; mild insomnia with general weakness). CONCLUSIONS: Levofloxacin-azithromycin combined triple therapy should not be recommended as the first-line or second-line H. pylori eradication regimen in Korea.     

A case of primary small cell carcinoma arising from the common bile duct]

Small cell carcinoma is usually seen in the lung, but rarely involves the gastrointestinal tract including biliary tract. A 65 year-old man was admitted because of obstructive jaundice. A smooth-surfaced round intraluminal mass with proximal bile duct dilatation was seen in the proximal common bile duct on endoscopic retrograde cholangiogram. Under the diagnosis of bile duct cancer, pylorus-preserving pancreatoduodenectomy was done. Pathology revealed a 2 cm sized small cell carcinoma in the proximal common bile duct and distal common hepatic duct. On immunohistochemical stain, the tumor cells were positive for neuroendocrine markers CD56 and synaptophysin. After surgery, the patient received 5 cycles of adjuvant chemotherapy with VIP (etoposide, ifosfamide, and cisplatin) regimen. However, the patient died of liver metastasis 12 months after the diagnosis. We report a case of extrapulmonary small cell carcinoma arising from the common bile duct.