CHERP Regulates the Alternative Splicing of pre-mRNAs in the Nucleus.

Calcium homeostasis endoplasmic reticulum protein (CHERP) is colocalized with the inositol 1,4,5-trisphosphate receptor (IP3R) in the endoplasmic reticulum or perinuclear region, and has been involved in intracellular calcium signaling. Structurally, CHERP carries the nuclear localization signal and arginine/serine-dipeptide repeats, like domain, and interacts with the spliceosome. However, the exact function of CHERP in the nucleus remains unknown. Here, we showed that poly(A)+ RNAs accumulated in the nucleus of CHERP-depleted U2OS cells. Our global analysis revealed that CHERP regulated alternative mRNA splicing events by interaction with U2 small nuclear ribonucleoproteins (U2 snRNPs) and U2 snRNP-related proteins. Among the five alternative splicing patterns analyzed, intron retention was the most frequently observed event. This was in accordance with the accumulation of poly(A)+ RNAs in the nucleus. Furthermore, intron retention and cassette exon choices were influenced by the strength of the 5' or 3' splice site, the branch point site, GC content, and intron length. In addition, CHERP depletion induced anomalies in the cell cycle progression into the M phase, and abnormal cell division. These results suggested that CHERP is involved in the regulation of alternative splicing.

Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds.

Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important not only for isoform diversity but also for regulating gene expression. Therefore, abnormal splicing leads to serious diseases such as cancer and neurodegenerative disorders. In the first part of this review, we describe the regulation of divergent transcriptomes using alternative mRNA splicing. In the second part, we present the relationship between the disruption of splicing and diseases. Recently, various compounds with splicing inhibitor activity were established. These splicing inhibitors are recognized as a biological tool to investigate the molecular mechanism of splicing and as a potential therapeutic agent for cancer treatment. Food-derived compounds with similar functions were found and are expected to exhibit anticancer effects. In the final part, we describe the compounds that modulate the messenger RNA (mRNA) splicing process and their availability for basic research and future clinical potential.

The isoflavone fraction from soybean presents mRNA maturation inhibition activity.

Recent findings indicate that mRNA splicing inhibitors can be potential anticancer candidates. We have previously established a screening system which monitors mRNA processing in order to identify mRNA processing inhibitors. Among a number of dietary resources, isoflavone fractions showed an inhibitory effect of mRNA processing. These findings demonstrate that a variety of dietary sources have an impact on mRNA biogenesis.

[Postoperative Analgesia for Video-assisted Thoracoscopic Surgery--Continuous Intravenous Infusion of Fentanyl Combined with Intercostal Nerve Block v.s. Continuous Epidural Analgesia].

BACKGROUND: Epidural analgesia or paravertebral block is widely used in postoperative analgesia for video-assisted thoracic surgery (VATS). We investigated the efficacy of the continuous intravenous infuion of fentanyl combined with intercostal nerve block, in comparison with the continuous epidural analgesia. METHODS: Forty-one patients received a bolus of 0.375% ropivacaine 6-10 ml through the epidural catheter placed at the T5-9 at the end of surgery. Then, continuous epidural infusion of 0.2% ropivacaine at a rate of 4 or 6 ml x hr(-1) was started (Group E). 44 patients received intercostal nerve block at three insertion points of thoracoscopy (using 0.75% ropivacaine 3-4 ml, respectively) at the end of surgery. Then, continuous intravenous infusion of fentanyl at a rate of 0.5 µg x kg(-1) x hr(-1) was started (Group F). The efficacy of post-operative analgesia was evaluated by additional analgesic requirements. RESULTS : There was no significant difference in the additional analgesic requirements between the two groups. However, the additional analgesics were required significantly earlier in Group E than Group F (P < 0.05). CONCLUSIONS: Continuous intravenous infusion of fentanyl combined with intercostal nerve block is effective in the postoperative analgesia for VATS, as well as continuous epidural analgesia.

[Effects of Sevoflurane or Desflurane Anesthesia on Perioperative Delirium in Elderly Patients Undergoing Surgical Repair of Hip Fracture].

BACKGROUND: Perioperative delirium increases the morbidity and mortality in elderly patients. The present retrospective study was carried out to evaluate whether desflurane or sevoflurane has influence on the incidence of perioperative delirium. METHODS: In 30 patients above 75 years of age undergoing surgical procedure, anesthesia was maintained with sevoflurane (group S), and with desflurane (group D). The incidence of perioperative delirium was obtained retrospectively from their medical chart The delirium was diagnosed with the Richmond agitation-sedation scale. RESULTS: The incidence of perioperative delirium on postoperative day (POD) 1-3 was not significantly different between group D and group S. The patients in group D were discharged earlier about 10 days compared with those group S. CONCLUSIONS: Desflurane anesthesia is same as sevoflurane regarding perioperative delirium in elderly patients. Shorter hospitalization in group D was achieved for 10 days compared with those in group S, due to the lower incidence of delirium on POD 3 and 5 in group D.

Food-Derived Compounds Apigenin and Luteolin Modulate mRNA Splicing of Introns with Weak Splice Sites.

Cancer cells often exhibit extreme sensitivity to splicing inhibitors. We identified food-derived flavonoids, apigenin and luteolin, as compounds that modulate mRNA splicing at the genome-wide level, followed by proliferation inhibition. They bind to mRNA splicing-related proteins to induce a widespread change of splicing patterns in treated cells. Their inhibitory activity on splicing is relatively moderate, and introns with weak splice sites tend to be sensitive to them. Such introns remain unspliced, and the resulting intron-containing mRNAs are retained in the nucleus, resulting in the nuclear accumulation of poly(A)+ RNAs in these flavonoid-treated cells. Tumorigenic cells are more susceptible to these flavonoids than nontumorigenic cells, both for the nuclear poly(A)+ RNA-accumulating phenotype and cell viability. This study illustrates the possible mechanism of these flavonoids to suppress tumor progression in vivo that were demonstrated by previous studies and provides the potential of daily intake of moderate splicing inhibitors to prevent cancer development.

Sinus floor elevation with platelet-rich fibrin alone: A Clinical retrospective study of 1-7 years.

BACKGROUND: Several sinus floor elevation procedures for implant placement have been introduced. The present study aimed to evaluate the implants placed with Platelet-rich fibrin (PRF) alone in atrophic posterior maxillae and survival rates and the potential factors associated with implant loss. MATERIAL AND METHODS: This retrospective study evaluated 71 implants in 34 patients after 1-7 years' follow-up time. Statistical models were used to determine the implant survival and the potential factors associated with loss. RESULTS: Overall, 7 implants were lost, and the cumulative survival rate at 7 years by implant-based and patient-bases analyses were 85.5% and 85.7%, respectively. The mean residual bone height (RBH) was 4.26 mm. The implant survival rate was significantly lower at RBH < 4 mm than RBH ≥ 4 mm. CONCLUSIONS: This retrospective study showed that sinus floor elevation with PRF alone could be applied in cases of lower RBH. However, it should be carefully performed in cases of RBH < 4 mm before surgery. Key words:Platelet-rich fibrin, dental implant, sinus augmentation, retrospective study.

Carcinoembryonic antigen-producing adrenal adenoma resected using combined lateral and anterior transperitoneal laparoscopic surgery.

A 74-year-old woman presented with symptoms consistent with hyperadrenocorticism and hyperca-techolaminism. She had a cushingoid appearance and her cortisol level was elevated. Her serum dopamine and noradrenalin levels were also elevated. Computed tomography detected a left adrenal mass measuring 3.5 cm multiply 3.0 cm in diameter. Metaiodobenzylguanidine scintigraphy was negative. Unexpectedly, the serum Serum carcinoembryonic antigen (CEA) level was elevated. Fluorodeoxyglucose positron emission tomography showed increased uptake in the adrenal tumor only, with a maximum standardized uptake value of 2.8. Selective venography and blood sampling revealed that the concentrations of cortisol, catecholamines and CEA were significantly elevated in the vein draining the tumor. A diagnosis of CEA-producing benign adenoma was made. After preoperative management, we performed a combined lateral and anterior transperitoneal laparoscopic adrenectomy. Her vital signs remained stable during surgery. Histopathological examination revealed a benign adenoma. Her cortisol, catecholamine and CEA levels normalized immediately after surgery. We present, to the best of our knowledge, the first case of CEA-producing adrenal adenoma, along with a review of the relevant literature, and discuss our laparoscopic surgery techniques.