RSK1 vs. RSK2 Inhibitory Activity of the Marine ß-Carboline Alkaloid Manzamine A: A Biochemical, Cervical Cancer Protein Expression, and Computational Study.

Manzamines are complex polycyclic marine-derived ß-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA's differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.

Ingestion of food grade hydrogen peroxide with resultant gastrointestinal and neurologic symptoms treated with hyperbaric oxygen therapy: case report and review with emphasis on the therapeutic value of HBO2 in vascular gas embolism.

A 52-year-old male accidentally ingested approximately 100 mL of 35% hydrogen peroxide (H2O2), resulting in the sudden onset of gastrointestinal and neurologic symptoms. Non-contrast abdominal CT revealed extensive portal venous gas and gastric pneumatosis. The patient was treated with hyperbaric oxygen therapy which resulted in complete resolution of symptoms. The case highlights the therapeutic value of hyperbaric oxygen therapy in the treatment of vascular gas embolism and mitigation of concentrated H2O2 ingestion toxicity.

Conservative management of esophageal perforation after a fall.

INTRODUCTION: Esophageal perforation in the setting of blunt trauma is rare, and diagnosis can be difficult due to atypical signs and symptoms accompanied by distracting injury. PRESENTATION OF CASE: We present a case of esophageal perforation resulting from a fall from height. Unexplained air in the soft tissues planes posterior to the esophagus as well as subcutaneous emphysema in the absence of a pneumothorax on CT aroused clinical suspicions of an injury to the aerodigestive tract. The patient suffered multiple injuries including bilateral first rib fractures, C6 lamina fractures, C4-C6 spinous process fractures, a C7 right transverse process fracture with associated ligamentous injury and cord contusion, multiple comminuted nasal bone fractures, and a right verterbral artery dissection. Esophageal injury was localized using a gastrograffin esophagram to the cervical esophagus and was most likely secondary to cervical spine fractures. Because there were no clinical signs of sepsis and the esophagram demonstrated a contained rupture, the patient was thought to be a good candidate for a trial of conservative management consisting of broad spectrum intravenous antibiotics, oral care with chlorhexadine gluconate, NPO, and total parenteral nutrition. No cervical spine fixation or procedure was performed during this trial of conservative management. The patient was received another gastrograffin esophagram on hospital day 14 and demonstrated no evidence of contrast extravasation. DISCUSSION: Early diagnosis and control of the infectious source are the cornerstones to successful management of esophageal perforation from all etiologies. Traditionally, esophageal perforation relied on a high index of clinical suspicion for early diagnosis, but the use of CT scan for has proved to be highly effective in diagnosing esophageal perforation especially in patients with atypical presentations. While aggressive surgical infection control is paramount in the majority of esophageal perforations, a select subset of patients can be successfully managed non-operatively. CONCLUSION: In the setting of blunt trauma, esophageal perforation is rare and is associated with a high morbidity. In select patients who do not show any clinical signs of sepsis, contained perforations can heal with non-operative management consisting of broad spectrum antibiotics, strict oral hygiene, NPO, and total parenteral nutrition.