Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome.

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient's cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of LmnaG609G/G609G mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of LmnaG609G/+ mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of LmnaG609G/+ mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in LmnaG609G/+ mouse. These results indicate that progerinin is a strong drug candidate for HGPS.

Retrospective analysis of the association between intraoperative magnesium sulfate infusion and postoperative acute kidney injury after major laparoscopic abdominal surgery.

Magnesium sulfate can be used as a co-adjuvant drug during the perioperative period and has multiple benefits. Recent evidence suggested that perioperative magnesium sulfate infusion may lower the risk of postoperative acute kidney injury (AKI). We investigated the association between intraoperative magnesium sulfate infusion and incidence of AKI after major laparoscopic abdominal surgery. We retrospectively analyzed the medical records of adult patients 20 years or older who underwent elective major laparoscopic abdominal surgery (>2 hours) between 2010 and 2016. We investigated the association between intraoperative magnesium sulfate infusion and the incidence of postoperative AKI until postoperative day (POD) 3 using a multivariable logistic regression analysis. We included 3,828 patients in this analysis; 357 patients (9.3%) received an intraoperative magnesium sulfate infusion and 186 patients (4.9%) developed postoperative AKI by POD 3. A multivariable logistic regression analysis showed that magnesium infusion was associated with a significant decrease (63%) in postoperative AKI (odds ratio, 0.37; 95% confidence interval, 0.14-0.94; P = 0.037). Our study suggested that intraoperative magnesium sulfate infusion is associated with a reduced risk of postoperative AKI until POD 3 for patients who underwent laparoscopic major abdominal surgery. Well-designed, prospective studies should be conducted to further substantiate these findings.

Interruption of progerin-lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated ß-gal (SA-ß-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin-lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.

The effect of magnesium sulphate on intubating condition for rapid-sequence intubation: a randomized controlled trial.

STUDY OBJECTIVES: We compared magnesium sulphate with control, ketamine, rocuronium prime, and large-dose rocuronium (0.9 mg/kg) with regard to intubation conditions during rapid-sequence induction. DESIGN: This is a prospective, randomized, double-blinded study. SETTING: The setting is at an operating room in a university-affiliated hospital. PATIENTS: One hundred ten patients scheduled for general anesthesia were randomly allocated to the following 5 groups in equal numbers. INTERVENTIONS: The control and rocuronium 0.9 groups received rocuronium 0.6 and 0.9 mg/kg, respectively; the ketamine group was given 0.5 mg/kg ketamine 2 minutes before 0.6 mg/kg rocuronium; the rocuronium prime group received 0.06 mg/kg rocuronium 3 minutes before 0.54 mg/kg rocuronium; and the magnesium group received 50 mg/kg magnesium sulphate. Intubation was initiated 50 seconds after the rocuronium injection. MEASUREMENTS: Intubating condition (primary outcome), rocuronium onset, rocuronium duration, train-of-four ratio upon intubation, and hemodynamic variables (secondary outcomes) were recorded. MAIN RESULTS: The excellent intubating condition was more frequent in the magnesium group (P < .05). Onset of neuromuscular block was shorter in the magnesium group than in the control, ketamine, and rocuronium prime groups (P < .05). No difference in onset time was found between the magnesium and rocuronium 0.9 groups. Block duration was longest in the rocuronium 0.9 group. The train-of-four ratio on intubation was lowest in the rocuronium prime group. The only adverse event was a burning or heat sensation reported by 5 patients in the magnesium group. CONCLUSIONS: Magnesium sulphate pretreatment was most likely to provide excellent intubating condition for rapid-sequence intubation compared with the control, ketamine pretreatment, rocuronium prime, and large-dose rocuronium. However, magnesium sulphate administration is associated with a burning or heat sensation.