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.

Kaurenoic acid activates TGF-ß signaling.

BACKGROUND: Kaurenoic acid (ent-kaur-16-en-19-oic acid: KA) is a key constituent found in the roots of Aralia continentalis Kitagawa (Araliaceae) that has been used for treating rheumatism in traditional Asian medicine. HYPOTHESIS: Although KA was reported to suppress inflammation by activating Nrf2, the anti-inflammatory function of KA is less characterized. Given the complex nature of the inflammatory response and the critical role of TGF-ß in resolving inflammation, we hypothesized that KA suppresses inflammatory response by activating TGF-ß signaling. METHODS: Murine macrophage RAW 264.7, human lung epithelial cell MRC-5, and a TGFßRII defective cell HCT116 were treated with various amounts of KA. KA was also administered to mouse lung via intratracheal (i.t.) route. Phosphorylated Smad2 and Smad3 were analyzed by western blot. TGFß-dependent gene expression was determined by immunoblotting of α-SMA and luciferase assay. RESULTS: KA induced the phosphorylation of Smad2 and Smad3, key activator molecules in TGF-ß signaling. EW7197, an inhibitor for activin receptor-like kinase 5/TGF-ß receptor I (TGFßR1) suppressed KA-mediated phosphorylation of Smad2. Similarly, KA failed to phosphorylate Smad2 in HCT116, suggesting that KA acts through the prototypic TGFßR. KA treatment increased the transcriptional activity driven by a Smad-binding element in a luciferase reporter assay and induced the α-smooth muscle actin (α-SMA). Similarly, i.t. KA induced the phosphorylation of Smad2 and increased the expression ofα-SMA in mouse lungs. CONCLUSION: KA activated TGF-ß signaling, suggesting that TGFß signaling is associated with KA suppressing inflammation.

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.

Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a Hepatitis B virus-endemic area.

BACKGROUND: This study was conducted to assess the efficacy and safety of sorafenib monotherapy in clinical practice settings for Korean patients with hepatocellular carcinoma (HCC) related primarily to HBV infection. METHODS: Medical records of 57 consecutive patients with unresectable or metastatic HCC treated with 400 mg bid sorafenib at the National Cancer Center, Korea between June 2007 and March 2008, were retrospectively reviewed. RESULTS: The median patient age was 55 years (range, 28-76 years), and all patients had performance status 0-2 and Child-Pugh class A or B disease. HCC was etiologically related to HBV in 79.0% of patients. Eleven patients (19.3%) had modified UICC stage III tumors, 11 (19.3%) had stage IVa, and 35 (61.4%) had stage IVb. Following sorafenib monotherapy, 3 patients (5.3%) achieved a partial response and 18 (35.1%) achieved stable disease, with a disease control rate of 40.4%. The median times to progression (TTP) was 9.1 weeks (95% CI 3.4-14.8 weeks). Multivariate analyses showed that serum alpha-fetoprotein (alpha-FP) > or =400 ng/mL (HR, 2.810; P = 0.023) and the presence of massive intrahepatic tumors (HR, 7.633; P = 0.033) were independent predictors of shorter TTP. The most common grade 3/4 adverse events were hand-foot syndrome (8.8%), diarrhea (7.0%), and skin rash (7.0%). Exacerbation of underlying chronic hepatitis B was not found. CONCLUSION: Sorafenib monotherapy showed better outcomes with tolerable toxicity in Korean advanced HCC patients, who had intrahepatic nodular tumors and/or metastatic tumors, coupled with low levels of serum alpha-FP.

The novel cytokine p43 stimulates dermal fibroblast proliferation and wound repair.

The multifunctional cytokine p43 acts on endothelial and immune cells to control angiogenesis and inflammation. In this report, we describe an additional activity of p43 that specifically promotes fibroblast proliferation and wound repair. In skin wound regions from mice, tumor necrosis factor-alpha induced p43 expression and secretion from macrophages recruited to the site. p43 also promoted fibroblast proliferation through its 146-amino acid N-terminal domain as revealed by deletion mapping. This p43-induced fibroblast proliferation was mediated by extracellular signal-regulated kinase (Erk). Depletion of endogenous p43 in mice by gene disruption retarded wound repair, whereas exogenous supplementation of recombinant human p43 to the wound area stimulated dermal fibroblast proliferation, collagen production, and wound closure. Thus, we have identified a novel p43 activity involving the stimulation of fibroblast proliferation, which could be applied therapeutically to aid wound repair.