Cellular senescence, one of the hallmarks of aging, refers to permanent cell cycle arrest and is accelerated during the aging process. Black ginseng (BG), prepared by a repeated steaming and drying process nine times from fresh ginseng (Panax ginseng C.A. Meyer), is garnering attention for herbal medicine due to its physiological benefits against reactive oxygen species (ROS), inflammation, and oncogenesis, which are common cues to induce aging. However, which key nodules in the cellular senescence process are regulated by BG supplementation has not been elucidated yet. In this study, we investigated the effects of BG on cellular senescence using in vitro and aged mouse models. BG-treated primary mouse embryonic fibroblasts (MEFs) in which senescence was triggered by ionizing radiation (IR) expressed less senescence-associated β-galactosidase (SA-β-gal)-positive stained cells. In our aged mice (18 months old) study, BG supplementation (300 mg/kg) for 4 weeks altered hepatic genes involved in the aging process. Furthermore, we found BG supplementation downregulated age-related inflammatory genes, especially in the complement system. Based on this observation, we demonstrated that BG supplementation led to less activation of the canonical senescence pathway, p53-dependent p21 and p16, in multiple metabolic organs such as liver, skeletal muscle and white adipose tissue. Thus, we suggest that BG is a potential senolytic candidate that retards cellular senescence.

Dietary interventions with bioactive compounds have been found to suppress the accumulation of senescent cells and senescence-associated secretory phenotypes (SASPs). One such compound, curcumin (CUR), has beneficial health and biological effects, including antioxidant and anti-inflammatory properties, but its ability to prevent hepatic cellular senescence is unclear. The objective of this study was to investigate the effects of dietary CUR as an antioxidant on hepatic cellular senescence and determine its benefits on aged mice. We screened the hepatic transcriptome and found that CUR supplementation led to the downregulation of senescence-associated hepatic gene expressions in both usually fed and nutritionally challenged aged mice. Our results showed that CUR supplementation enhanced antioxidant properties and suppressed mitogen-activated protein kinase (MAPK) signaling cascades in the liver, particularly c-Jun N-terminal kinase (JNK) in aged mice and p38 in diet-induced obese aged mice. Furthermore, dietary CUR decreased the phosphorylation of nuclear factor-κB (NF-κB), a downstream transcription factor of JNK and p38, and inhibited the mRNA expression of proinflammatory cytokines and SASPs. The potency of CUR administration was demonstrated in aged mice via enhanced insulin homeostasis along with declined body weight. Taken together, these results suggest that CUR supplementation may be a nutritional strategy to prevent hepatic cellular senescence.

Aging is a physiological decrease of several biological activities in an organ that all organisms go through. The presence of a gradual deterioration of cell functioning, due to damage accumulation in metabolic organs, accelerates biological aging. Recently, dietary interventions with food‐active compounds have been linked to suppressing the accumulation of senescent cells and senescence‐associated secretory phenotype (SASP). Curcumin has potent biochemical and biological activities, including antioxidant and anti‐inflammatory actions. However, it largely remains unclear how curcumin has anti‐aging properties such as protection of DNA damage and cell survival/cell fate decisions. The objective of this study is to examine the regulatory effect of dietary curcumin on hepatic cellular senescence in the aged mouse model. Aged (18‐20 months old) male C57BL/6 mice were fed a normal chow diet (NCD) or NCD containing 0.4% (w/w) curcumin ‐ equivalent to 2g/day for a 60 kg adult ‐ (NCD+CUR), high fat high sugar diet (HFHSD) or a HFHSD+CUR (N=7‐9 per group) for 15 weeks. Mice given an HFHSD supplemented with curcumin displayed a different metabolic phenotype compared to mice given an HFHSD alone. To examine the phenotypic plasticity led by transcriptomic alteration, we used RNA‐Seq and analyzed differential gene expression in Gene Ontology (GO) terms and KEGG pathway analysis. There were 1687 and 3794 number of genes that showed a significant change with curcumin in NCD and HFHSD groups compared to their respective control groups. There were at least 8‐fold higher uniquely upregulated and 6‐fold uniquely downregulated genes in the HFHSD+CUR group when compared with their NCD counterparts. To this extent, curcumin supplementation altered hepatic gene expression profiling, especially in senescence pathways and their associated genes. Thus, to validate downregulation in senescence pathway involved genes from the RNA‐Seq data results, we compared the distribution of hepatic senescent cells by β‐gal staining in HFHSD groups. It revealed that HFHSD+CUR mice showed less density of the hepatic senescent cell (Figure A). We then mechanistically sought how curcumin regulates the hepatic senescence pathway. We found that curcumin supplementation decreased senescence effectors, specifically p38 and JNK protein expression levels in the liver (Figure B, C). Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age‐induced metabolic diseases.

Enantiopure 2-alkyl-1,3,3-trinitroazetidines 4 were efficiently synthesized by the nitrolysis of enantiopure 2-alkyl-3,3-dinitro-1-tosylazetidines 3 using an excess of fuming nitric acid in CHCl 3 at ambient temperature. In addition, elaboration of (S)-2-(2-methoxyethyl)-1,3,3-trinitroazetidine (4c) was successfully performed to synthesize a variety of enantiopure 2-alkyl-1,3,3-trinitroazetidines 5-7. The advantage of this strategy is that 2-alkyl-1,3,3-trinitroazetidines can be synthesized either asymmetrically or racemically depending on the presence or absence of chirality in N-sulfinyl aldimines 2 used as the starting material. Furthermore, the sensitivity measurement results of racemic 2-methyl-1,3,3-trinitroazetidine (racemic 4a) showed that the introduction of an alkyl substituent at the C2 position of 1,3,3-trinitroazetidine had a significant effect on the sensitivity of the resulting 2-alkyl-1,3,3-trinitroazetidine.

Organocatalytic Enantioselective Formal Synthesis of Bromopyrrole Alkaloids via Aza-Michael Addition. -An enantioselective aza-Michael addition to protected 4-hydroxy butenal (II) using pyrroles (I) and (IV) as the N-centered nucleophile is utilized to construct the nitrogen-substituted stereogenic carbon center in bromopyrrole alkaloids. The aza-Michael product (IIIa) is converted to the key intermediate (IX) via lactamization using a Staudinger-type reductive cyclization, which is previously used in the total synthesis of bromopyrrole alkaloid natural products. -(LEE, S.-J.; YOUN, S.-H.; CHO*, C.-W.; Org. Biomol. Chem. 9 (2011) 22, 7734-7741, http://dx.doi.org/10.1039/c1ob06078c ; Dep. Chem., Kyungpook Natl. Univ., Daegu 702-701, S. Korea; Eng.) -M. Paetzel