Cyclooxygenase-2 inhibitors modulate skin aging in a catalytic activity-independent manner

Mi Eun Lee,So Ra Kim,이승구,정유진,최선심,김우진,한정아 생화학분자생물학회 2012 Experimental and molecular medicine Vol.44 No.9

It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1.

Osteoblast differentiation of human bone marrow stromal cells (hBMSC) according to age for bone tissue engineering

Gin-Ah Song,Hyun-Mo Ryoo,Jin-Young Choi 대한구강악안면외과학회 2010 대한구강악안면외과학회지 Vol.36 No.4

Tissue engineered bone (TEB) can replace an autogenous bone graft requiring an secondary operation site as well as avoid complications like inflammation or infection from xenogenic or synthetic bone graft. Adult mesenchymal stem cells (MSC) for TEB are considered to have various ranges of differentiation capacity or multipotency by the donor site and age. This study examined the effect of age on proliferation capacity, differentiation capacity and bone morphogenetic protein-2 (BMP-2) responsiveness of human bone marrow stromal cells (hBMSC) according to the age. In addition, to evaluate the effect on enhancement for osteoblast differentiation, the hBMSC were treated with Trichostatin A (TSA) and 5-Azacitidine (5-AZC) which was HDAC inhibitors and methyltransferase inhibitors respectively affecting chromatin remodeling temporarily and reversibly. The young and old group of hBMSC obtained from the iliac crest from total 9 healthy patients, showed similar proliferation capacity. Cell surface markers such as CD34, CD45, CD90 and CD105 showed uniform expression regardless of age. However, the young group showed more prominent transdifferentiation capacity with adipogenic differentiation. The osteoblast differentiation capacity or BMP responsiveness was low and similar between young and old group. TSA and 5-AZC showed potential for enhancing the BMP effect on osteoblast differentiation by increasing the expression level of osteogenic master gene, such as DLX5, ALP. More study will be needed to determine the positive effect of the reversible function of HDAC inhibitors or methyltransferase inhibitors on enhancing the low osteoblast differentiation capacity of hBMSC.

Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors

홍상모,정창희,한송,박철영 대한당뇨병학회 2022 Diabetes and Metabolism Journal Vol.46 No.1

Background: It is not known which type 2 diabetes mellitus (T2DM) patients would most benefit from dipeptidyl peptidase-4 (DPP-4) inhibitor treatment. We aimed to investigate the predictors of response to DPP-4 inhibitors considering degree of DPP-4 inhibition.Methods: This study is a post hoc analysis of a 24-week, randomized, double-blind, phase III trial that compared the efficacy and safety of a DPP-4 inhibitor (gemigliptin vs. sitagliptin) in patients with T2DM. Subjects were classified into tertiles of T1 <65.26%, T2=65.26%–76.35%, and T3 ≥76.35% by DPP-4 inhibition. We analyzed the change from baseline in glycosylated hemoglobin (HbA1c) according to DPP-4 inhibition with multiple linear regression adjusting for age, ethnicity, body mass index, baseline HbA1c, and DPP-4 activity at baseline.Results: The mean age was greater in the high tertile group compared with the low tertile group (T1: 49.8±8.3 vs. T2: 53.1±10.5 vs. T3: 55.3±9.5, P<0.001) of DPP-4 inhibition. Although HbA1c at baseline was not different among tertiles of DPP-4 inhibition (P=0.398), HbA1c after 24-week treatment was lower in the higher tertile compares to the lower tertile (T1: 7.30%±0.88% vs. T2: 7.12%±0.78% vs. T3: 7.00%±0.78%, P=0.021). In multiple regression analysis, DPP-4 enzyme inhibition rate was not a significant determent for HbA1c reduction due to age. In subgroup analysis by tertile of DPP-4 inhibition, age was the only significant predictor and only in the highest tertile (R2=0.281, B=–0.014, P=0.024).Conclusion: This study showed that HbA1c reduction by DPP-4 inhibitor was associated with increasing age, and this association was linked with higher DPP-4 inhibition.

노화관련 질환에서 mTOR의 억제제의 임상적 적용과 가능성

신현영(Hyun-Young Shin),추상희(Sang Hui Chu),이향규(Hyangkyu Lee),이지원(Ji Won Lee) 대한임상노인의학회 2011 대한임상노인의학회지 Vol.12 No.4

mTOR (mammalian target of rapamycin)는 PI3K-related family kinase에 속하는 serine/threonine kinase로 성장인자(growth factor)와 영양, 스트레스 자극에 의하여 세포의 성장과 증식, 자가포식(autophagy), 단백질 합성을 조절하는 기능이 있는 것으로 알려져 왔다 mTOR 억제제는 현재 면역억제의 역할 때문에 신이식을 받은 환자들에게 널리 사용되고 있으며 일부 암에서 항암작용이 증명되어 항암제로 사용되고 있으며 다양한 암질환에서 임상시험이 진행되고 있다. 최근 mTOR 기전은 비만, 당뇨병을 포함한 대사질환, 신경퇴행성 질환, 심혈관 질환 등의 노화관련 질환과 관련이 있다고 알려졌을 뿐 아니라, mTOR 억제제의 직접적인 수명연장 가능성이 제시되어 많은 연구들이 진행 중에 있다. 하지만 노화와 관련된 mTOR 메커니즘 연구는 아직 기초 단계에 머물러 있으며, 면역억제를 할 경우 생길 수 있는 감염의 증가 등 mTOR 억제제 관련 부작용을 규명하는 연구들이 필요하다. 향후 mTOR 억제제 관련 연구는 건강한 수명연장을 위해 기반 연구에 도움을 줄 것으로 기대한다. mTOR (mammalian target of rapamycin) is a serine/threonine kinase belonging to the PI3K (phosphoinositide 3-kinase)-related family kinase. mTOR is known to regulate cell growth, proliferation, autophagy and protein synthesis in response to growth factor, nutrient, stress. mTOR inhibitor has been broadly used as an immunosuppressant for kidney transplant patients. Clinical results of the data have showed mTOR inhibitor as an anticancer agent to several kinds of cancers and many clinical trials are still undergoing. Recently, mTOR signaling pathway has been studied with, not only metabolic disease, neurodegenerative disease, cardiovascular disease, which are related to the ageing process, but also the possibility of direct prolongation of human life. However, the studies of mTOR pathway with age-related disease are still in the early stage, we need more studies about increasing infectivity after immunosuppression and other adverse events of mTOR inhibitor. In this article, we will review age-related disease with mTOR pathway and discuss mTOR inhibitor as a potential agent for extending healthy life in the future.

Aldose-Reductase- and Protein-Glycation-Inhibitory Principles from the Whole Plant of Duchesnea chrysantha

Kim, Jong Min,Jang, Dae Sik,Lee, Yun Mi,Yoo, Jeong Lim,Kim, Young Sook,Kim, Joo-Hwan,Kim, Jin Sook WILEY-VCH Verlag 2008 Chemistry & biodiversity Vol.5 No.2

<P>Ellagic acid (1), 3,3′-di-O-methylellagic acid (2), 3,3′,4-tri-O-methylellagic acid (3), isovitexin (4), kaempferol 3-O-β-D-glucuronide methyl ester (5), quercetin 3-O-α-L-arabinopyranosyl-(1→6)-β-D-galactopyranoside (6), ursolic acid, pomolic acid, tormentic acid, euscaphic acid, euscaphic acid 28-O-β-D-glucopyranoside, and maslinic acid were isolated from the AcOEt- and BuOH-soluble MeOH extract of Duchesnea chrysantha (whole plant). The isolates were subjected to in vitro bioassays to evaluate their inhibitory activity on rat-lens aldose reductase (RLAR) and formation of advanced glycation end products (AGEs). The ellagic acids and flavonoids, compounds 1–6, exhibited moderate inhibitory effects on RLAR. However, compounds 1 and 4–6 showed excellent inhibitory activities towards the formation of AGEs. This is the first report that 4 and 6 exhibit inhibitory activity towards AR and AGEs formation.</P>

비병원성 야생효모들로부터 생산된 항산화물질과 항통풍성 Xanthin 산화효소 저해물질의 부분정제 및 특성

문정수, 김하근, 이종수 배재대학교 자연과학연구소 2023 自然科學論文集 Vol.34 No.1

비병원성 Rhodosporidium paludigenum HHGG35-1와 Rhodosporidium diobovatum NMD18-1 균주들이 생산하는 항산화물질과 항통풍성 물질을 산업적으로 응용하기 위하여 먼저 이들 각각의 YPD 배양 상등액을 한외여과를 실시하여 3kDa 이하의 활성물질을 얻은 후 Sephadex G-50으로 여과하여 부분 정제된 항산화물질과 xanthin 산화효소 저해물질을 얻었다. 부분 정제한 항산화물질의 작용 최적 온도와 pH는 각각 30℃, pH 7.0 이었고, xanthin 산화효소 저해물질의 작용 최적 온도와 pH는 각각 15℃, pH 5.0 이었다. The antioxidants of Rhodosporidium paludigenum HHGG35-1 was partially purified by ultrafiltration and Sephadex G-50 filtration and investigated its optimal reaction condition. Optimal reaction temperature and pH of the partial purified antioxidants were 30℃ and pH 7.0. The xanthin oxidase inhibitor from Rhodosporidium diobovatum NMD18-1 was purified partially by enzyme treatment, ultrafiltration and Sephadex G-50 filtration. Optimal reaction temperature and pH of the partial purified xanthin oxidase inhibitor were 15℃ and pH 5.0. Some heavy metal ions and sugars did not affect inhibitory activity of the parial purified xanthin oxidase inhibitor.

Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model

Park Jung-Eun,Lee Jiyoun,Ok Soonhyuck,Byun Seunghee,Chang Eun-Ju,Yoon Sung-Eun,Kim Young-Joon,Kang Min-Ji 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

The endoplasmic reticulum (ER) is a subcellular organelle essential for cellular homeostasis. Perturbation of ER functions due to various conditions can induce apoptosis. Chronic ER stress has been implicated in a wide range of diseases, including autosomal dominant retinitis pigmentosa (ADRP), which is characterized by age-dependent retinal degeneration caused by mutant rhodopsin alleles. However, the signaling pathways that mediate apoptosis in response to ER stress remain poorly understood. In this study, we performed an unbiased in vivo RNAi screen with a Drosophila ADRP model and found that Wg/Wnt1 mediated apoptosis. Subsequent transcriptome analysis revealed that ER stress-associated serine protease (Erasp), which has been predicted to show serine-type endopeptidase activity, was a downstream target of Wg/Wnt1 during ER stress. Furthermore, knocking down Erasp via RNAi suppressed apoptosis induced by mutant rhodopsin-1 (Rh-1P37H) toxicity, alleviating retinal degeneration in the Drosophila ADRP model. In contrast, overexpression of Erasp resulted in enhanced caspase activity in Drosophila S2 cells treated with apoptotic inducers and the stabilization of the initiator caspase Dronc (Death regulator Nedd2-like caspase) by stimulating DIAP1 (Drosophila inhibitor of apoptosis protein 1) degradation. These findings helped identify a novel cell death signaling pathway involved in retinal degeneration in an autosomal dominant retinitis pigmentosa model.

Olive Leaf Extracts Are a Natural Source of Advanced Glycation End Product Inhibitors

Vassiliki G. Kontogianni,Pantelis Charisiadis,Evangelia Margianni,Fotini N. Lamari,Ioannis P. Gerothanassis,Andreas G. Tzakos 한국식품영양과학회 2013 Journal of medicinal food Vol.16 No.9

Advanced glycation end products (AGEs), which are readily formed and accumulated with sustained hyperglycemia,contribute to the development of diabetic complications. As a consequence, inhibition of AGE formation constitutes an attractive therapeutic/preventive target. In the current study, we explored the phytochemical composition and the in vitro effect of two different olive leaf extracts (an aqueous and a methanolic) on AGE formation. The methanolic olive leaf extract inhibited fluorescent AGE formation in a bovine serum albumin (BSA)-ribose system, whereas the aqueous extract had no effect in both BSA-fructose and BSA-ribose systems. The phytochemical profile was investigated with liquid chromatographyultraviolet-visible (UV-Vis) diode array coupled to electrospray ionization multistage mass spectrometry (LC/DAD/ESIMSn). Quantification of the major phenolic compounds was performed with high performance liquid chromatography with UV-Vis diode array detection and nuclear magnetic resonance spectroscopy. Among the major phenolic components (luteolin,hydroxytyrosol, luteolin-40-O-b-D-glucopyranoside, luteolin-7-O-b-D-glucopyranoside, and oleuropein), luteolin and luteolin-40-O-b-D-glucopyranoside were assigned as potent inhibitors of AGE formation. The extraction procedure greatly affects the composition and therefore the anti-glycation potential of olive leaves.

The Changing Epidemiology of Gastroesophageal Reflux Disease: Are Patients Getting Younger?

( Takahisa Yamasaki ),( Colin Hemond ),( Mohamed Eisa ),( Stephen Ganocy ),( Ronnie Fass ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2018 Journal of Neurogastroenterology and Motility (JNM Vol.24 No.4

Background/Aims Gastroesophageal reflux disease (GERD) is a common disease globally with increasing prevalence and consequently greater burden on the Healthcare system. Traditionally, GERD has been considered a disease of middle-aged and older people. Since risk factors for GERD affect a growing number of the adult population, concerns have been raised that increasingly younger people may develop GERD. We aim to determine if the proportion of younger patients has increased among the GERD population. Methods The incidence of GERD as well as several variables were evaluated during an 11-year period. Explorys was used to evaluate datasets at a “Universal” and Healthcare system in northern Ohio to determine if trends at a local level reflected those at a universal level. GERD patients were classified into 7 age groups (15-19, 20-29, 30-39, 40-49, 50-59, 60-69, and ≥ 70 years). Results The proportion of patients with GERD increased in all age groups, except for those who were ≥ 70 years in the universal dataset (P< 0.001) and those who were ≥ 60 years in the Healthcare system (P < 0.001). The greatest rise was seen in 30-39 years in both datasets (P < 0.001). Similarly, the proportion of GERD patients who were using proton pump inhibitors increased in all age groups except for those who were ≥ 70 years in both datasets (P < 0.001), with the greatest increase being the group 30-39 years (P <0.001). Conclusion Over the last decade, there has been a significant increase in the proportion of younger patients with GERD, especially those within the age range of 30-39 years. (J Neurogastroenterol Motil 2018;24:559-569)

Suppression of neuroinflammation by matrix metalloproteinase-8 inhibitor in aged normal and LRRK2 G2019S Parkinson's disease model mice challenged with lipopolysaccharide

Kim, Jisun,Jeong, Yeon-Hui,Lee, Eun-Jung,Park, Jin-Sun,Seo, Hyemyung,Kim, Hee-Sun Elsevier 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>Microglial priming is caused by aging and neurodegenerative diseases, and is characterized by an exaggerated microglial inflammatory response to secondary and sub-threshold challenges. In the present study, we examined the effects of the matrix metalloproteinase-8 (MMP-8) inhibitor (M8I) on the brain of aged normal and leucine-rich repeat kinase 2 (LRRK2) G2019S Parkinson's disease (PD) model mice systemically stimulated with lipopolysaccharide (LPS). The results indicated that Iba-1 positive microglia and GFAP-positive astrocytes, which were increased by LPS, significantly decreased by M8I in aged normal and PD model mice. M8I also decreased the expression of pro-inflammatory markers in the hippocampus and midbrain of aged normal and PD model mice challenged with LPS, while it also improved the motor coordination of aged normal mice after LPS challenge in rotor rod test and the general crossing locomotor activities of LPS-treated LRRK2G2019S PD mice after LPS challenge in open field test. To assess the effects of M8I in an <I>in vitro</I> priming model, BV2 microglia were pretreated with macrophage colony-stimulating factor (CSF)-1 or interleukin (IL)-34, and subsequently stimulated with LPS or polyinosinic-polycytidylic acid (poly[I:C]). M8I inhibited the LPS- or poly(I:C)-induced production of the tumor necrosis factor-α and nitric oxide, alone or in combination with CSF-1 or IL-34. Collectively, the data suggested that M8I has a therapeutic potential in treating neurodegenerative diseases that are aggravated by systemic inflammation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> M8I decreased glial activation in aged normal and PD mice challenged with LPS. </LI> <LI> M8I suppressed LPS-induced neuroinflammation in aged normal and PD mice. </LI> <LI> M8I ameliorated LPS-induced behavioral deficits in aged normal and PD mice. </LI> <LI> M8I also showed anti-inflammatory effects in an <I>in vitro</I> priming model. </LI> </UL> </P>