Pro‐apoptotic Noxa is involved in ablative focal irradiation‐induced lung injury

Kim, Jee&#x2010,Youn,An, Yong&#x2010,Min,Choi, Won Hoon,Kim, Jin&#x2010,Mo,Cho, Samju,Yoo, Byung Rok,Kang, Jeong Wook,Lee, Yun&#x2010,Sil,Lee, Yoon&#x2010,Jin,Cho, Jaeho CAROL DAVILA UNIVERSITY PRESS 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.4

<P><B>Abstract</B></P><P>Although lung injury including fibrosis is a well‐documented side effect of lung irradiation, the mechanisms underlying its pathology are poorly understood. X‐rays are known to cause apoptosis in the alveolar epithelial cells of irradiated lungs, which results in fibrosis due to the proliferation and differentiation of fibroblasts and the deposition of collagen. Apoptosis and BH3‐only pro‐apoptotic proteins have been implicated in the pathogenesis of pulmonary fibrosis. Recently, we have established a clinically analogous experimental model that reflects focal high‐dose irradiation of the ipsilateral lung. The goal of this study was to elucidate the mechanism underlying radiation‐induced lung injury based on this model. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice for 14 days. About 9 days after irradiation, the mice began to show increased levels of the pro‐apoptotic protein Noxa in the irradiated lung alongside increased apoptosis and fibrosis. Suppression of Noxa expression by small interfering RNA protected cells from radiation‐induced cell death and decreased expression of fibrogenic markers. Furthermore, we showed that reactive oxygen species participate in Noxa‐mediated, radiation‐induced cell death. Taken together, our results show that Noxa is involved in X‐ray‐induced lung injury.</P>

DMSO‐ and Serum‐Free Cryopreservation of Wharton's Jelly Tissue Isolated From Human Umbilical Cord

Shivakumar, Sharath Belame,Bharti, Dinesh,Subbarao, Raghavendra Baregundi,Jang, Si&#x2010,Jung,Park, Ji&#x2010,Sung,Ullah, Imran,Park, Ji&#x2010,Kwon,Byun, June&#x2010,Ho,Park, Bong&#x2010,Wook,Rho, G John Wiley and Sons Inc. 2016 Journal of cellular biochemistry Vol.117 No.10

<P><B>ABSTRACT</B></P><P>The facile nature of mesenchymal stem cell (MSC) acquisition in relatively large numbers has made Wharton's jelly (WJ) tissue an alternative source of MSCs for regenerative medicine. However, freezing of such tissue using dimethyl sulfoxide (DMSO) for future use impedes its clinical utility. In this study, we compared the effect of two different cryoprotectants (DMSO and cocktail solution) on post‐thaw cell behavior upon freezing of WJ tissue following two different freezing protocols (Conventional [−1°C/min] and programmed). The programmed method showed higher cell survival rate compared to conventional method of freezing. Further, cocktail solution showed better cryoprotection than DMSO. Post‐thaw growth characteristics and stem cell behavior of Wharton's jelly mesenchymal stem cells (WJMSCs) from WJ tissue cryopreserved with a cocktail solution in conjunction with programmed method (Prog‐Cock) were comparable with WJMSCs from fresh WJ tissue. They preserved their expression of surface markers, pluripotent factors, and successfully differentiated in vitro into osteocytes, adipocytes, chondrocytes, and hepatocytes. They also produced lesser annexin‐V‐positive cells compared to cells from WJ tissue stored using cocktail solution in conjunction with the conventional method (Conv‐Cock). Real‐time PCR and Western blot analysis of post‐thaw WJMSCs from Conv‐Cock group showed significantly increased expression of pro‐apoptotic factors (BAX, p53, and p21) and reduced expression of anti‐apoptotic factor (BCL2) compared to WJMSCs from the fresh and Prog‐Cock group. Therefore, we conclude that freezing of fresh WJ tissue using cocktail solution in conjunction with programmed freezing method allows for an efficient WJ tissue banking for future MSC‐based regenerative therapies. J. Cell. Biochem. 117: 2397–2412, 2016. © 2016 The Authors. <I>Journal of Cellular Biochemistry</I> published by Wiley Periodicals, Inc.</P>

Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors

Gambacorti&#x2010,Passerini, Carlo,Kantarjian, Hagop M.,Kim, Dong&#x2010,Wook,Khoury, Hanna J.,Turkina, Anna G.,Brü,mmendorf, Tim H.,Matczak, Ewa,Bardy&#x2010,Bouxin, Nathalie,Shapiro, Mark,Turnbu John Wiley and Sons Inc. 2015 American journal of hematology Vol.90 No.9

<P>Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, <I>n =</I> 79] chronic myeloid leukemia [CML], blast‐phase [BP, <I>n =</I> 64] CML, acute lymphoblastic leukemia [ALL, <I>n =</I> 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (<I>n =</I> 9) for AP and pyrexia (<I>n =</I> 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.</P>

3′‐Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis

Jeon, Jimin,Kang, Li&#x2010,Jung,Lee, Kwang Min,Cho, Chanmi,Song, Eun Kyung,Kim, Wook,Park, Tae Joo,Yang, Siyoung John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.1

<P><B>Abstract</B></P><P>3′‐Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3′‐sialyllactose on osteoarthritic cartilage destruction. <I>In vitro</I> and <I>ex vivo</I>, biochemical and histological analysis demonstrated that 3′‐sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL‐1β, IL‐6, IL‐17 and TNF‐α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3′‐sialyllactose, whereas the direct binding of NF‐κB to the <I>Mmp3</I>,<I> Mmp13</I> and <I>Cox2</I> promoters was reduced by 3′‐sialyllactose in IL‐1β‐treated chondrocytes. Additionally, IL‐1β induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3′‐sialyllactose in a dose‐dependent manner. <I>In vivo</I>, 3′‐sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3′‐sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration <I>via</I> promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3′‐sialyllactose could be attributed in part to its regulation of Sox9 or NF‐κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3′‐sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.</P>

3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Kang, Li&#x2010,Jung,Kwon, Eun&#x2010,Soo,Lee, Kwang Min,Cho, Chanmi,Lee, Jae&#x2010,In,Ryu, Young Bae,Youm, Tae Hyun,Jeon, Jimin,Cho, Mi Ra,Jeong, Seon&#x2010,Yong,Lee, Sang&#x2010,Rae,Kim, Wook,Yang John Wiley and Sons Inc. 2018 British journal of pharmacology Vol.175 No.23

<P><B>Background and Purpose</B></P><P>3′‐Sialyllactose (3′‐SL) is a safe compound that is present in high levels in human milk. Although it has anti‐inflammatory properties and supports immune homeostasis, its effect on collagen‐induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3′‐SL on the progression of rheumatoid arthritis (RA) in <I>in vitro</I> and <I>in vivo</I> models.</P><P><B>Experimental Approach</B></P><P>The anti‐arthritic effect of 3′‐SL was analysed with fibroblast‐like synoviocytes <I>in vitro</I> and an <I>in vivo</I> mouse model of CIA. RT‐PCR, Western blotting and ELISA were performed to evaluate its effects <I>in vitro</I>. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin‐O and haematoxylin staining.</P><P><B>Key Results</B></P><P>3′‐SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3′‐SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro‐inflammatory cytokines, https://en.wikipedia.org/wiki/Matrix_metalloproteinases and osteoclastogenesis <I>via</I> NF‐κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF‐κB signalling pathway, was totally blocked by 3′‐SL in the RA models.</P><P><B>Conclusions and Implications</B></P><P>3′‐SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated <I>via</I> blockade of the NF‐κB signalling pathway. Therefore, 3′‐SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.</P>

Protein‐Induced Pluripotent Stem Cells Ameliorate Cognitive Dysfunction and Reduce Aβ Deposition in a Mouse Model of Alzheimer's Disease

Cha, Moon&#x2010,Yong,Kwon, Yoo&#x2010,Wook,Ahn, Hyo&#x2010,Suk,Jeong, Hyobin,Lee, Yong Yook,Moon, Minho,Baik, Sung Hoon,Kim, Dong Kyu,Song, Hyundong,Yi, Eugene C.,Hwang, Daehee,Kim, Hyo&#x2010,Soo,Mo John Wiley and Sons Inc. 2017 Stem cells translational medicine Vol.6 No.1

<P><B>Abstract</B></P><P>Transplantation of stem cells into the brain attenuates functional deficits in the central nervous system via cell replacement, the release of specific neurotransmitters, and the production of neurotrophic factors. To identify patient‐specific and safe stem cells for treating Alzheimer's disease (AD), we generated induced pluripotent stem cells (iPSCs) derived from mouse skin fibroblasts by treating protein extracts of embryonic stem cells. These reprogrammed cells were pluripotent but nontumorigenic. Here, we report that protein‐iPSCs differentiated into glial cells and decreased plaque depositions in the 5XFAD transgenic AD mouse model. We also found that transplanted protein‐iPSCs mitigated the cognitive dysfunction observed in these mice. Proteomic analysis revealed that oligodendrocyte‐related genes were upregulated in brains injected with protein‐iPSCs, providing new insights into the potential function of protein‐iPSCs. Taken together, our data indicate that protein‐iPSCs might be a promising therapeutic approach for AD. S<SMALL>TEM</SMALL> C<SMALL>ELLS</SMALL> T<SMALL>RANSLATIONAL</SMALL> M<SMALL>EDICINE</SMALL><I>2017;6:293–305</I></P>

Inhibition of VEGF ‐dependent angiogenesis and tumor angiogenesis by an optimized antibody targeting CLEC 14a

Kim, Taek&#x2010,Keun,Park, Chang Sik,Jang, Jihye,Kim, Mi Ra,Na, Hee&#x2010,Jun,Lee, Kangseung,Kim, Hyun Jung,Heo, Kyun,Yoo, Byong Chul,Kim, Young&#x2010,Myeong,Lee, Je&#x2010,Wook,Kim, Su Jin,Kim, Eu John Wiley and Sons Inc. 2018 MOLECULAR ONCOLOGY Vol.12 No.3

<P>The C‐type lectin‐like domain of CLEC14a (CLEC14a‐C‐type lectin‐like domain [CTLD]) is a key domain that mediates endothelial cell–cell contacts in angiogenesis. However, the role of CLEC14a‐CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity‐determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti‐angiogenic human monoclonal antibody that specifically targets CLEC14a‐CTLD and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits CLEC14a‐CTLD‐mediated endothelial cell–cell contact and simultaneously downregulates expression of CLEC14a on the surface of endothelial cells. Using various <I>in vitro</I> and <I>in vivo</I> functional assays, we demonstrated that this antibody effectively suppresses vascular endothelial growth factor (VEGF)‐dependent angiogenesis and tumor angiogenesis of SNU182 human hepatocellular carcinoma, CFPAC‐1 human pancreatic cancer, and U87 human glioma cells. Furthermore, we also found that this antibody significantly inhibits tumor angiogenesis of HCT116 and bevacizumab‐adapted HCT116 human colorectal cancer cells. These findings suggest that antibody targeting of CLEC14a‐CTLD has the potential to suppress VEGF‐dependent angiogenesis and tumor angiogenesis and that CLEC14a‐CTLD may be a novel anti‐angiogenic target for VEGF‐dependent angiogenesis and tumor angiogenesis.</P>

Survival benefits from reduced‐intensity conditioning in allogeneic stem cell transplantation for young lower‐risk MDS patients without significant comorbidities

Lee, Sung&#x2010,Eun,Kim, Yoo&#x2010,Jin,Yahng, Seung&#x2010,Ah,Cho, Byung&#x2010,Sik,Eom, Ki&#x2010,Sung,Lee, Seok,Min, Chang&#x2010,Ki,Kim, Hee&#x2010,Je,Cho, Seok&#x2010,Goo,Kim, Dong&#x2010,Wook,L Blackwell Publishing Ltd 2011 European journal of haematology Vol.87 No.6

<P><B>Abstract</B></P><P><I>Objective:</I> The aim of this study was to determine the optimum conditioning intensity for allogeneic stem cell transplantation (SCT) in young (age ≤50), lower‐risk (INT‐1 by IPSS) Myelodysplastic syndrome (MDS) patients without significant comorbidities (hematopoietic cell transplantation‐comorbidity index score ≤3). <I>Methods:</I> Transplant outcomes from 46 consecutive patients were retrospectively analyzed according to the conditioning intensity: reduced‐intensity conditioning (RIC; <I>n</I> = 14), intensified RIC by adding low‐dose total body irradiation (iRIC; <I>n</I> = 15), and myeloablative conditioning (MAC; <I>n</I> = 17). <I>Results:</I> After a median follow‐up of 73.7 months, RIC had a better 4‐yr overall survival (OS) (92.9%) compared with the iRIC (64.2%) or MAC (70.6%). Multivariate analysis showed that RIC was associated with improved OS compared with the MAC [relative risk (RR) of 0.08, <I>P </I>=<I> </I>0.022] because of a lower transplant‐related mortality (TRM) (RR, 0.08, <I>P </I>=<I> </I>0.035). iRIC failed to show survival benefits over the MAC (RR of 0.77, <I>P </I>=<I> </I>0.689) because of similarly high TRM (RR of 0.41, <I>P </I>=<I> </I>0.480). Cumulative incidence of acute and chronic graft‐versus‐host disease (GVHD) after RIC was higher, but GVHD‐specific survival was significantly better (RIC 100% vs. iRIC 45.7% vs. MAC, <I>P </I>=<I> </I>0.018). Relapse rate was not different among the three groups, but in the RIC group, azacitidine was available and useful for inducing remission in two patients. <I>Conclusion:</I> This study shows that RIC improved OS by directly lowering TRM and indirectly giving an additional chance for relapsed MDS in the era of hypomethylating treatment. RIC–SCT should be considered for relative healthy lower‐risk MDS patients.</P>

Effect of fixed‐dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS‐ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe)

Kim, Kyung&#x2010,Jin,Kim, Sang&#x2010,Hyun,Yoon, Young Won,Rha, Seung&#x2010,Woon,Hong, Soon&#x2010,Jun,Kwak, Choong&#x2010,Hwan,Kim, Weon,Nam, Chang&#x2010,Wook,Rhee, Moo&#x2010,Yong,Park, Tae&#x201 John Wiley and Sons Inc. 2016 CARDIOVASCULAR THERAPEUTICS Vol.34 No.5

<P><B>Summary</B></P><P><B>Aim</B></P><P>We aimed to compare the effects of fixed‐dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS).</P><P><B>Method</B></P><P>This multicenter eight‐week randomized double‐blind phase III study evaluated the safety and efficacy of fixed‐dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid‐lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed‐dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily).</P><P><B>Results</B></P><P>Fixed‐dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed‐dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%–63%, 37%–43%, and 19%–24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non‐DM or non‐MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non‐DM or MetS vs non‐MetS patients.</P><P><B>Conclusion</B></P><P>Fixed‐dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS.</P>

Angiotensin II Causes Apoptosis of Adult Hippocampal Neural Stem Cells and Memory Impairment Through the Action on AMPK‐PGC1α Signaling in Heart Failure

Kim, Min&#x2010,Seok,Lee, Geun&#x2010,Hee,Kim, Yong&#x2010,Min,Lee, Byoung&#x2010,Wook,Nam, Hae Yun,Sim, U&#x2010,Cheol,Choo, Suk&#x2010,Jung,Yu, Seong&#x2010,Woon,Kim, Jae&#x2010,Joong,Kim Kwon, Yunh unknown 2017 Stem cells translational medicine Vol.6 No.6

<P><B>Abstract</B></P><P>Data are limited on the mechanisms underlying memory impairment in heart failure (HF). We hypothesized that angiotensin II (Ang II) may determine the fate of adult hippocampal neural stem cells (HCNs), a cause of memory impairment in HF. HCNs with neurogenesis potential were isolated and cultured from adult rat hippocampi. Ang II decreased HCN proliferation in dose‐ and time‐dependent manners. Moreover, Ang II treatment (1 µM) for 48 hours induced apoptotic death, which was attenuated by pretreatment with Ang II receptor blockers (ARBs). Ang II increased mitochondrial reactive oxygen species (ROS) levels, which was related to mitochondrial morphological changes and functional impairment. Moreover, ROS activated the AMP‐activated protein kinase (AMPK) and consequent peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) expression, causing cell apoptosis. In the HF rat model induced by left anterior descending artery ligation, ARB ameliorated the spatial memory ability which decreased 10 weeks after ischemia. In addition, neuronal cell death, especially of newly born mature neurons, was observed in HF rat hippocampi. ARB decreased cell death and promoted the survival of newly born neural precursor cells and mature neurons. In conclusion, Ang II caused HCN apoptosis through mitochondrial ROS formation and subsequent AMPK‐PGC1α signaling. ARB improved learning and memory behaviors impaired by neuronal cell death in the HF animal model. These findings suggest that HCN is one treatment target for memory impairment in HF and that ARBs have additional benefits in HF combined with memory impairment. S<SMALL>TEM</SMALL> C<SMALL>ELLS</SMALL> T<SMALL>RANSLATIONAL</SMALL> M<SMALL>EDICINE</SMALL><I>2017;6:1491–1503</I></P>