Adjuvant role of macrophages in stem cell-induced cardiac repair in rats

Lim, Soo yeon,Cho, Dong Im,Jeong, Hye-yun,Kang, Hye-jin,Kim, Mi Ra,Cho, Meeyoung,Kim, Yong Sook,Ahn, Youngkeun Nature Publishing Group UK 2018 Experimental and molecular medicine Vol.50 No.11

<▼1><P>Bone marrow-derived mesenchymal stem cells (BMMSCs) are used extensively for cardiac repair and interact with immune cells in the damaged heart. Macrophages are known to be modulated by stem cells, and we hypothesized that priming macrophages with BMMSCs would enhance their therapeutic efficacy. Rat bone marrow-derived macrophages (BMDMs) were stimulated by lipopolysaccharide (LPS) with or without coculture with rat BMCs. In the LPS-stimulated BMDMs, induction of the inflammatory marker iNOS was attenuated, and the anti-inflammatory marker Arg1 was markedly upregulated by coculture with BMMSCs. Myocardial infarction (MI) was induced in rats. One group was injected with BMMSCs, and a second group was injected with MIX (a mixture of BMMSCs and BMDMs after coculture). The reduction in cardiac fibrosis was greater in the MIX group than in the BMC group. Cardiac function was improved in the BMMSC group and was substantially improved in the MIX group. Angiogenesis was better in the MIX group, and anti-inflammatory macrophages were more abundant in the MIX group than in the BMMSC group. In the BMMSCs, interferon regulatory factor 5 (IRF5) was exclusively induced by coculture with macrophages. IRF5 knockdown in BMMSCs failed to suppress inflammatory marker induction in the macrophages. In this study, we demonstrated the successful application of BMDMs primed with BMMSCs as an adjuvant to cell therapy for cardiac repair.</P></▼1><▼2><P><B>Heart attacks: mixed cell therapy for heart regeneration</B></P><P>A tailored technique involving stem cells and anti-inflammatory immune cells shows promise for repairing heart tissue damage. Immune cells called anti-inflammatory macrophages are vital for healing of the heart following a heart attack. Youngkeun Ahn, Yong Sook Kim and co-workers at Chonnam National University Hospital in Gwangju, South Korea trialed a novel stem cell therapy on rats to improve cardiac repair. They took bone marrow-derived macrophages and stem cells from each rat and incubated the two cell types together to create individualized treatments. Following induced heart attacks, they injected one group of rats with both cell types, and another group with stem cells only. While heart function improved in both groups, the group treated with both cell types showed significant improvements with a greater reduction in cardiac fibrosis and increased the reparative activity of macrophages.</P></▼2>

Adenosine triphosphate-based chemotherapy response assay-guided chemotherapy in unresectable colorectal liver metastasis

Hur, H,Kim, N K,Kim, H G,Min, B S,Lee, K Y,Shin, S J,Cheon, J H,Choi, S H Nature Publishing Group 2012 The British journal of cancer Vol.106 No.1

<P><B>Background:</B></P><P>This study aims to evaluate the effectiveness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided neoadjuvant chemotherapy for increasing resectability in patients with unresectable colorectal liver metastasis.</P><P><B>Patients and methods:</B></P><P>Patients were randomised into two groups: Group A was treated by conventional chemotherapy regimen and Group B was treated by chemotherapy regimen according to the ATP-CRA. Three chemotherapeutic agents (5-fluorouracil, oxaliplatin and irinotecan) were tested by ATP-CRA and more sensitive agents were selected. Either FOLFOX or FOLFIRI was administered. Between Group A and B, treatment response and resectability were compared.</P><P><B>Results:</B></P><P>Between November 2008 and October 2010, a total 63 patients were randomised to Group A (<I>N</I>=32) or Group B (<I>N</I>=31). FOLFOX was more preferred in Group A than in Group B (26 out of 32 (81.3%) <I>vs</I> 20 out of 31 (64.5%)). Group B showed better treatment response than Group A (48.4% <I>vs</I> 21.9%, <I>P</I>=0.027). The resectability of hepatic lesion was higher in Group B (35.5% <I>vs</I> 12.5%, <I>P</I>=0.032). Mean duration from chemotherapy onset to the time of liver resection was 11 cycles (range 4–12) in Group A and 8 cycles (range 8–16) in Group B.</P><P><B>Conclusion:</B></P><P>This study showed that tailored-chemotherapy based on ATP-CRA could improve the treatment response and resectability in initially unresectable colorectal liver metastasis.</P>

Oleuropein prevents the progression of steatohepatitis to hepatic fibrosis induced by a high-fat diet in mice

Kim, Sung Woo,Hur, Wonhee,Li, Tian Zhu,Lee, Young Ki,Choi, Jung Eun,Hong, Sung Woo,Lyoo, Kwang-Soo,You, Chan Ran,Jung, Eun Sun,Jung, Chan Kun,Park, Taesun,Um, Soo-Jong,Yoon, Seung Kew Nature Publishing Group 2014 Experimental and molecular medicine Vol.46 No.4

<P>Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased levels of triglycerides in the liver. The purposes of this study were to establish a mouse model of NASH by feeding mice a 60% high-fat diet (HFD) and to demonstrate the anti-fibrotic effects of oleuropein, which has been shown to have anti-oxidant and anti-inflammatory properties, in this HFD-induced mouse model of NASH. C57BL/6 mice were divided into three groups: a regular diet group (Chow), a HFD group and an oleuropein-supplemented HFD group (OSD), which was fed a 0.05% OSD for 6 months. The effects of oleuropein in this model were evaluated using biochemical, histological and molecular markers. The expression levels of alpha-smooth muscle actin (α-SMA)and collagen type I in the HFD and OSD groups were evaluated using real-time PCR and western blotting. The body weight, biochemical marker levels, nonalcoholic fatty liver disease activity score, homeostasis model of assessment-insulin resistance (HOMA-IR) and leptin levels observed in the HFD group at 9 and 12 months were higher than those observed in the Chow group. The HOMA-IR and leptin levels in the OSD group were decreased compared with the HFD group. In addition, α-SMA and collagen type I expression were decreased by oleuropein treatment. We established a NASH model induced by HFD and demonstrated that this model exhibits the histopathological features of NASH progressing to fibrosis. Our results suggest that oleuropein may be pharmacologically useful in preventing the progression of steatohepatitis and fibrosis and may be a promising agent for the treatment of NASH in humans.</P>

Tolerability and adequate therapeutic dosage of oral clomipramine for the treatment of premature ejaculation: A randomized, double-blind, placebo-controlled, fixed-dose, parallel-grouped clinical study

Kim, Sae Woong,Choi, Jin Bong,Kim, Su Jin,Kim, Kyung Soo,Kim, Churl Min,Lee, Dong Hyeon,Choi, Whan Seok Nature Publishing Group UK 2018 International journal of impotence research Vol.30 No.2

<P>To evaluate the adequate therapeutic dosage of clomipramine 15 mg/day and clomipramine 30 mg/day in male patients with premature ejaculation (PE), this study enrolled men aged 20-65 years who met diagnostic criteria for PE including Intravaginal Ejaculation Latency Time (IELT) less than 2 min for at least 75% of their sexual intercourses. Subjects received placebo, clomipramine 15 mg, or clomipramine 30 mg prn (2 similar to 6 h before intercourse) for 4 weeks. Efficacy was assessed using fold change, percentile change, and mean change of IELT, as well as Drug Coitus Interval Time (DCIT). A total of 101 patients were randomized into the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group. Analyses of fold changes of IELT in each group revealed that the IELT of both the clomipramine 15 mg group and clomipramine 30 mg group was significantly increased 4 weeks after administration than the placebo group. Adverse events were reported by 11.76, 32.35, and 57.57% of patients in the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group, respectively. Most common adverse events in the clomipramine treatment groups were gastrointestinal disorders and psychiatric disorders of mild to moderate severity. On-demand regimen of clomipramine 15 mg resulted in a significant improvement in IELT and was superior to a regimen of clomipramine 30 mg in terms of risk-to-benefit ratio.</P>

Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study

Ryu, S Y,Kim, M H,Nam, B H,Lee, T S,Song, E S,Park, C Y,Kim, J W,Kim, Y B,Ryu, H S,Park, S Y,Kim, K T,Cho, C H,Lee, C,Kim, S M,Kim, B G,Bae, D S,Kim, Y T,Nam, J-H Nature Publishing Group 2014 The British journal of cancer Vol. No.

<P><B>Background:</B></P><P>In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy.</P><P><B>Methods:</B></P><P>In total, 2158 patients with pathologically proven stage IB–IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis.</P><P><B>Results:</B></P><P>Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size ⩾3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence.</P><P><B>Conclusion:</B></P><P>This study identified a ‘four-factor model' in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.</P>

Iron status and its association with pregnancy outcome in Korean pregnant women

Lee, H S,Kim, M S,Kim, M H,Kim, Y J,Kim, W Y Nature Publishing Group 2006 European journal of clinical nutrition Vol.60 No.9

Objective:The purpose of this study was to assess the prevalence of iron deficiency anemia among Korean pregnant women and to assess the association between maternal hemoglobin (Hb) level and pregnancy outcome.Design:A longitudinal study.Setting:Ewha Womans University Hospital, Seoul, Korea.Subjects:A total of 248 normal pregnant women of 24–28 weeks gestation and 190 babies born to the pregnant subjects.Methods:Maternal anthropometry, blood parameters and pregnancy outcomes were measured.Results:Mean Hb, serum iron concentration, transferrin saturation and total iron binding capacity of the subjects were 11.4 g/dl, 89.4 μg/dl, 18.7% and 484.6 μg/dl, respectively, and 30.2% of the subjects were anemic judged by Hb concentration of <10.5g/dl. When subjects were classified into tertile groups based on Hb levels, the lowest tertile (HbT1) group had significantly lower concentrations of cord serum iron and albumin than those in the highest tertile (HbT3) group. Newborn infants from the HbT1 group had significantly higher rates of preterm delivery, low birth weight and low Apgar scores than those in other groups. Logistic regression analysis showed that maternal serum albumin and Hb level were the most important predictive variables for low birth weight.Conclusions:A substantial proportion of Korean pregnant women were at risk of anemia. Infants born to women with a low Hb level showed a lower birth weight, height and Apgar scores.Sponsorship:This study was supported by a grant from the Korea Health 21 R&#38;D project, Ministry of Health and Welfare, Republic of Korea (no. 01-PJ1-PG1-01CH15-0009).European Journal of Clinical Nutrition (2006) 60, 1130–1135. doi:10.1038/sj.ejcn.1602429; published online 26 April 2006

Antimicrobial effect of alexidine and chlorhexidine against <i>Enterococcus faecalis</i> infection

Kim, Hyun-Shik,Woo Chang, Seok,Baek, Seung-Ho,Han, Seung Hyun,Lee, Yoon,Zhu, Qiang,Kum, Kee-Yeon Nature Publishing Group 2013 International journal of oral science. Vol.5 No.1

<P>A previous study demonstrated that alexidine has greater affinity for the major virulence factors of bacteria than chlorhexidine. The aim of this study was to compare the antimicrobial activity of 1% alexidine with that of 2% chlorhexidine using <I>Enterococcus faecalis</I>-infected dentin blocks. Sixty bovine dentin blocks were prepared and randomly divided into six groups of 10 each. <I>E. faecalis</I> was inoculated on 60 dentin blocks using the Luppens apparatus for 24 h and then the dentin blocks were soaked in 2% chlorhexidine or 1% alexidine solutions for 5 and 10 min, respectively. Sterile saline was used as a control. The antimicrobial efficacy was assessed by counting the number of bacteria adhering to the dentin surface and observing the degradation of bacterial shape or membrane rupture under a scanning electron microscope. Significantly fewer bacteria were observed in the 2% chlorhexidine- or 1% alexidine-soaked groups than in the control group (<I>P</I><0.05). However, there was no significant difference in the number of bacteria adhering to the dentinal surface between the two experimental groups or between the two soaking time groups (<I>P</I>>0.05). Ruptured or antiseptic-attached bacteria were more frequently observed in the 10-min-soaked chlorhexidine and alexidine groups than in the 5-min-soaked chlorhexidine and alexidine groups. In conclusion, 10-min soaking with 1% alexidine or 2% chlorhexidine can be effective against <I>E. faecalis</I> infection.</P>

Cup-to-disc and arteriole-to-venule ratios in preterm birth

Kim, J,Choi, D Y,Park, K-A,Oh, S Y Nature Publishing Group 2015 Eye Vol.29 No.9

AimsTo investigate the influence of preterm birth on the optic disc and retinal vessels by measurements of cup-to-disc (C/D) ratio and arteriole-to-venule (A/V) ratio.MethodsEighty-three eyes of 42 preterm births were included. In the age- and sex-matched control group, 83 eyes of 42 full-term births were used. Fundus color photographs were taken. ImageJ software was used to calculate C/D and A/V ratios from the fundus images.ResultsFundus photographs were taken at 8.01±2.22 years of age for the preterm group and 8.01±2.13 years of age for the control group. The mean gestational age of the preterm group was 27<SUP>4</SUP>/<SUB>7</SUB> weeks (range, 24–34 weeks). The preterm group had significantly larger C/D ratio and smaller A/V ratio (mean±standard deviation: 0.46±0.12 and 0.59±0.08, respectively) than the control group (0.36±0.07 and 0.68±0.07, respectively) after spherical equivalent refractive error was adjusted.ConclusionsPreterm birth is significantly associated with larger C/D ratio and smaller A/V ratio. These findings show the effect of preterm birth on the development of optic disc and retinal vessel development.

Global transcriptome analysis identifies weight regain-induced activation of adaptive immune responses in white adipose tissue of mice

Kyung, D S,Sung, H R,Kim, Y J,Kim, K D,Cho, S Y,Choi, J H,Lee, Y-H,Kim, I Y,Seong, J K Nature Publishing Group 2018 International Journal of Obesity Vol.42 No.4

<P><B>Objective:</B></P><P>Studies have indicated that weight regain following weight loss predisposes obese individuals to metabolic disorders; however, the molecular mechanism of this potential adverse effect of weight regain is not fully understood. Here we investigated global transcriptome changes and the immune response in mouse white adipose tissue caused by weight regain.</P><P><B>Design:</B></P><P>We established a diet switch protocol to compare the effects of weight regain with those of weight gain without precedent weight loss, weight loss maintenance and chow diet. We conducted a time course analysis of global transcriptome changes in gonadal white adipose tissue (gWAT) during the weight fluctuation. Co-expression network analysis was used to identify functional modules associated with the weigh regain phenotype. Immune cell populations in gWAT were characterized by flow-cytometric immunophenotyping. Metabolic phenotypes were monitored by histological analysis of adipose tissue and liver, and blood-chemistry and body weight/composition analyses.</P><P><B>Results:</B></P><P>In total, 952 genes were differentially expressed in the gWAT in the weight regain vs the weight gain group. Upregulated genes were associated with immune response and leukocyte activation. Co-expression network analysis showed that genes involved in major histocompatibility complex I and II-mediated antigen presentation and T-cell activation function were upregulated. Consistent with the transcriptome analysis results, flow cytometry demonstrated significant increases in subsets of T cells and proinflammatory M1 macrophages in the gWAT in the weight regain as compared to the weight gain group. In addition, upregulation of adaptive immune responses was associated with high incidence of adipocyte death and upregulation of high mobility group box 1, a well-known component of damage-associated molecular patterns.</P><P><B>Conclusions:</B></P><P>Our global transcriptome analysis identified weight regain-induced activation of adaptive immune responses in mouse white adipose tissue. Results suggest that activation of adipocyte death-associated adaptive immunity in adipose tissue may contribute to unfavorable metabolic effects of weight regain following weight loss.</P>

Reinvigorating natural product combinatorial biosynthesis with synthetic biology

Kim, Eunji,Moore, Bradley S,Yoon, Yeo Joon NATURE PUBLISHING GROUP 2015 NATURE CHEMICAL BIOLOGY Vol. No.

Natural products continue to play a pivotal role in drug-discovery efforts and in the understanding if human health. The ability to extend nature's chemistry through combinatorial biosynthesis—altering functional groups, regiochemistry and scaffold backbones through the manipulation of biosynthetic enzymes—offers unique opportunities to create natural product analogs. Incorporating emerging synthetic biology techniques has the potential to further accelerate the refinement of combinatorial biosynthesis as a robust platform for the diversification of natural chemical drug leads. Two decades after the field originated, we discuss the current limitations, the realities and the state of the art of combinatorial biosynthesis, including the engineering of substrate specificity of biosynthetic enzymes and the development of heterologous expression systems for biosynthetic pathways. We also propose a new perspective for the combinatorial biosynthesis of natural products that could reinvigorate drug discovery by using synthetic biology in combination with synthetic chemistry.