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>

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>

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>

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>

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.

Molecular basis of flowering under natural long-day conditions in <i>Arabidopsis</i>

Song, Young Hun,Kubota, Akane,Kwon, Michael S.,Covington, Michael, F.,Lee, Nayoung,Ella, R. Taagen,Cintró,n, Dianne Laboy,Hwang, Dae Yeon,Akiyama, Reiko,Sarah, K. Hodge,Huang, He,Nguyen, Nhu H. Nature Publishing Group 2018 Nature plants Vol.4 No.10

<P>Plants sense light and temperature changes to regulate flowering time. Here we show that expression of the <I>Arabidopsis</I> florigen gene, <I>FLOWERING LOCUS T</I> (<I>FT</I>), peaks in the morning during spring, a different pattern than we observe in the lab. Providing our lab growth conditions with a red/far-red light ratio similar to open field conditions and daily temperature oscillation is sufficient to mimic the <I>FT</I> expression and flowering time in natural long days. Under the adjusted growth conditions, key light signaling components, such as phytochrome A (phyA) and EARLY FLOWERING 3 (ELF3), play important roles in morning <I>FT</I> expression. These conditions stabilize CONSTANS (CO) protein, a major <I>FT</I> activator, in the morning, which is likely a critical mechanism for photoperiodic flowering in nature. Refining the parameters of our standard growth conditions to more precisely mimic plant responses in nature can provide a powerful method for improving our understanding of seasonal response.</P>

Nature-inspired thermo-responsive multifunctional membrane adaptively hybridized with PNIPAm and PPy

Kim, Hyejeong,Kim, Kiwoong,Lee, Sang Joon Nature Publishing Group 2017 NPG Asia Materials Vol.9 No.10

<P>Specialized plant tissues, such as the epidermis of a leaf covered with stomata, consist of soft materials with deformability and electrochemical properties to achieve specific functions in response to various environmental stimuli. Stimulus-responsive hydrogels with electrochemical properties are good candidates for imitating such special functionalities in nature and thus have great potential in a wide range of academic and industrial applications. However, hydrogel-incorporated conductive materials are usually mechanically rigid, which limits their application in other fields. In addition, the fabrication technology of structured functional hydrogels has low reproducibility due to the required multistep processing. Here, inspired by nature, specifically the stimulus-responsive functionalities of plants, a new thermo-responsive multifunctional hybrid membrane (HM) is synthesized through the in situ hybridization of conductive poly(pyrrole) (PPy) on a photopolymerized poly(N-isopropylacrylamide) (PNIPAm) matrix. The morphological and electrical properties of the fabricated HM are investigated to characterize various aspects of its multiple functions. In terms of morphology, the HM can be easily fabricated into various structures by smartly utilizing photopolymerization patterning, and it exhibits thermo-responsive deformability. In terms of functionality, it exhibits various electrical and charge responses to thermal stimuli. This simple and efficient fabrication method can be used as a promising platform for fabricating a variety of functional devices.</P>

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>

Role of the histone deacetylase inhibitor valproic acid in high-fat diet-induced hypertension via inhibition of HDAC1/angiotensin II axis

Choi, J,Park, S,Kwon, T K,Sohn, S I,Park, K M,Kim, J I Nature Publishing Group 2017 International Journal of Obesity Vol.41 No.11

Background:Obesity is known as an epidemic worldwide because of consumption of westernized high-fat diets and one of the major risk factors of hypertension. Histone deacetylases (HDACs) control gene expression by regulating histone/non-histone protein deacetylation. HDAC inhibitors exert anti-cancer and anti-inflammatory effects and play a protective role in cardiovascular diseases. In the present study, we tested the effect of an FDA-approved pan-HDAC inhibitor valproic acid (VPA) on high-fat diet (HFD)-induced hypertension in mice. Furthermore, we examined the mechanism of VPA-induced prevention of hypertension.Methods:Nine-week-old male C57BL/6 mice were fed either a normal diet (ND) or HFD. When the HFD group reached a pre-hypertensive phase (130–140 mm Hg systolic blood pressure), VPA was administered for 6 days (300 mg kg<SUP>−1</SUP> per day). Body weights and blood pressure (BP), expression of renin-angiotensin system (RAS) components and HDAC1 were determined. The direct role of HDAC1 in the expression of RAS components was investigated using gene silencing.Results:HFD accelerated the increase in body weight from 22.4±1.3 to 31.9±3.0 compared to in the ND group from 22.7±0.9 to 26.0±1.7 (P=0.0134 ND vs HFD), systolic BP from 118.5±5.7 to 145.0±3.0 (P<0.001), and diastolic BP from 91.0±13.6 to 121.0±5.0 (P=0.006); BP was not altered in the ND group. HFD increased RAS components and HDAC1 in the kidneys as well as leptin in the plasma. VPA administration prevented the progression of hypertension and inhibited the increase in expression of HDAC1 and RAS components. VPA did not affect plasma leptin level. Knockdown of HDAC1 in MDCK cells decreased the expression of angiotensinogen and type 1 angiotensin II receptor.Conclusions:VPA prevented HFD-induced hypertension by downregulating angiotensin II and its receptor via inhibition of HDAC1, offering a novel therapeutic option for HFD-induced hypertension.