找到子宮內膜異位症早期發展的關鍵細胞激素–IL-10的雙重角色

[簡介]

子宮內膜異位症是惱人的婦科疾病,生育年齡的婦女約有6–10%的人患有此病,主要症狀是經痛、性交疼痛與不孕,治療後又很容易復發,是很不容易治癒的婦科疾病

[迷路的內膜組織]

這種百年無法解決的婦女疾病,成因到底為何呢?目前最被接受的說法是「經血逆流」理論,婦女每月剝落的子宮內膜組織,有部分可能會逆流回腹腔,此時體內免疫系統的白血球細胞會吞噬清除這些異位組織,這個清除過程會發生短暫且微弱的發炎反應,若這發炎反應能夠調控得當的話,就能順利清除逆流組織而又不產生副作用(強烈發炎),這樣這些異位組織就不會累積、黏附、與生長於腹腔中,變成子宮內膜異位的良性腫瘤,每個月報到的「好朋友」也就不會造成女性的生理與心理負擔。

[失調的發炎反應]

那什麼原因會使清除異位組織的發炎反應失調呢?高醫大孫昭玲副教授研究團隊發現「抗發炎因子IL-10」的濃度過高,可能是重要的原因之一;IL-10是各種發炎反應都會伴隨產生的細胞激素(蛋白質),當腹腔中的白血球在清除迷路的內膜組織時,也會產生適量的IL-10,功能是讓發炎不至於太強烈而傷害自己組織,但是如果IL-10量太高,反而會抑制白血球的吞噬功能而阻礙異位組織的清除,而高醫研究團隊利用小鼠模式與斑馬魚模式,發現IL-10居然還能促進血管的新生成,新生血管會讓幸運躲過攻擊的內膜組織生長於腹腔中,四處流竄與沾黏,最終變成子宮內膜異位瘤,成為婦女生活中的夢靨

[IL-10的雙重角色]

異位內膜組織中IL-10量太高,不僅阻礙了異位細胞清除,又促進血管新生成支持異位組織生長,那甚麼白血球會產生IL-10? 高醫研究團隊利用小鼠動物模式發現可能類漿性樹突細胞(plasmacytoid dendritic cell)在早期子宮內膜異位瘤生長時,就會產生IL-10支持子宮內膜異位瘤的生長與血管新生,而且在病人第四期子宮內膜異位瘤的病理組織中,也確實發現分泌IL-10的類漿性樹突細胞的蹤跡。

[結語]

我們正進行深入研究釐清類漿性樹突細胞在這疾病早期發展時的角色,還有哪些環境汙染物會影響免疫細胞產生IL-10的能力,希望將來能針對這複雜疾病提供預防與新的治療方法。

圖形摘要

11 子宮內膜異位組織

圖說:月經週期時部分子宮內膜組織會逆流回腹腔,內膜組織內的免疫細胞類漿性樹突細胞(pDC)可能在清除異位細胞時產生IL-10,若IL-10產量太高,會促進子宮內膜細胞遷移與血管新生,這可能奠定了早期異位瘤的發展,異位瘤長大後就有多種免疫細胞也會產生IL-10,而過多的IL-10使得疾病惡化快速,進入後期的發展,病人多在此時出現症狀並就醫治療。(本圖修改自Suen et al. J Pathol. 2019 Dec;249(4):485-497.)

本校主要研究者之簡介:

1.        高醫大醫研所孫昭玲副教授為本研究第一作者,研究領域為先天免疫細胞在過敏性氣喘的調控角色,近年也探究慢性發炎促進子宮內膜異位瘤癌化的免疫機制

2.        高醫大醫研所蔡英美教授為本研究責任作者,不只為高醫婦產科主治醫師,專長生殖醫學,也長期從事內膜異位症機制研究。

3.        高醫大生化學科侯自銓教授為本研究共同責任作者,專攻泌尿腫瘤與血管新生機制研究。

研究聯繫Emailjlsuen@kmu.edu.tw

期刊出處: J Pathol. 2019 Dec;249(4):485-497. doi: 10.1002/path.5339.

期刊線上參閱網址:https://pubmed.ncbi.nlm.nih.gov/31418859/ 

Popular Science Format in Academic and Research Column

[Introduction]

Endometriosis is a chronic inflammation-associated and common benign gynecological disorder. It affects 6–10% of women of reproductive age with syndromes, including dysmenorrhea, dyspareunia, and infertility. Because endometriosis recurrence following conservative surgery is relatively high, it substantially affects patients’ daily activities.   

[Lost way of endometrial tissue]

What is the pathogenesis of endometriosis? The wildly accepted hypothesis nowadays is the “retrograde menstruation/transplantation theory. The endometrial tissue shed during the menstrual cycle flow from the uterus into the peritoneal cavity. The retrograded cells or tissue are cleared by white blood cells. During this process, it would locally happen mild and transient inflammation in peritoneal cavity. If the process between clearance and inflammation keeps balance, the ectopic endometrial tissue can be effectively cleared and the inflammation would not damage the tissue in peritoneal cavity. Therefore, the lost-way endometrial tissue would not become endometriotic tumor and disturb daily activity in women of reproductive age.     

[Dysregulated inflammation]

What might disturb the balance between clearance and inflammation when retrograde tissue loses its way into peritoneal cavity? The research team led by Dr. Jau-Ling Suen at Kaohsiung Medical University discovered that the high local activity of anti-inflammatory cytokine IL-10 may promote the growth of the endometriotic tissue. It has been demonstrated that IL-10 can control unwanted inflammation to avoid tissue damage; however, high activity or level of IL-10 may inhibit the functions of white blood cells and diminish the clearance of ectopic tissue. In addition, Dr. Suen and her colleges discovered that IL-10 can promote angiogenesis through IL-10R signaling in vitro and in vivo, including a murine model as well as a zebra fish model. Thus, the IL-10-mediated angiogenesis may promote the growth of endometriotic lesions through enhancing angiogenesis during the early stage of endometriosis. 

[The dual activity of IL-10]

These findings discovered by Dr. Suen’s team suggest that the dual functions of IL-10 with respect to suppressing immunity against unwanted cells and promoting angiogenesis in the microenvironment may substantially contribute to the development of endometriosis. The next question is which immune cell type can secrete IL-10 in the microenvironment, particularly during the early stage of disease? Using a surgery-induced endometriosis murine model, Dr. Suen’s team demonstrated that local plasmacytoid dendritic cell (pDC), a key innate cell type in viral immunity, can secrete IL-10 to enhance angiogenesis in and promote growth of endometriotic lesions. In addition, IL-10–secreting pDCs have been found in the human endometrioma tissues, in which higher percentages of cells express IL-10 receptor and angiogenic marker CD31 compared with the corresponding normal counterparts.

[Conclusion]

We continue to put effort in elucidating the pathogenic role of IL-10–secreting pDCs and developing strategy targeting the IL-10–IL-10 receptor pathway in the endometriotic milieu.

Graphical Abstract

11 Endometriotic implants

Figure. The cartoon shows the effect and immune cell sources of IL-10 during the early and late stages of endometriosis. During the menstrual cycle and the early stage of endometriosis, retrograded endometrial cells or tissue enter peritoneal cavity. Lesion plasmacytoid dendritic cells (pDCs) may produce IL-10 in response to unwanted cells. Local IL-10 further promotes lesion growth by either suppressing anti-ectopic fragment immunity or stimulating angiogenesis. During the late stage of disease, the complex interaction among genetic factors, endogenous hormones, environmental endocrine disruptors (EEDs), and impaired immune surveillance leads to chronic inflammation. In the context of chronic inflammation in the peritoneal cavity, other immune cells can secrete IL-10 and other mediators to further promote the growth and maintenance of ectopic implants. [The figure is cited from Suen et al. 2019. (J Pathol. 2019 Dec;249(4):485-497)]

Main researcher Intro.

1.        Dr. Jau-Ling Suen, the first author, at Kaohsiung Medical University study the role of innate immune cells in the pathogenesis of allergic asthma and endometriosis.

2.        Dr. Eing-Mei Tsai, the corresponding author, a gynecologist and reproductive endocrinologist, at Kaohsiung Medical University Hospital. She has devoted in the mechanistic study in endometriosis.

3.        Dr. Tzyh-Chyuan Hour, the equally contributed corresponding author, at Kaohsiung Medical University focus on the mechanistic study in prostate cancer and angiogenesis.

Author Email

jlsuen@kmu.edu.tw

Paper cited from: J Pathol. 2019 Dec;249(4):485-497. doi: 10.1002/path.5339.

Paper online website: https://pubmed.ncbi.nlm.nih.gov/31418859/

口腔癌篩檢效益評估-學術研究與國家政策實務的連結

口腔癌是國人常見的十大癌症之一,在我國男性常見癌症發生部位更高居第五位,且我國口腔癌的平均發生年齡為55歲左右,比全世界口腔癌平均發病年齡足足早了10年,我國口腔癌好發於青壯年男性,發病後對家庭乃至於整體社會的影響甚鉅;且早期的口腔癌的治療預後相當良好,不僅五年存活率可達到8成以上,治療後對生活品質的影響亦相對較小,因此對口腔癌的防治上,如何發現早期口腔癌個案則是我國衛生單位相當關注的重點。

何佩珊副教授、王文岑醫師及楊奕馨教授團隊研究利用現存的國家級資料庫- 癌症登記系統、口腔癌篩檢資料庫及全國死因登記檔等三個資料庫進行統整,並經由統計模式進行分析,得到以下結果:1. 若單純針對有無參與篩檢來進行比較,發現有參與篩檢及沒有參與篩檢的口腔癌個案的癌症分期並沒有太大差異;2. 若進一步依據篩檢結果分析發現,篩檢發現口腔癌前病變的個案,之後被確診為口腔癌時,其癌症分期有較高的比例是屬於早期的診斷;綜合以上結果,我們提出一個重要結論,要提升口腔癌的篩檢效益的重點除了要鼓勵口腔癌高危險群民眾進行篩檢外,篩檢時若能對口腔癌前病變病灶做比較準確地辨別,使得口罹患腔癌前病變的個案能有機會做進一步的追蹤確診,對於提升我國口腔癌篩檢政策的效益較有幫助。本研究結果發表後,亦將本研究的結論提供我國口腔癌篩檢政策面的回饋,強調口腔癌篩檢時發現口腔癌前病變的重要性,我國國民健康署亦因此特別在口腔強篩檢策略中,強調篩檢口腔癌前病變的重要性並擬訂提升篩檢口腔癌前病變的準確度的相關策略。

本篇研究論文-“Finding an oral potentially malignant disorder in screening program is related to early diagnosis of oral cavity cancer-Experience from real world evidence.”由何佩珊副教授、王文岑醫師及楊奕馨教授團隊發表,在2019年刊登於”Oral Oncology”,該期刊在牙科領域排名為前10%(2017年領域排名為3/91=3.3%),在牙科專業領域上具相當權威性。本篇研究結合我國衛生福利部建置的癌症登記系統、口腔癌篩檢資料庫及全國死因登記檔等三個資料庫進行口腔癌篩檢效益的評估,並提供口腔癌篩檢政策規劃的參考。

論文:https://pubmed.ncbi.nlm.nih.gov/30732947/

Finding an oral potentially malignant disorder in screening program is related to early diagnosis of oral cavity cancer-Experience from real world evidence.

This paper is practiced by Dr. Pei-Shan Ho, Dr. Wen-Chen Wang, and Dr. Yi-Hsin Yang, and published in “Oral Oncology”, which is top 10% in (the ranking is 3/91=3.3% o f the Dentistry, Oral surgery and Medicine in 2017 JCR).

The Objectives of this study are to evaluate the effectiveness of the Taiwan Oral Mucosal Screening (TOMS) program in stage-shift among oral cavity cancer patients, and identifies the related factors with early cancer diagnosis. This retrospective cohort study used the Taiwan Cancer Registry (TCR), TOMS and

Taiwan Death Registry (TDR) databases. We identified oral cavity cancer patients (ICD-C-O: C00-C06) from the TCR during 2012–2015. Patients’ screening history, first screening status and subsequent screenings were

analyzed with cancer stages and survival outcomes.

The major results of this study is that the 5-year survival rates for stages 0–4 were 83.9%, 82.1%, 72.7%, 60.1% and 38.0%. Among 18,625 patients identified from the TCR, 37% did not have any prior screenings. Patients with prior positive or negativescreenings all had better survival rates (3-year: 71.4% and 68.7% vs. 63.5%, Log-rank p-value < 0.0001). Thebest chance for early-stage diagnosis occurs in oral potentially malignant disorder (OPMD, OR=1.99, 95% CI=1.78–2.22, p < 0.0001) patients at their first screenings. The hazard ratios (HR) for patients with prior screenings indicated a significant survival benefit. The group of incomplete diagnosis confirmation also has better survival (HR=0.78, 95% CI=0.81–0.93, p < 0.0001), and a greater chance of early diagnosis at

subsequent screenings. Some important conclusions was found in this study.  While TOMS improved stage-shift for early cancer diagnosis, we found no obvious differences in participants with cancers at screening (stages 0–1: 26.3% vs. 27.8% in non-screening group). Survival benefit and early diagnosis are found in most of screening groups, and identifying an OPMD is particularly essential to early diagnosis of oral cavity cancer patients.

Research available at :https://pubmed.ncbi.nlm.nih.gov/30732947/

內毒素為革蘭氏陰性菌細胞壁的成分,過去研究指出,居家室內空氣中內毒素會讓氣喘孩童氣喘症狀惡化,然目前尚不清楚家戶空氣污染物對空氣中內毒素與學童肺功能之間影響。本校公共衛生學系陳培詩主任研究團隊長期致力於探討室內空氣品質與孩童健康研究。研究團隊與美國德克薩斯大學休士頓醫學中心合作,針對高雄國小學童居家,探討室內空氣污染物是否會影響室內空氣中內毒素與學童肺功能之間的關係。論文近期刊登於《整體環境科學》(Science of the Total Environment) 其研究成果,對於公共衛生領域有重大研究貢獻,更進一步了解在氧和PM10濃度較高的環境,空氣內毒素越高,發現學童肺功能越不好,未來可藉由控制室內空氣中內毒素,達到保護呼吸道健康之目的。

 

陳培詩主任指出,內毒素為革蘭氏陰性菌細胞壁的成分,在空氣中,即使細菌死亡,從破碎之細胞壁釋出之內毒素,仍然有造成氣喘惡化之疑慮,然而,到目前為止,內毒素對過敏與肺功能影響結果並不一致,有動物實驗指出,空氣汙染物會影響內毒素對老鼠健康的關係,因此,本團隊與美國德克薩斯大學休士頓醫學中心合作,在高雄國小學童家中實際評估室內空氣污染物,例如:一氧化碳,二氧化碳,二氧化氮,二氧化硫,臭氧, PM10PM2.5對室內空氣中內毒素與學童肺功能關係的影響。本研究團隊發現學童居家空氣中臭氧和PM10的濃度均會顯著的影響空氣內毒素與學童肺功能之間的關係。 在臭氧和PM10濃度較高的家庭(臭氧0.01 ppmPM1062μg/ m3),空氣內毒素越高,發現學童肺功能越不好,但是在臭氧和PM10濃度較低的家戶(臭氧<0.01 ppmPM1062μg/ m3)的家庭中,就沒有此現象,本研究提供了過去研究結果不一致的原因,內毒素對健康的影響,其實還跟室內的臭氧與PM10有關。本研究經費由高雄市衛生局,高雄醫學大學及科技部教育部計畫共同支持。

 

圖形摘要

本研究團隊發現學童居家空氣中臭氧和PM10的濃度均會顯著的影響空氣內毒素與學童肺功能之間的關係。 在臭氧和PM10濃度較高的家庭(臭氧0.01 ppmPM1062μg/ m3),空氣內毒素越高,發現學童肺功能越不好,但是在臭氧和PM10濃度較低的家戶(臭氧<0.01 ppmPM1062μg/ m3)的家庭中,就沒有此現象

09 家戶臭氧和PM10會影響空氣內毒素與學童肺功能的關係

本校主要研究者之簡介:

陳培詩 研究員

研究聯繫Email:

pschen@kmu.edu.tw

期刊出處:

Science of the Total Environment 705 (2020) 135810

研究全文下載:

https://www.sciencedirect.com/science/article/pii/S004896971935805X

Endotoxin is the constituent of the cell wall of gram-negative bacteria that initiates the inflammatory response. Previous studies showed consistent results that airborne endotoxin exposure may increase the risk of respiratory symptoms in asthmatic children. Moreover, previous studies displayed that the air pollutants- nitrogen dioxide (NO2) and nicotine may modify the association between airborne endotoxin and asthma outcome (acute visit, symptoms, etc.) and airway inflammation (the fractional concentration of exhaled nitric oxide) in asthmatic children.  

So far, limited studies have explored the effects of interactions between airborne endotoxin and air pollutants. The team led by Pei-Shih Chen, the Chair of Public Health of Kaohsiung Medical University, evaluated whether indoor air pollutants in a heavy industrial city, including NO2, PM, the carbon monoxide (CO), carbon dioxide (CO2), sulfur dioxide (SO2), and ozone (O3), can modify the association between indoor airborne endotoxin and lung function. 120 elementary school-age children in Kaohsiung City, Taiwan was recruited. Airborne endotoxin and air pollutants were collected for 24 hours in living rooms while schoolchildren’s lung function was measured. The modification of air pollutants on the relationship between airborne endotoxin and children’s lung function was estimated after adjusting the gender, age, height, weight, and case-control status. The team in collaborating with Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, TX, United States, found that household O3 and PM can modify the association between household airborne endotoxin and lung functions. Our findings suggest that the combination of higher concentrations of O3 or PM10 exposure and concomitant indoor airborne endotoxin exposure may affect schoolchildren’s lung function in a heavy industrial city. These findings also highlight the importance of understanding the complexity of indoor exposures and their effects on lung functions to develop effective approaches to environmental control. The results have been published in the journal Science of the Total Environment .

 

Graphical Abstract

Our findings suggest that the combination of higher concentrations of O3 or PM10 exposure and concomitant indoor airborne endotoxin exposure may affect schoolchildren’s lung function in a heavy industrial city.

09 Indoor ozone and particulate matter modify the association between

Main researcher Intro.

Researcher Pei-Shih Chen

Author Email

pschen@kmu.edu.tw

Paper cited from:

Science of the Total Environment 705 (2020) 135810

Research Paper available online on website

https://www.sciencedirect.com/science/article/pii/S004896971935805X

辛伐他汀透過保護粒線體對抗血管緊張素II所引發的心臟衰竭

 

在常見的心血管疾病包括「心臟衰竭」,通常伴隨著有粒線體功能障礙的情形。而羥甲基戊二酸單醯輔酶A還原酶(他汀類藥物)能夠抑制有害的氧自由基的產生,因此在慢性心臟衰竭中具有心臟保護作用。但是,他汀類藥物在心臟衰竭過程中是如何達到效果的? 以及對於心肌細胞內的能量提供的來源「粒線體」是否也有保護作用?這是我們研究團隊欲探索的項目。

    透過心衰竭大鼠的動物實驗方式,我們團隊將大鼠分成: 1) 給予血管緊張素II1.5 mg / kg //14天。2血管緊張素II合併給予辛伐他汀組(口服10 mg/kg經治療14天後在接下來的14天中停止給藥,終止實驗。

    我們的研究成果發現:血管緊張素II會促進細胞內氧自由基的生成進而降低了粒線體的膜電位,導致粒線體的失能或是被破壞。然而透過給予辛伐他汀能夠有效地避免胞內氧自由基的生成進而維持了粒線體的膜電位使粒線體不致失能。而其中的關鍵在於辛伐他汀能夠在粒線體受損透過溶酶體將脂質油滴分解成脂肪酸產生能量,讓細胞有機會透過細胞自噬體來將受損的粒線體修復、或是移除。進而保護並維持細線體的功能,減緩心臟衰竭過程中對於心肌細胞的傷害。

圖形摘要

08 辛伐他汀透過保護粒線體對抗血管緊張素II所引發的心臟衰竭 

 

圖片說明: 管緊張素II促進細胞內氧自由基的增加,降低了粒線體的膜電位,促使粒線體產生障礙無法提供心肌能量。透過給予辛伐他汀能夠有效地降低氧自由基並維持了粒線體的膜電位。同時辛伐他汀促進脂質油滴聚集於受損的粒腺體周圍並分解成脂肪酸提供粒線體透過自噬體的方式來自我修復,或是將無用的粒線體移除、進而維持細線體的功能減緩心臟衰竭對於心肌所帶來的傷害。

 

本篇為高雄醫學大學2019年月傑出論文10月份得獎文章,代表作者為醫學院呼吸治療學系劉博侖教授。

 

本校主要研究者之簡介:

論文第一作者為本校臨床醫學所博士班學生謝炯昭主治醫師,其為本校呼吸治療學系劉博侖教授所領導的團隊的一員。感謝科技部提供研究經費。

研究聯繫Email:

kisa@kmu.edu.tw

期刊出處:

British Journal of Pharmacology. 2019 Oct;176(19):3791-3804.

期刊線上參閱網址:

https://pubmed.ncbi.nlm.nih.gov/31265743/

Mitochondrial protection by simvastatin against Angiotensin II-mediated heart failure

 

BACKGROUND AND PURPOSE

Mitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), which inhibit reactive oxygen species (ROS) synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear.

EXPERIMENTAL APPROACH

Rats were treated with Angiotensin II (Ang II) (1.5 mg/kg/day) or co-administered simvastatin (oral, 10 mg/kg) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated and intracellular ROS and mitochondrial membrane potential (ΔΨm) changes were measured by flow cytometry and JC-1 staining, respectively. Autophagy and mitophagy-related and mitochondria-regulated apoptotic proteins were identified by immunohistochemistry and western blotting.

 

Graphical Abstract

 08 Mitochondrial protection by simvastatin against Angiotensin II mediated heart failure

This article-“Mitochondrial protection by simvastatin against angiotensin II-mediated heart failure” , written by Rept. Author Professor Po-Len Liu from Department of Respiratory Therapy in College of Medicine,, is presented for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in Oct.

 

Main researcher Intro.

Summary scheme of the mitochondrial protection mechanism of simvastatin in Ang II-induced HF. Simvastatin might reduce ROS generation, regulate LDs and lysosome levels to provide energy to maintain ΔΨm, regulate mitochondrial quality control to promote mitophagy, and prevent mitochondrial-regulated apoptosis.

 

Researcher

The first author of the paper is the attending physician Chong-Chao Hsieh, a student of the School of Clinical Medicine, and a member of the team led by Professor Po-Len Liu of the Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University. Thanks to the Ministry of Science and Technology for providing research funding.

 

Author Email

kisa@kmu.edu.tw

Paper cited from:

kisa@kmu.edu.tw

Paper online website

https://pubmed.ncbi.nlm.nih.gov/31265743/

擾亂登革病毒增殖的殺手:前列腺素(Prostasin)基因

登革病毒是藉由蚊子傳播的病毒,埃及斑蚊(Aedes aegypti)或白線斑(Aedes albopictus)是最主要的病媒蚊,登革病毒感染會導致威脅生命的疾病,例如登革出血熱或登革熱休克症候群。在熱帶和亞熱帶地區是一個嚴重的公共衛生問題,台灣位於熱帶和亞熱帶地區的交界處,每年都有登革病毒感染病例,特別是在台灣南部,在2014年至2015年,台南和高雄就曾經爆發登革病毒感染,感染病毒的人數分別超過一萬和兩萬多人,且造成百餘人死亡。目前並尚未有有效的疫苗和藥物用於預防和臨床治療,因此,尋找具有抗登革病毒感染之潛力藥物標靶是重要的研究議題。眾所周知,病毒是一種寄生的病原體,也就是說,病毒的增殖需要依賴宿主基因表達的支持。在過去數年中,高雄醫學大學李景欽教授和陳彥旭醫師合作致力於了解登革病毒複製機制並尋找引起登革熱疾病的標靶基因。根據臨床檢驗分析,研究團隊首先發現,相較於健康個體,登革熱患者血液樣本中前列腺素(prostasin) (一個細胞膜蛋白酶)的表達量較低,並進而揭示前列腺素表達量跟登革病毒RNA感染量呈現負相關,意即,病毒感染量越多,前列腺素量越少。而回到實驗室進行一系列的細胞學實驗,結果顯示登革病毒感染確實會顯著降低前列腺素基因表現量。因此,研究小組認為登革病毒感染會抑制前列腺素表現的原因是因為前列腺素會對病毒登革病毒的增殖產生干擾作用。為了證明這個假設,研究小組在登革病毒感染的細胞或小鼠中大量表達外源性的前列腺素,結果發現大量表達的前列腺素確實可以抑制病毒增殖並保護小鼠免於受登革病毒感染的死亡威脅,意即減緩老鼠的死亡率。由進一步的抑制機轉的研究顯示,前列腺素對登革病毒增殖的抑制作用是藉由抑制上皮生長因子受體(epithelial growth factor receptor; EGFR)的表達,進而導致Akt /NF-B調控的環氧合酶-2cyclooxygenase-2; COX-2)訊息路徑受到抑制。先前研究小組的研究已經證實登革病毒增殖需要COX-2訊息路徑的活化。同時根據報導,EGFR活化路徑會擾亂細胞干擾素(Interferon)的抗病毒反應,進而達到幫助病毒增殖的目的。因此,前列腺素透過降低EGFR的表達,進而恢復干擾素和干擾素所誘發的抗病毒基因的表達,包括2'-5'-寡腺苷酸合成酶1 OAS1),OAS2OAS3和雙鏈RNA依賴性蛋白激酶(PKR)而達到抗病毒目的。總之,我們的結果證明前列腺素的表達是一個值得做為臨床診斷標記的特徵,同時也提供治療登革病毒感染的潛在靶標。

圖形摘要

07 前列腺素藉由降低EGFR蛋白進而抑制登革病毒複製的模型

前列腺素藉由降低EGFR蛋白進而抑制登革病毒複製的模型。

1. 前列腺素的外源表達保護老鼠免受登革病毒感染造成的的死亡並抑制病毒的繁殖。

2. 前列腺素的抗病毒機制是降低上皮生長因子受體(EGFR)的表達量,導致抑制Akt/NF-B所調控的環氧合酶2COX-2)訊息傳遞路徑而不利於病毒增殖。

本校主要研究者之簡介:

團隊負責人是本校生物科技學系李景欽教授,合作的臨床檢驗負責人是陳彥旭醫師/教授。 合著者包括:林俊光(第一作者,博士生),曾敬凱,吳宇軒,林俊佑(臨床醫生; 博士),黃崇豪(臨床醫師; 博士),王文宏博士,廖志中教授。

研究聯繫Email:

李景欽: jclee@kmu.edu.tw

陳彥旭: infchen@gmail.com

期刊出處:

The Journal of Infectious Diseases, the 16th of April 2019. “Prostasin impairs epithelial growth factor activation to suppress dengue virus propagation”

期刊線上參閱網址:

https://academic.oup.com/jid/article-abstract/219/9/1377/5200723?redirectedFrom=fulltext

Prostasin gene expression interferes dengue virus propagation 

Dengue virus (DENV) is a mosquito-transmitted virus. The most important vector mosquito is the Aedes aegypti or Aedes albopictus. DENV infection leads to life-threatening diseases, such as dengue hemorrhagic fever or dengue shock syndrome. It is a serious public health problem in tropical and subtropical regions of the world. Taiwan is located at the junction of tropical and subtropical regions and had cases of dengue infections every year, especially in southern Taiwan. An outbreak of dengue infections occurred in Tainan and Kaohsiung from 2014 to 2015, there are more than 10,000 and 20,000 dengue-infected patients and hundreds of deaths, respectively. Currently, there are no effective vaccines and drugs used in the prevention and clinical treatment. Therefore, searching for a potential target for drug development against DENV infection is an important issue. As we know, the virus is a parasitic pathogen, that is, virus propagation needs the support of host gene expression. In the past year, Prof. Jin-Ching Lee and Dr. Yen-Hsu Chen focus on the understanding of dengue virus replication and to find the target against DENV-caused diseases. Based on clinical studies, the research team first found the relatively low expression of prostasin, a membrane protease, in blood samples from patients with dengue fever compared with healthy individuals and further revealed a negative correlation between prostasin expression and DENV RNA copy number, that is, more amount of virus infection resulted in the lower amount of prostasin. In the laboratory experiment of cell-based assay, the results indicated that DENV infection significantly decreased prostasin RNA levels. Therefore, the research team suggested that the reason why the DENV inhibits prostasin is due to the interference of prostasin on virus DENV propagation. To prove this hypothesis, we express the exogenous prostasin in DENV-infected mice and found that the over-expressed prostasin could protect DENV-infected mice from life-threatening DENV infection. Further mechanistic studies showed that inhibition of DENV propagation by prostasin was due to reducing expression of epithelial growth factor receptor (EGFR), leading to suppression of the Akt/NF-kB -mediated cyclooxygenase-2 (COX-2) signaling pathway. Previously, the research team had proved that COX-2 expression is required for DENV propagation. Meanwhile, EGFR activation was reported to facilitate virus propagation by interfering antiviral-mediated interferon responses. Therefore, the overexpression of prostasin induced the expression of IFN and IFN-stimulated antiviral genes, including 2-5-oligoadenylate synthetase 1 (OAS1), OAS2, OAS3, and double-stranded RNA-dependent protein kinase (PKR) for its antiviral activity. In conclusion, our results demonstrate prostasin expression as a noteworthy clinical feature as a clinical biomarker and a potential therapeutic target against DENV infection.

07 Model for the mechanism of prostasin mediated inhibition of DENV replication via modulation of EGFR proteolysisjpg 

Model for the mechanism of prostasin-mediated inhibition of DENV replication via modulation of EGFR proteolysis.

Exogenous expression of prostasin protected ICR suckling mice from DENV-induced mortality and suppressed DENV propagation. The antiviral mechanism of prostasin was the reduction effect on EGFR, leading to suppression of the Akt/NF-kB-mediated cyclooxygenase 2 (COX-2) signaling pathway.

This article-“Prostasin Impairs Epithelial Growth Factor Receptor Activation to Suppress Dengue Virus Propagation” , written by Rept. Author Prof. Jin-Ching Lee, from Department of Biotechnology, is award for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in May.

Main researcher Introduction:

The team leader is Prof. Jin-Ching Lee. The collaborative clinical leader is Dr. Yen-Hsu Chen (Ph.D.). The co-authors include Chun-Kuang Lin as first author (a Ph.D. student), Chin-Kai Tseng, Yu-Hsuan Wu, Chun-Yu Lin (a clinical Doctor), Chung-Hao Huang (a clinical Doctor), Dr. Weng-Hung Wang, Prof. Chih-Chuang Liaw.

Author Email

Prof. Jin-Ching Lee: jclee@kmu.edu.tw

Dr. Yen-Hsu Chen: infchen@gmail.com

Paper cited from:

This study was published online in The Journal of Infectious Diseases, the 16th of April 2019. The full research article entitled “Prostasin impairs epithelial growth factor activation to suppress dengue virus propagation”

Paper online website: https://academic.oup.com/jid/article-abstract/219/9/1377/5200723?redirectedFrom=fulltext

全球有1/3C型肝炎患者位於亞洲,慢性C型肝炎小分子抗病毒藥物(DAA既往亞洲真實世界報告多為日本單中心或單一醫療體系發表。亞洲C型肝炎分布人口學及地域分佈複雜,在亞洲多國綜觀的大規模治療報告仍付之闕如。此研究針對亞洲多國慢性C型肝炎患者接受小分子抗病毒藥物的真實世界療效及安全性作進一步探討。REAL-C (Real-world Evidence from the Asia Liver consortium for HCV)為亞洲多國包含台灣、日本、韓國及香港超過20個多中心大規模C型肝炎研究聯盟註冊系統(Registry),此研究的主要目的為探討亞洲C型肝炎族群小分子抗病毒藥物療效(持續性病毒反應;定義為抗病藥物停藥後12週體內偵測不到病毒;SVR12)及安全性研究,以及探討新藥治療失敗原因。本研究收錄來自台灣、日本、韓國及香港一共6,287慢性C型肝炎患者接受小分子抗病毒藥物。相較其他國家患者,日本患者年紀較老、身體質量比少,且有較高比例非肝癌惡性腫瘤。整體亞洲族群C肝治療療效為96.4%,且無種族之間差別。不同藥物及不同肝病嚴重程度整體治療成果在91.1%99.4%之間唯病毒基因型第一型肝硬化干擾素治療失敗患者使用daclatasvir/asunaprevir(87%)及第二型肝硬化干擾素治療失敗患者使用sofosbuvir/ribavirin(85.9%)有較差治療療效。整體治療中斷率為1.9%且無種族之間差別。多變項結果顯示與治療失敗有關因素為高病毒量、肝硬化及之前DAA治療失敗經驗。種族地域差異非影響治療療效之獨立預測因子。此多國多中心研究顯示小分子抗病毒藥物可有效及安全治療亞洲慢性C型肝炎患者,此實證醫學證據可對於疾病負擔沉重的亞洲國家提供C肝治療真實世界證據及各國C肝公衛政策制定之參考

圖形摘要

 06 亞洲慢性C型肝炎患者接受治療小分子抗病毒藥物REAL C大規模真實世界研究

本篇為高雄醫學大學2019年月傑出論文9月份得獎研究,代表作者為肝炎研究中心黃釧峰教授。

本校主要研究者之簡介:

黃釧峰 教授

高醫 肝膽內科

高醫大內科學科

研究聯繫Email:

fengcheerup@gmail.com

期刊出處:

Hepatol Int. 2019 Sep;13(5):587-598.

研究全文下載:

https://link.springer.com/article/10.1007/s12072-019-09974-z

Direct-acting antivirals in East Asian hepatitis C patients: Real-world experience from the REAL-C Consortium

Background & Aims

One-third of the global hepatitis C virus (HCV) burden is found in Asia. Real-world data from diverse East Asian cohorts remain limited. This study addressed the real-world status of direct-acting antiviral (DAA) therapy among patients from East Asia.

Methods

Chronic hepatitis C (CHC) patients from clinical sites in Japan, Taiwan, South Korea and Hong Kong were recruited in the REAL-C registry, an observational chart review registry. The primary outcome was sustained virologic response (SVR12, HCV RNA PCR .

Results

A total of 6,287 CHC patients were enrolled. Compared to other East Asian patients, patients from Japan were older (66.3 vs. 61.5 years, p<0.0001), had lower body mass indices (22.9 kg/m2 vs. 24.6 kg/m2, p<0.001), and were more likely to have non-liver malignancy history (12.2% vs. 5.0%, p<0.001).The overall SVR12 rate was 96.4%, similar to patients both inside and outside Japan (96.6% vs. 96%, p=0.21). The SVR12 rate ranged from 91.1-99.4% except treatment-experienced cirrhotic HCV genotype-1 patients who received daclatasvir/asunaprevir (85.9%) and the treatment-experienced cirrhotic HCV genotype-2 patients treated with sofosbuvir/ribavirin (87%). The overall rate of drug discontinuation was 1.9%, also similar across regions. Logistic regression analysis revealed that significant independent factors predictive of treatment failure were higher HCV RNA levels (odds ratio [OR], 95%CI: 0.73, 0.59-0.90; p=0.004), the presence of liver cirrhosis (0.68, 0.49-0.84, p=0.046), prior treatment failure with IFN (0.57, 0.42-0.79, p=0.001), and prior treatment failure with DAA other than BOC and TVR (0.04, 0.02-0.08, p<0.001), but not geographic region (non-Japan versus Japan, 1.09, 0.74-1.60, P=0.68).

Conclusions 

In this large multinational CHC cohort from the East Asia, oral DAAs were highly effective and well-tolerated across the region. Policies should encourage treatment for all CHC patients with DAAs in Asia with its heavy burden of HCV.

Graphical Abstract

 06 Direct acting antivirals in East Asian hepatitis C patients

This article-“Direct-acting antivirals in East Asian hepatitis C patients: real-world experience from the REAL-C Consortium” , written by Rept. Author researcher Chung-Feng Huang, from Hepatitis Research Center, is award for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in Sept.

Main researcher Intro.

Researcher :

Chung-Feng Huang MD.PhD.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

Author Email

fengcheerup@gmail.com

Paper cited from:

Hepatol Int. 2019 Sep;13(5):587-598.

Research Paper available online on website https://link.springer.com/article/10.1007/s12072-019-09974-z

第 1 頁,共 10 頁