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標題: 六價鉻和三價鉻對人類腎皮細胞生長的差異影響與它們個別的生物意義
The differential effect of hexavalent and trivalent chromium on the growth of human kidney epithelial cells and their respective biological significance
作者: 戴偉竣
Wei-Chun Tai
關鍵字: 六價鉻;三價鉻;自噬作用;hexavalent chromium;trivalent chromium;autophagy
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隨著新時代進步的工業化與家庭用具、用品的現代化,許多具有耐熱、抗蝕、防鏽特性的重金屬也逐漸被帶入每個人的家裡面,例如:不鏽鋼水管、水龍頭、不鏽鋼鍋、不鏽鋼飲水器、果汁機、菜刀等等,慢慢地影響每個人、每天的生活。尤其,鉻在人體中是必需的微量元素,三價鉻在糖和脂肪的代謝作用中更具有特殊作用;在天然食品中,三價鉻存在於啤酒酵母、糖蜜、乾酪、蛋、蘋果皮、香蕉、麵粉、馬鈴薯、肉類產品以及內臟等等,可知三價鉻自有其的生物意義。可是,自然界最常見到的六價鉻卻對人體有毒。六價鉻除了會造成皮膚、腸道、胃和腎臟的直接傷害,並會增加肺部、腸胃和腎臟罹患癌症的風險。吸入含鉻粉塵能顯著地增加六價鉻所引發的肺癌。此外,香菸或電焊粉塵中所含的微量鉻金屬,會先累積在肺中,然後經由肺泡被吸收進入循環系統,抵達全身各部重要臟器,尤其是腎臟。雖然六價鉻傷害過後曾有兩種和腎元與腎管的修補有關之腎臟母細胞被發現;六價鉻對這些細胞的生物反應至今仍未完全了解。另一個具謎樣的問題即是三價鉻對DNA/RNA的效應,三價鉻已知能在DNA/RNA的核苷酸鹼基上產生附加物 (adducts),藉此穩定核苷酸,防止基因物質的突變並預防癌症。可是,有機多環碳氫芳香族 (polycyclic hydrocarbons) 與DNA/RNA上的核苷酸鹼基所產生的附加物卻是導致基因變異和細胞癌化的主因。因此,三價鉻所衍生的核苷酸鹼基附加物的防癌作用,就成我們的研究方向之一。本研究的目的就是探討六價鉻和三價鉻對人類腎皮細胞生長的差異影響與它們個別的生物意義。我們發現六價鉻處理增加細胞表現間質細胞和幹細胞的標記蛋白,說明腎皮細胞轉化為間質細胞或幹細胞,可能是細胞對抗惡劣環境的自然反應,而這種結果的生物和醫學應用,尤其是腎皮細胞再生與腎臟功能的修護更有特殊的潛在意義。此外,這種發現應該也可以應用到皮膚的再生方面。我們已知道在美容界有幾類的神經醯胺被用在化妝品中以為保濕之用,而這些神經醯胺都是可在皮膚表層發現的游離性神經醯胺,主要是糖化神經醯胺;而這些化學物也都侷限在皮膚表皮細胞,以免傷害其他具生長功能的有核細胞,可能是因為神經醯胺會與離子通道作用而影響膜的通透性,尤其是暴露於神經醯胺中,會活化atg6 而引發自噬作用。我們也發現三價鉻會引起大量的HK-2細胞自噬,但是不會引起細胞凋亡或直接死亡;此外有機三價鉻也被大量用在預防、治療胰臟beta細胞第二型糖尿病的胰島素缺失,應用類似的原理到肌膚保養上,有機三價鉻應該可以與神經醯胺互補共用,或者直接取代神經醯胺。它們的基本機制可能落在會引起細胞自噬,明確的加強細胞胞器與蛋白質、脂肪類的新陳代謝。

Following advanced industrialization of the new century, as well as the modernization of family utensils and consumables, many heavy metals, which consist of beneficial effects, such as heat-, corrosion and rust-resistance, are gradually forced into everybody's everyday life. In particular, stainless pipes, water faucets, stainless cooking wares, stainless drinking machines, blenders, and kitchen knives that contain metallic chromium are becoming indispensable. In fact, chromium, as essential microelements in human bodies, plays significant roles in the metabolism of ingested sugars and fats. In natural foods, trivalent chromium [Cr(III)] has been frequently detected in beer yeasts, honey, dry cheeses, eggs, apple peels, bananas, wheat flour, potatoes, meat products and livestock entrails, suggesting the biological significance of Cr(III) in the Nature. However, the naturally most prevalent hexavalent chromium [Cr(VI)] is toxic to the human bodies, which could directly damage human lungs, gastrointestinal tracts and kidneys as well as increase carcinogenesis risks of those organs. Inhaled chromium dusts could markedly elevated lung cancer incidences. Even traced amounts of chromium in the cigarette or from electric welding could be accumulated first in the lungs before absorbing through pulmonary alveoli into the circulation system, and distributed to the important organs, including kidneys. Although following chromium damage, kidney progenitor cells, which are closely associated with glomerular and tubular repairs, have been identified, the biological effect of Cr(VI) on these cells have not been well studied. Our lab had recently characterized these cells and their biological responses post-chromium insults. In addition, the biological function of Cr(III) in the formation of DNA/RNA adducts that could strengthen DNA/RNA structural stabilization to prevent genetic mutations as well as carcinogenesis intrigues us to pursue their difference from DNA/RNA adducts formed by polycyclic aromatic hydrocarbons (PAH). Therefore, the aims of this study are to investigate the differential effect of hexavalent and trivalent chromium on the growth of human kidney epithelial cells and their respective biological significance. Our results showed that Cr(VI) could increase expressions of epithelial-to mesenchymal transition and stem cell markers of human kidney epithelial HK-2 cells. Such reactions could be spontaneous responses of human kidney epithelial cells. The biological and medical applications of these findings to the regeneration of kidney epithelium and repair of kidney functions could be tremendous. Moreover, these results could be applied to the skin maintenance and restoration. As we already know that several kinds of ceramide have been used for cosmetic moisturization, and these ceramides, in particular, the glycosylated ceramides, are nature products of the skin, which are secreted by the epidermis to protect underlying growing basal layers via affecting ion channels. Nonetheless, exposure to ceramide could activate ATG6 to provoke cell autophagy, which corresponded well with our observations that showed Cr(III) could induce massive autophagy as well. Cr(III)-induced autophagy, however, did not directly lead to cell apoptosis or cell death. Our result further support the previous findings in application of Cr(III) in prevention of type II diabetes. Such theories could be applied to the youthful skin maintenance. Organic trivalent chromium could be complimentary to the use of ceramide, or Cr(III) could replace ceramide usage directly in the future to induce functional cosmetic autophagy as well as to maintain organelle activities and metabolism of proteins and lipids.
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