醫學與健康科學

Substance losses, burns and injuries arising from various causes represent a constant problem encountered by homo sapiens throughout its existence. Rudimentary treatments, relatively effective and less effective, have left their mark on the way we perceive the presence and treatment of wounds caused by various factors. Searching through medical archives, we can trace the specific protocols for these medical conditions back to 2200 BC, when they were structured in three steps: 1) cleaning the skin lesion, 2) applying a dressing (from glue to various preparations) and 3 ) bandaging the skin lesion. Currently, the appearance of wounds on the skin is caused both by accidents in the performance of various activities and by certain diseases that manifest themselves through skin rashes or skin lesions. Their frequency is in the thousands, according to the latest statistics, affecting the majority of the population non-selectively. It is vital that skin lesions receive the necessary care and attention, commensurate with their severity. Being open wounds on the surface of the skin, it is essential that the treatment be meticulous and appropriate to their type, as skin lesions represent a threat to the patient's life. From infections to hydroelectrolytic imbalances specific to burns, the multitude of factors that influence healing highlight the need for a dressing that can be easily customized according to the specificity of the wound, the needs of the patient and that is affordable both from the point of view of production cost as well as its use, making death from skin lesions easily avoidable through an intelligent approach. One of the most complex biological processes and indispensable to humans is the healing of skin lesions. Healing involves a carefully regulated series of biochemical and cellular activities in tandem. Traditional therapies and substances of natural origin have been used to facilitate the regeneration process and accelerate the wound healing process, being applied with encouraging results. Despite the fact that these generally present a low cost, they can be more expensive than contemporary treatments and can be influenced by regional, seasonal factors, showing fluctuations from batch to batch, which could lead to unpredictable allergic reactions, side effects and inconsistent clinical findings. Currently, the standard of care for skin lesions is to clean the wound with antiseptic solutions to prevent infection, apply a dressing followed by bandaging to keep the dressing in place, and if necessary excision of the tissue that has become non-viable. In the case of diabetic ulcers, it is necessary to excise the tissue that has become non-viable and to maintain control over the level of glucose in the body.

Calcineurin (CN) activation is a main cause of cancerous tumor formation, one of the leading causes of death globally. Cyclosporine-A (CsA) is a commercially available oral drug that inhibits CN activation; however, low bioavailability limits its use. Nine patented CsA conjugates are potential alternatives to CsA as they have improved cytotoxicities and bioavailabilities but unknown CN-binding affinity. This study aimed to identify the CNinhibition strength and bioavailability of CsA conjugates in silico drug-likeness evaluation via modified Lipinski’s Rule of Five was done on CsA, voclosporin, and CsA conjugates to test bioavailability. The binding affinities of bioavailable compounds were computed via docking to CN in five trials, and the binding affinities were compared. The Water-soluble, RVal, IIA, Alpha, and MeBmt 2 conjugates showed improved bioavailabilities compared to CsA as they passed the drug-likeness screening. After five trials of computational docking to CN, the IIA and RVal conjugates showed improved binding affinities at -15.8 kcal/mol and -15.2 kcal/mol, respectively, compared to CsA at -14.3 kcal/mol. Notably, IIA also showed an improved binding affinity compared to voclosporin at -15.5 kcal/mol. These results suggest that CsA conjugates may be better oral chemotherapeutic drugs than CsA.

慢性腎衰竭的病人係腎功能在幾個月到數年期間逐漸而難以逆轉的衰退，其中腎臟纖維化在慢性腎臟病中的一個重要病理變化。此種現象主要是發生在腎臟的腎單位經由過濾或再吸收過程所造成。一旦腎臟損傷時腎絲球或空腔滲透發炎細胞活化，因而產生 ROS、纖維化訊息和發炎細胞激素等訊息。淋巴細胞質蛋白-1 (LCP-1) 是一種 F-肌動蛋白結合蛋白，與多種惡性腫瘤和非酒精性肝炎有相關性。但 LCP-1 在腎小管間質纖維化之功能性角色及分子機轉，至今仍然未知。本研究利用臨床慢性腎衰竭病人資料及細胞模式來釐清 LCP-1 是腎小管間質纖維化之生物指標蛋白及其調控腎小管間質纖維化之分子機制。

二甲雙胍(metformin)為第二型糖尿病的口服藥。現有研究已知粒線體在肝癌組織中有過度表現的情形，且二甲雙胍與粒線體自噬作用相關然其機制尚未清楚，故本研究探討二甲雙胍對於肝臟細胞粒線體自噬作用的活化機制以了解其是否具肝癌治療的潛力。以西方墨點法測試加入二甲雙胍前後人類肝癌細胞(Huh7)的 LC3B-I、LC3B-II的表現，發現加藥後表現上升。以串聯螢光標記實驗，透過螢光顯微鏡觀察加藥前後粒線體的型態從線狀變為橄欖球狀，LC3表現上升，PARKIN有明顯位移至粒線體外膜的情形，顯示二甲雙胍可刺激自噬體的形成。並透過 mito-QC(mito-quality control)的技術，可觀察到加藥後粒線體與溶酶體結合的情形也有所提升。本研究推論二甲雙胍可活化人類肝癌細胞中 PINK1-PARKIN 依賴型選擇性粒線體自噬作用的形成，未來有望應用於肝臟疾病相關治療。