Table_1_Synergistic Effects and Mechanisms of Combined Treatment With Harmine Hydrochloride and Azoles for Resistant Candida albicans.docx

Several studies have demonstrated the significant antiviral, antimicrobial, antiplasmodial, antioxidative, antifungal, antimutagenic, and antitumor properties of harmine hydrochloride (HMH). The main objective of the present study was to investigate the antifungal effects and underlying mechanisms of HMH when combined with azoles to determine whether such combinations act in a synergistic manner. As a result, we found that HMH exhibits synergistic antifungal effects in combination with azoles against resistant Candida albicans (C. albicans) planktonic cells, as well as resistant C. albicans biofilm in the early stage. Antifungal potential of HMH with fluconazole was also explored in vivo using an invertebrate model. Our results suggest that HMH combined with azoles is synergistic against resistant C. albicans in vitro and in vivo. No synergy is seen with azole sensitive C. albicans strains nor with other Candida species. Such synergistic mechanisms on resistance C. albicans are involved in increasing intracellular azoles, inhibiting hyphal growth, disturbing cytosolic calcium concentration, and inducing apoptosis of resistant C. albicans cells.

多项研究已证实盐酸哈拉明（HMH）在抗病毒、抗菌、抗疟、抗氧化、抗真菌、抗突变和抗癌等方面具有显著的功效。本研究的首要目标是探讨盐酸哈拉明与唑类药物联合使用时的抗真菌作用及其潜在机制，以确定这种联合作用是否呈现协同效应。研究结果表明，盐酸哈拉明与唑类药物联合使用，对耐药性白色念珠菌（C. albicans）浮游细胞以及早期阶段的耐药性白色念珠菌生物膜，均表现出协同的抗真菌作用。此外，本研究还利用无脊椎动物模型，在体内探索了盐酸哈拉明与氟康唑的抗真菌潜力。我们的研究结果表明，盐酸哈拉明与唑类药物的联合使用在体外和体内对耐药性白色念珠菌均呈现协同作用，而与对唑类药物敏感的白色念珠菌菌株及其他念珠菌属物种则未观察到协同效应。这种对耐药性白色念珠菌的协同机制涉及增加细胞内唑类药物浓度、抑制菌丝生长、扰乱细胞质钙离子浓度以及诱导耐药性白色念珠菌细胞的凋亡。