Al-Khazaleh Ahmad K, Alsherbiny Muhammad A, Chang Dennis, Münch Gerald, Bhuyan Deep Jyoti
NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia.
Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Int J Mol Sci. 2025 Jul 30;26(15):7369. doi: 10.3390/ijms26157369.
Lymphoma continues to pose a serious challenge to global health, underscoring the urgent need for new therapeutic strategies. Recently, the gut microbiome has been shown to play a potential role in regulating immune responses and influencing cancer progression. However, its molecular mechanisms of action in lymphoma remain poorly understood. This study investigates the antiproliferative and apoptotic activities of gut microbiota-derived metabolites, specifically nisin (N) and urolithin B (UB), individually and in combination 7:3 (5750 μM), against the human lymphoma cell line HKB-11. Comprehensive evaluations were performed using Alamar Blue viability assays, combination index (CI) analyses, reactive oxygen species (ROS) quantification, flow cytometry for apoptosis detection, and advanced bottom-up proteomics analyses. N and UB exhibited potent antiproliferative activity, with the 7:3 combination demonstrating strong synergistic effects (CI < 1), significantly enhancing apoptosis ( < 0.01) and ROS production ( < 0.0001) compared to the untreated control. Proteomics analyses revealed substantial alterations in proteins crucial to ribosomal biogenesis, mitochondrial function, cell cycle control, and apoptosis regulation, including a marked downregulation of ribosomal proteins (RPS27; LogFC = -3.47) and UBE2N (LogFC = -0.60). These findings highlight the potential of N and UB combinations as a novel and practical therapeutic approach for lymphoma treatment, warranting further in vivo exploration and clinical validation.
淋巴瘤仍然对全球健康构成严峻挑战，凸显了对新治疗策略的迫切需求。最近，肠道微生物群已被证明在调节免疫反应和影响癌症进展方面发挥潜在作用。然而，其在淋巴瘤中的分子作用机制仍知之甚少。本研究调查了肠道微生物群衍生代谢产物，特别是乳酸链球菌素（N）和尿石素B（UB）单独及以7:3（5750μM）组合对人淋巴瘤细胞系HKB-11的抗增殖和凋亡活性。使用阿拉玛蓝活力测定、联合指数（CI）分析、活性氧（ROS）定量、流式细胞术检测凋亡以及先进的自下而上蛋白质组学分析进行了综合评估。N和UB表现出强大的抗增殖活性，7:3组合显示出强烈的协同作用（CI<1），与未处理的对照相比，显著增强了凋亡（<0.01）和ROS产生（<0.0001）。蛋白质组学分析揭示了对核糖体生物发生、线粒体功能、细胞周期控制和凋亡调节至关重要的蛋白质的大量改变，包括核糖体蛋白（RPS27；LogFC=-3.47）和UBE2N（LogFC=-0.60）的显著下调。这些发现突出了N和UB组合作为淋巴瘤治疗新的实用治疗方法的潜力，值得进一步进行体内探索和临床验证。
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