Berberine (BBR) is a multi-target drug (MTD) that has proven effective in the treatment of metabolism-related chronic diseases (CDs). However, the mode of action (MOA) of BBR remains to be clarified. At a cellular level, the inhibitory effect of BBR on mitochondrial enzymes is probably responsible for many of its biological activities, including the activation of low-density lipoprotein receptor (LDLR), AMP-activated protein kinase (AMPK) and insulin receptor (InsR); these biological activities contribute to ameliorate peripheral blood metabolic profiles, e.g. by reducing plasma lipids and glucose levels, thus improving signs and symptoms of metabolic disorders. In this perspective, BBR acts as a targeted therapy. However, it also exerts pleiotropic systemic activities on some root causes of CDs that include antioxidant / anti-inflammatory effects and modifications of gut microbiota composition and metabolism, which may also contribute to its disease-modifying effects. After reviewing the different MOA of BBR, here we propose that BBR acts through a drug-cloud (dCloud) mechanism, as different to a drug-target effect. The dCloud here is defined as a group of terminal molecular events induced by the drug (or/and related metabolites), as well as the network connections among them. In this scenario, the therapeutic efficacy of BBR is the result of its dCloud effect acting on symptoms/signs as well as on root causes of the diseases. The dCloud concept is applicable to other established MTDs, such as aspirin, metformin, statins as well as to nutrient starvation, thus providing a novel instrument for the design of effective therapies against multifactorial metabolism-related CDs.

中文翻译：

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小碱在治疗与代谢有关的慢性疾病中的作用：针对多种因素疾病的药云（dCloud）效应。

小ber碱（BBR）是一种多靶点药物（MTD），已被证明可有效治疗与代谢有关的慢性病（CDs）。但是，BBR的作用方式（MOA）有待澄清。在细胞水平上，BBR对线粒体酶的抑制作用可能是其许多生物学活性的原因，包括低密度脂蛋白受体（LDLR），AMP激活的蛋白激酶（AMPK）和胰岛素受体（InsR）的激活; 这些生物学活性例如通过降低血浆脂质和葡萄糖水平，从而改善了外周血的代谢状况，从而改善了代谢紊乱的体征和症状。从这个角度来看，BBR可以作为靶向治疗。然而，它还在CD的某些根本原因上发挥多效性全身活性​​，包括抗氧化剂/抗炎作用以及肠道菌群组成和代谢的改变，这也可能有助于其疾病缓解作用。在回顾了BBR的不同MOA之后，我们建议BBR通过药物云（dCloud）机制起作用，这与药物靶向作用不同。此处的dCloud定义为一组由药物（或相关代谢物）诱导的末端分子事件，以及它们之间的网络连接。在这种情况下，BBR的治疗功效是其dCloud效应作用于症状/体征以及疾病根本原因的结果。dCloud概念适用于其他既定的MTD，例如阿司匹林，二甲双胍，他汀类药物以及营养匮乏，