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      Targeting NLRP3 Inflammasome in the Treatment Of Diabetes and Diabetic Complications: Role of Natural Compounds from Herbal Medicine


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          Diabetes, a common metabolic disease with various complications, is becoming a serious global health pandemic. So far there are many approaches in the management of diabetes; however, it still remains irreversible due to its complicated pathogenesis. Recent studies have revealed that nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a vital role in the progression of diabetes and many of its complications, making it a promising therapeutic target in pharmaceutical design. Natural derived herbal medicine, known for its utilization of natural products such as herbs or its bioactive ingredients, is shown to be able to ameliorate hyperglycemia-associated symptoms and to postpone the progression of diabetic complications due to its anti-inflammatory and anti-oxidative properties. In this review, we summarized the role of NLRP3 inflammasome in diabetes and several diabetic complications, as well as 31 active compounds that exert therapeutic effect on diabetic complications via inhibiting NLRP3 inflammasome. Improving our understanding of these promising candidates from natural compounds in herbal medicine targeting NLRP3 inflammasome inspires us the relationship between inflammation and metabolic disorders, and also sheds light on searching potential agents or therapies in the treatment of diabetes and diabetic complications.

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          A role for mitochondria in NLRP3 inflammasome activation.

          An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
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            The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation

            The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage have been shown to trigger its activation. How NLRP3 responds to those signaling events and initiates the assembly of the NLRP3 inflammasome is not fully understood. In this review, we summarize our current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3.
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              Inflammation and metabolic disorders.

              Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.

                Author and article information

                Aging Dis
                Aging Dis
                Aging and Disease
                JKL International LLC
                October 2021
                1 October 2021
                : 12
                : 7
                : 1587-1604
                [1-ad-12-7-1587] 1College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
                [2-ad-12-7-1587] 2Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
                [3-ad-12-7-1587] 3Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
                Author notes
                [* ]Correspondence should be addressed to: Dr. Dandan Zhao (Email: bucmzhaodandan@ 123456163.com ) and Dr. Sihua Gao (Email: gaosihua1216@ 123456163.com ), College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

                these authors equally contributed this work.

                copyright: © 2021 Bai et al.

                this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                : 23 February 2021
                : 17 March 2021
                : 18 March 2021

                nlrp3 inflammasome,diabetes,diabetic complications,natural compounds,herbal medicine


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