Efficacy of the monocarbonyl curcumin analog C66 in the reduction of diabetes-associated cardiovascular and kidney complications

Abstract

Curcumin is a polyphenolic compound derived from turmeric that has potential beneficial properties for cardiovascular and renal diseases and is relatively safe and inexpensive. However, the application of curcumin is rather problematic due to its chemical instability and low bioavailability. The experimental results showed improved chemical stability and potent pharmacokinetics of one of its analogs – (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66). There are several advantages of C66, like its synthetic accessibility, structural simplicity, improved chemical stability (in vitro and in vivo), presence of two reactive electrophilic centers, and good electron-accepting capacity. Considering these characteristics, we reviewed the literature on the application of C66 in resolving diabetes-associated cardiovascular and renal complications in animal models. We also summarized the mechanisms by which C66 is preventing the release of pro-oxidative and pro-inflammatory molecules in the priming and in activation stage of cardiomyopathy, renal fibrosis, and diabetic nephropathy. The cardiovascular protective effect of C66 against diabetes-induced oxidative damage is Nrf2 mediated but mainly dependent on JNK2. In general, C66 causes inhibition of JNK2, which reduces cardiac inflammation, fibrosis, oxidative stress, and apoptosis in the settings of diabetic cardiomyopathy. C66 exerts a powerful antifibrotic effect by reducing inflammation-related factors (MCP-1, NF-κB, TNF-α, IL-1β, COX-2, and CAV-1) and inducing the expression of anti-inflammatory factors (HO-1 and NEDD4), as well as targeting TGF-β/SMADs, MAPK/ERK, and PPAR-γ pathways in animal models of diabetic nephropathy. Based on the available evidence, C66 is becoming a promising drug candidate for improving cardiovascular and renal health.

NF-κB pathway as a molecular target for curcumin in diabetes mellitus treatment: Focusing on oxidative stress and inflammation

“…These results underscore curcumin's potential in ameliorating diabetic lung injury through its antioxidative and counter-inflammatory responses, particularly by inhibiting the NF-κB pathway, thus mitigating pulmonary inflammation and OS in the STZ-diabetic rats [105]. C66, a novel derivative of curcumin, has garnered attention for its potential therapeutic properties [106]. Exhibiting anti-inflammatory effects, it curtails high glucose-provoked inflammatory reactions within both laboratory conditions and living organisms, effectively mitigating renal damage in diabetic rat models through its Counter-inflammatory effects [107].…”

Metabolic memory: mechanisms and diseases

“… 391 – 393 Inhibition of p300/CBP effectively reduces H3K9/14Ac levels, offering a potential therapeutic approach for managing hyperglycemia-mediated long-term kidney injury. 394 …”

“…[391][392][393] Inhibition of p300/CBP effectively reduces H3K9/14Ac levels, offering a potential therapeutic approach for managing hyperglycemia-mediated long-term kidney injury. 394 ncRNAs also serve as essential regulators in the progression of DKD. miR-192 was first found to be downregulated in DKD, which targets TGF-β/Smad3 to upregulate ECM and collagen, as well as to promote renal fibrosis.…”

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer

“…It is interesting to note that synthetic analogues of curcumin showed a stronger anti-cancer activity than natural curcumin [160,161]. Thus, researchers aimed to synthetize these compounds in order to evaluate their potential role in treatment of several pathologies including prostate cancer [28,[160][161][162][163].…”