A Novel Modified-Curcumin Promotes Resolvin-Like Activity and Reduces Bone Loss in Diabetes-Induced Experimental Periodontitis

Abstract

Purpose: Clinically, it is challenging to manage diabetic patients with periodontitis. Biochemically, both involve a wide range of inflammatory/collagenolytic conditions which exacerbate each other in a "bi-directional manner." However, standard treatments for this type of periodontitis rely on reducing the bacterial burden and less on controlling hyperinflammation/excessive-collagenolysis. Thus, there is a crucial need for new therapeutic strategies to modulate this excessive host response and to promote enhanced resolution of inflammation. The aim of the current study is to evaluate the impact of a novel chemicallymodified curcumin 2.24 (CMC2.24) on host inflammatory response in diabetic rats. Methods: Type I diabetes was induced by streptozotocin injection; periodontal breakdown then results as a complication of uncontrolled hyperglycemia. Non-diabetic rats served as controls. CMC2.24, or the vehicle-alone, was administered by oral gavage daily for 3 weeks to the diabetics. Micro-CT was used to analyze morphometric changes and quantify bone loss. MMPs were analyzed by gelatin zymography. Cell function was examined by cell migration assay, and cytokines and resolvins were measured by ELISA. Results: In this severe inflammatory disease model, administration of the pleiotropic CMC2.24 was found to normalize the excessive accumulation and impaired chemotactic activity of macrophages in peritoneal exudates, significantly decrease MMP-9 and proinflammatory cytokines to near normal levels, and markedly increase resolvin D 1 (RvD 1 ) levels in the thioglycolate-elicited peritoneal exudates (tPE). Similar effects on MMPs and RvD 1 were observed in the non-elicited resident peritoneal washes (rPW). Regarding clinical relevance, CMC2.24 significantly inhibited the loss of alveolar bone height, volume and mineral density (ie, diabetes-induced periodontitis and osteoporosis). Conclusion:In conclusion, treating hyperglycemic diabetic rats with CMC2.24 (a triketonic phenylaminocarbonyl curcumin) promotes the resolution of local and systemic inflammation, reduces bone loss, in addition to suppressing collagenolytic MMPs and proinflammatory cytokines, suggesting a novel therapeutic strategy for treating periodontitis complicated by other chronic diseases.

Potential Therapeutic Applications of Natural Compounds in Diabetes-Associated Periodontitis

“…The advantages of this compound over the natural CUR includes greater efficacy as an MMP inhibitor and improved bioavailability. There was a consensus among the three studies, confirming the impact of CMC2.24 on bone loss reduction and inflammatory markers, where the activity of MMPs and the levels of pro-inflammatory cytokines were inhibited [22][23][24]. The outcomes of the mentioned studies confirmed that administration of CMC2.24 has an anti-inflammatory effect, and suggests it as an efficacious treatment for reducing bone resorption.…”

“…no change; ANI, animal study; CLIN, clinical study; ABL, alveolar bone loss; BG, blood glucose; CAL, clinical attachment level; CMC2.24, chemically modified curcumin; DM, diabetes mellitus; HbA1c, hemoglobin A1c; IL, interleukin; INS, insulin; MAPK, mitogen-activated protein kinase; MMPs, matrix metalloproteinases; PD, pocket depth; RANKL/OPG, receptor activator of nuclear factor-kappa B ligand/osteoprotegerin; SIRT, silent information regulator; sost, sclerostin; SRP, non-surgical scaling and root planning. This review identified three animal studies that evaluated the effect of a chemically modified curcumin (CMC2.24) on DP [22][23][24]. CMC2.24 is a phenylamino carbonyl curcumin, which is tri-ketonic in contrast to di-ketonic natural curcumin compounds.…”

“…To this end, this review includes all animal and clinical studies that have reported outcomes for natural compounds in DP. To date, the natural compounds that can modulate DP are resveratrol [17][18][19][20][21], curcumin [22][23][24][25][26][27], melatonin [28][29][30][31][32], propolis [33][34][35], vitamin C [36][37][38], green tea [39][40][41], ginger [42], aloe vera [43], rutin [26], and vitamin E [44]. Thus, this review will cover the pathogenesis of DP and the therapeutic effects of the above mentioned extracts on DP.…”

Gene expression of inflammatory immune factors and clinical parameters in diabetes and nondiabetes patients with periodontal disease

“…Regarding genetic expression of inflammatory immune factors, Southerland et al (Southerland et al, 2000) state that increased Advanced Glycation End Produtcts (AGE), because of the hyperglycemic state associated with an inflammatory host response, is the cause of the exacerbation of diabetes systemic complications and severity of periodontal disease (Deng et al, 2021). The AGE-RAGE (RAGE -receptors for AGE) interactions result in the production of inflammatory mediators such as IL-1β, TNF-α and IL-6, and enzymes like MMPs which are responsible for bone resorption (Preshaw & Taylor, 2011).…”

HO-1 in Bone Biology: Potential Therapeutic Strategies for Osteoporosis

“…Many phytochemicals have been reported to exert protective effects on bone cells and osteoporosis animal models through activation of HO-1 ( Haines et al, 2012 ; Su et al, 2013 ). Among them, the most promising drug candidates are curcumin and resveratrol, both of which have been suggested to be effective in the treatment of osteoporosis in laboratory, translational and clinical studies (see Table 3 ) ( Deng et al, 2021 ; Moschen and Shakibaei, 2013 ; Sharan et al, 2009 ). In a double-blind randomized controlled trial (RCT), postmenopausal osteoporotic women treated with the combination of curcumin and alendronate showed significant increases in total hip, lumbar spine and femoral neck BMDs accompanied by increased bone turnover markers ( Khanizadeh et al, 2018 ).…”