Current Medicinal Chemistry, 2017, 24, 1453-1468

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Impact Factor: 3.45 Medicinal Therapeutic Strategies of Plant-derived Compounds for Diabetes Via Chemistry

The International Journal for Regulation of Monocyte Chemoattractant Protein-1 Timely In-depth Reviews in Medicinal Chemistry

BENTHAM SCIENCE

Magdalena Czemplik1,*, Anna Kulma2, Yu Fu Wang3 and Jan Szopa2,4,5

1Department of Physico-Chemistry of Microorganisms, Institute of Genetics and Microbiology, Faculty of Biological Sciences, University of Wrocław, Wrocław, Poland; 2Faculty of Biotechnology, University of Wrocław, Wrocław, Poland; 3Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha City, China; 4Department of Genetics, Plant Breeding and Seed Production, Wrocław University of Environmental and Life Sciences, Wrocław, Poland; 5Linum Foundation, Wrocław, Poland

Abstract: Background: Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family that plays a key role in the inflammatory process. It has been broadly studied in the aspect of its role in obesity and diabetes related diseases. MCP-1 causes the infiltra-

tion of macrophages into obese adipose tissue via binding to the CCR2 receptor and is involved in the development of insulin resistance. Methods: We reviewed the available literature regarding the importance of plant metabolites that regulate MCP-1 activity and are used in the treatment of diabetic disorders. The character- istics of screened papers were described and the important findings were included in this re-

view.

A R T I C L E H I S T O R Y Results: This mini-review provides a summary of functions and therapeutic strategies of this

Received: October 10, 2016 chemokine, with a special focus on plant-derived compounds that possess a putative antidia- Revised: February 14, 2017 betic function via a mechanism of MCP-1 interaction. The highlights of this review include the Accepted: February 28, 2017 roles of MCP-1 in development of diabetes, the evaluation of plant metabolites that specifi- DOI: 10.2174/0929867324666170303162935 cally or non-specifically inhibit MCP-1 overproduction, and the molecular mechanisms of this activity. Among these metabolites, we particularly focused on phenolic acids and their derivatives, flavonoids, stilbenes, anthocyanins, capsaicin, alkaloids, plant sterols, terpenes, saponins, unsaturated fatty acids and plant-derived extracts. Conclusion: Regarding the increasing number of diabetic patients yearly, the recent progress in the putative therapies needs to be summarized. This article underlines the significance and involvement of the chemokine MCP-1 in the development of obesity, type 2 diabetes, and diabetic complications, with an emphasis on the role of plant metabolites in the regulation of this chemokine and thus the role in the prevention or therapy of diabetes. We suggest that MCP-1 might be a molecular marker of type 2 diabetes.

Keywords: Diabetes, monocyte chemoattractant protein-1 (MCP-1), CCR2, plant extracts, plant metabolites.

1. MCP-1 CHEMICAL STRUCTURE cle, astrocytic, monocyte, mesangial and microglial cells. Nevertheless, monocytes or macrophages are Monocyte chemoattractant protein-1 (MCP-1) is thought to be the major source of MCP-1 chemokine produced by different cell types crucial for the immune [1-3]. MCP-1 is the first discovered human chemokine, response, such as fibroblasts, epithelial, smooth mus- which has been intensively studied recently, as it was

shown to be a crucial factor for the treatment of various *Address correspondence to this author at the Department of Phys- diseases such as atherosclerosis [4], rheumatoid arthri- ico-Chemistry of Microorganisms, Institute of Genetics and Micro- biology, University of Wrocław, Wrocław, Poland, ul. Przy- tis [5] and diabetes [6]. It was primarily purified from byszewskiego 63/77, 51-148, Wrocław, Poland, human cell lines on the basis of its monocyte chemoat- Tel:. 0048713756337; tractant properties. It is a member of the chemokine- E-mail: [email protected]

Current Medicinal Chemistry 1454 Current Medicinal Chemistry, 2017, Vol. 24, No. 14 Czemplik et al. beta family of cytokines, which tend to attract and acti- which accelerates monocyte accumulation. The CCR2 vate monocytes [7]. The human mcp-1 gene is located expression is highly regulated and depends on different on chromosome 17 (chr. 17, q11.2), and the MCP-1 factors. It was demonstrated that proinflammatory cy- protein is composed of 76 amino acids and is 13 kDa in tokines such as IFNg, IL-1, or TNF decreased CCR2 size [3, 8]. It contains structural domains typical for all gene expression, which retained monocytes at sites of chemokines: a flexible N-terminal domain, constrained inflammation and prevent their reverse transmigration by disulfide bonds; a long loop that leads into three [18]. Macrophage maturation exhibited similar effects antiparallel β-pleated sheets; and an α-helix that over- on CCR2 expression, and differentiated macrophages lies the sheets [9]. Zhang et al. showed that the amino- could not migrate in response to MCP-1. In contrast, terminal region is necessary for MCP-1 activity, and IL-2 increased the expression of CCR2 and augmented the carboxyl-terminal α-helix is not required for signal- the chemotactic capacity of resting natural killer cells ing per se but is required for maximal specific activity and T lymphocytes[19]. It is also suggested that HDL [10]. The presence of four cysteine residues that form may inhibit monocyte CCR2 expression and reduce the intramolecular disulphide bridges enables the peptide chemotaxis mediated by MCP-1. Although the exact folding to be stabilized. Two regions of the primary mechanisms by which lipoproteins affect CCR2 gene structure have been identified as crucial for the activity expression is still unclear, but intracellular cholesterol of MCP-1, namely the sequence Thr-Cys-Cys-Tyr is thought to play a regulatory function. Incubation of (amino acids 10-13) and Ser-34 and Lys-35. Point mu- monocytes with LDL or free cholesterol increased tations of Thr-10 to Arg and Tyr-13 lead to signifi- CCR2 expression, and lowering the level of cellular cantly lowered MCP-1 activity, and insertion of a Pro cholesterol reduced its expression. There is also a sig- between these two residues, or their substitution by the nificant correlation between plasma LDL levels and sequence Gly-Pro-His, caused nearly complete loss of monocyte CCR2 expression, but only in individuals MCP-1 activity [11]. It was shown that MCP-1 forms with low HDL levels. High levels of HDL (50 mg/dl) dimers at physiological concentrations and wild-type significantly reduced the LDL-induced expression of homodimers interact with the MCP-1 receptor and gen- CCR2 in hypercholesterolemic subjects [20]. In con- erate a signal [12]. trast, monocyte CCR2 biosynthesis was not affected by MCP-1 is glycosylated in human and murine cells, triglycerides. which affects the biological activity of this chemokine. The glycosylated form of MCP-1 shows lower chemotactic activity for monocytes and lymphocytes, but exhibits enhanced functional stability compared with non- glycosylated MCP-1 [13, 14].

2. MONOCYTE RECRUITMENT MECHANISMS The general mechanism of chemokines’ activity combines their secretion in response to signals, and the consequent selective recruitment of monocytes, neutro- phils, and lymphocytes. Once induced, they direct migration of the cells that express the appropriate chemokine receptors, which occurs along a chemical ligand gradient Fig. (1). As a consequence, the cells move toward high local concentrations of chemokines [15]. MCP-1 chemokine activity is mediated by the CCR2 receptor, which is expressed in different leuko- cyte populations of cells. CCR2 consists of two isoforms, CCR2A and CCR2B, derived from a single gene Fig. (1). Schematic presentation of monocyte recruitment with alternatively spliced carboxyl tails [16]. CCR2B is mechanisms via MCP-1. the dominant form in human monocytes, and CCR2A in mononuclear cells and vascular smooth muscle cells It was found that CCR2 decreases after the mono- [17]. If the CCR2 expression is enhanced, the MCP-1– cytes have differentiated into macrophages [21]. MCP- induced monocyte chemotaxis increases several folds, 1 recruits monocytes to the inflammation site [22]. The putative mechanism of this action assumes that MCP-1 Therapeutic Strategies of Plant-derived Compounds Current Medicinal Chemistry, 2017, Vol. 24, No. 14 1455 dimerizes and associates with glycosaminoglycan in culating concentrations of pro-inflammatory cytokines tissues, which establishes a gradient for redirection of and chemokines as well as the activation of several monocytes towards sites of inflammation. When the kinases that regulate inflammation such as including c- amino acid substitutions in MCP-1 were performed to Jun NH2-terminal kinase (JNK), IκB-kinase β prevent dimerization or association with glycosamino- (IKKβ)/nuclear factor κB (NF-κB), and mammalian glycan, the recruitment processes were impaired [23]. target of rapamycin (mTOR)/S6 kinase (SK6), which MCP-1 plays a critical role in the recruitment of mono- affect insulin metabolism in adipocytes and hepato- cytes to sites of immune responses, which was con- cytes [26]. A crucial role in obesity-associated systemic firmed by an MCP-1-deficient mouse study [24]. inflammation is played by the adipose tissue macrophages, which are a prominent source of pro- 3. KEY ASPECTS OF TYPE 2 DIABETES ETI- inflammatory cytokines, such as tumor necrosis factor OLOGY (TNF)-α and interleukin (IL)-6, that can block insulin 95% of diabetic cases are classified as type 2 diabe- action in the liver, adipose tissue, and skeletal muscle tes, and its etiology is closely related to obesity and via autocrine and/or paracrine signaling. Consequently, insulin resistance. this causes systemic insulin resistance [31]. Insulin resistance involves the decreased ability of Reactive oxygen species (ROS) are known to play a tissues to respond to insulin activity. Adipose tissue is crucial role during the pathogenesis of type 2 diabetes. an insulin-responsive tissue, but in the event of exces- They are produced under diabetic conditions in various sive accumulation of triacylglycerol in adipose tissue, pathways: during the non-enzymatic glycosylation re- insulin resistance occurs. Free fatty acids (FFAs) play action [32], the electron transport chain in mitochon- an important role in induction of insulin resistance. dria [33], and membrane-bound NADPH oxidase [34]. FFAs concentration in blood is increased in obese peo- It is known that membrane-bound NADPH oxidase is ple. Excessive accumulation of FFAs inhibits glucose one of the major sources of ROS in the vasculature and uptake, as it impairs the functioning of signal pathways that NADPH oxidase-derived ROS play a critical role regulated by diacyloglicerole. It was shown that in the development of atherosclerosis. Under diabetic chronic exposition of beta cells of the pancreatic islets conditions, ROS are also involved in an increase of on high FFAs concentration leads to insulin resistance pancreatic β-cell dysfunction. These cells are vulner- and to the inhibition of insulin release [25]. Moreover, able to ROS due to the relatively low expression of an- alteration in functioning of nuclei PARP receptors, as tioxidant enzymes such as catalase and glutathione well as alteration in secretion of adipokines or proin- peroxidase. The production of ROS decreases insulin flammatory cytokines, are suggested to contribute to gene expression and secretion and finally brings about insulin resistance [26, 27]. As a result of metabolic apoptosis of β-cells. Moreover, it has been reported that overload, the functioning of mitochondrial enzymes is ROS are involved in the progression of insulin resis- impaired. The increased concentration of non-esterified tance [35]. ROS disrupted insulin-induced cellular re- fatty acids (NEFA) leads to the alterations in lipid me- distribution of insulin receptor substrate-1 (IRS-1) and tabolism and accumulation of acetyl- CoA in the cells, phosphatidylinositol-3-kinase (PI 3-K), and thus im- which influences key enzymes of Krebs cycle activity paired insulin-induced GLUT4 translocation in 3T3-L1 and inhibits glycolysis [28]. Insulin resistance may lead adipocytes [36]. to severe effects, as insulin enables storage of triglyc- An interesting relationship of the effects of electro- erides in adipose tissue by promoting the differentia- magnetic fields (EMFs) with diabetes has been re- tion of preadipocytes to adipocytes, increasing the up- ported. It was shown that EMFs frequently can stimu- take of glucose and fatty acids derived from circulating late glandular activity in the short term, but long-term lipoproteins and lipogenesis in mature adipocytes, and exposure is often harmful for the glands. Glands are inhibiting lipolysis [29]. thought to be particularly sensitive to radiation as their One of the crucial factors contributing to the devel- secretions are normally produced in internal membrane opment of type 2 diabetes is obesity- associated sys- systems, which can be damaged by electromagnetic temic inflammation. In humans, it is characterized by fields. If these lesions are severe, the activity of the the infiltration of macrophages into adipose tissue and whole gland can be affected, which is serious for the the liver in combination with an increase in body glands of the endocrine system (those that coordinate weight [30], which is positively correlated with insulin our bodily functions), since it can affect many aspects resistance. This state is characterized by increased cir- of the metabolism and may be partially responsible for 1456 Current Medicinal Chemistry, 2017, Vol. 24, No. 14 Czemplik et al. the development of obesity. Thyroid gland exposed to crosis factor-α (TNF-α) and IL-6, influence glucose power line frequencies underwent deterioration [37] and lipid metabolism. MCP-1 exhibits a direct effect on and lost its capacity for producing thyroid hormones angiogenesis of endothelial cells [44] and therefore it [38]. The expected consequences of this hypothyroid- may be involved in the expansion and remodeling of ism are fatigue and obesity. Moreover, the prolonged the adipose tissue during development of obesity. It is exposure to EMFs limits the release of hormones re- suggested that MCP-1 may have a broader role in adi- lated to appetite regulation such as ghrelin and peptide pocyte physiology than only inflammatory cell re- YY, which increases the risk of obesity. Although there cruitment, as it was shown to be also an insulin- is no sufficient literature data concerning how MCP-1 responsive gene. Sartipy and Loskutoff showed that is associated with obesity- induced electromagnetic insulin induces expression and secretion of MCP-1 in fields, but there are some reports on up- regulating ex- vitro in insulin-resistant 3T3-L1 adipocytes and also in pression of MCP-1 by EMFs [39]. Therefore, we sug- vivo in insulin-resistant obese mice [45]. It was also gest the interesting subject of further research might be shown that MCP-1 may promote insulin resistance in the elaboration if EMFs could putatively contribute to differentiated adipocytes due to prolonged exposure to the development of diabetes by up- regulating MCP-1. MCP-1. The differentiated 3T3-L1 adipocytes were The application of a number of electrical devices in treated with low concentrations of MCP-1. As a result, living and working environments caused that humans the insulin-stimulated glucose uptake was severely di- are exposed to different levels of EMFs and its putative minished by MCP-1 [45]. Similar mechanisms have hazardous effects on human health have been recently been suggested to have relevance in humans, as circu- widely discussed. lating MCP-1 has been found significantly increased in Obesity can also be regarded as a result of micro- patients with type 2 diabetes [46]. biome alteration in humans. However, no evidence Many studies have shown a correlation between concerning participation of MCP-1molecule in gut mi- high glucose concentrations and MCP-1 level. crobiome alteration has been reported so far, but it is Hyperglycemia initiates the increase of MCP-1 release worth mentioning that these alterations might play a in the endothelium of diabetic patients in vitro and role in 2 diabetes pathophysiology. Recent studies have elevated expression of vascular cell adhesion molecule- shown that gut microbiota differ in composition be- 1, which might cause initiation of atherosclerosis [47]. tween obese and lean subjects. Different ratios of Bac- The endothelial dysfunction is known to be related to teroidetes and Firmicutes, the two dominant intestinal the vascular inflammatory process and can lead to bacteria, were found in a leptin-deficient ob/ob mouse diabetic vascular disorders. Elevation of the model [40]. Similar differences in this ratio were found intracellular glucose level causes the overproduction of in humans [41]. Products of intestinal bacteria play a adhesion molecules, which is suggested to be one of role in type 2 diabetes pathophysiology. Butyrate, ace- the earliest events of the vascular inflammation tate and propionate are short-chain fatty acids (SCFAs), process. Intracellular adhesion molecule-1 and MCP-1 which are absorbed in the intestine and have both are up-regulated through the interaction between metabolic and epigenetic effects. It was suggested that monocytes and endothelial cells by activation of propionate affects hepatic lipogenesis and glu- nuclear factor-kappa B (NF-κB). Human endothelial coneogenesis, whereas peripherally acetate functions as ECV304 cells exposed to high glucose for 24 h caused a substrate for cholesterol synthesis [42]. SCFAs were an increase in MCP-1 and intercellular adhesion also shown to reduce inflammation, and butyrate im- molecule-1, and promoted cell adhesion between proved insulin sensitivity and increased energy expen- monocyte and ECV304 cells [48]. Another study inves- diture by enhancing mitochondrial function in mice tigated the effect of high glucose level on chemokines [43]. and signaling mechanisms in human aortic smooth muscle cells. Exposure of these cells to a high glucose 4. MCP-1 – A CANDIDATE MOLECULAR MAR- level resulted in an increase of fractalkine and MCP-1 KER OF TYPE 2 DIABETES expression and the activated mitogen-activated protein MCP-1 is involved in the development of diabetes. kinase signaling pathway [49]. Similarly, 7-day It participates in the recruitment of monocytes, and incubation of human umbilical vein endothelial cells thus it may contribute to the development of inflamma- with high glucose increased mRNA expression and the tory state in the adipose tissue. Moreover, MCP-1 and production rate of MCP-1 in a time- and concentration other pro-inflammatory cytokines, such as tumor ne- (10–35 mM)-dependent manner, through upregulation of reactive oxygen species (ROS) generation and subsequent activation of p38 MAPK (Takaishi et al., Therapeutic Strategies of Plant-derived Compounds Current Medicinal Chemistry, 2017, Vol. 24, No. 14 1457

MAPK (Takaishi et al., 2003). These findings suggest biome. It was reported that polyphenols can stimulate that MCP-1 contributes to the initiation and progres- the growth of commensal and beneficial microbiota, sion of hyperglycemia and diabetes. while pathogenic strains are inhibited. For instance, the It is known that pro-inflammatory cytokines such as growth of Clostridium perfringens, C. difficile and MCP1, but also ICAM1 and TGF-β1, are elevated in Bacteroides spp. was significantly inhibited by tea diabetic kidneys, and thus renal inflammation can con- phenolics and their derivatives, while commensal an- tribute to the development of diabetic nephropathy [50, aerobes such as Clostridium spp. and Bifidobacterium 51]. Activated nuclear factor-κB (NF-κB) translocates spp. and probiotics such as Lactobacillus spp. were less from the cytoplasm to the nucleus and induces the ex- severely affected [64]. Similarly, the consumption of pression of its target genes including MCP1, ICAM1, red wine polyphenols significantly increased the num- and TGF-β1, resulting in induction of inflammation, bers of Enterococcus, Prevotella, Bacteroides, Bifi- which leads to glomerulosclerosis and tubulointerstitial dobacterium, Bacteroides uniformis, Eggerthella lenta, fibrosis [52, 53]. and Blautia coccoides-E. rectal group members, while the quantity of Lactobacillus spp. was unaltered [65]. 5. THERAPEUTIC STRATEGIES OF PLANT- Plant phenolics can interact with certain proteins, thus DERIVED COMPOUNDS FOR DIABETES influencing the development of type 2 diabetes. Phe- nolics possess anti-glycated properties, one mechanism All the previously presented factors that contribute of this activity being via binding to the protein mole- to the development of type 2 diabetes could be poten- cule with a non-covalent bond, and in this way make tial targets for prevention and therapy using plant me- glycation targets on the protein molecule (usually tabolites or plant extracts via interaction with MCP-1. amino acids such as lysine) unavailable to take part in This is a result of some important properties and activi- the glycation reaction [66]. Vlassopoulos et al. reported ties of plant metabolites. The most important plant me- that pre-treatment of albumin with phenolic acids in- tabolites are known antioxidants and are able to attenu- hibits fructosamine production, especially in the pres- ate ROS activity. Their role in scavenging free radicals ence of oxidative stress or oxidative damage [67]. Pro- has already been broadly described [54, 55]. Apart tein glycation is implicated in the development of sev- from the ability to scavenge ROS, plant-derived pheno- eral chronic diseases, particularly diabetic micro- and lic compounds can regulate ROS-related enzymes. macro-vascular complications. They can decrease the cellular level of free radicals either by inhibiting the activity or expression of free In light of the evidence, we suggest that the role of radical generating enzymes such as NADPH oxidase plant-derived phenolics might be crucial in the preven- and xanthine oxidase (XO) or by enhancing the activity tion of type 2 diabetes, as they may influence many and expression of antioxidant enzymes such as super- metabolic processes involved in the development of oxide dismutase (SOD), catalase (CAT) and glu- this disease. tathione peroxidase (GPX) [56, 57]. Plant-derived phe- 6. PLANT METABOLITES INTERACTING nolics are also immunomodulatory, which makes them WITH MCP-1 ACTIVITY (TABLE 1) attractive agents that modulate the complex immune system response in the prevention of infections, as According to the literature data, the number of pub- most of the immunomodulators are cytotoxic drugs. lications indicating the pathological role of MCP-1 in Plant phenolics cause many different effects on the obesity and diabetes has grown. Therefore this immune system: among others, they down-regulate T- chemokine seems to be an accurate target for a type 2 helper cell cytokines and IL-4 production [58], reduce diabetes prevention strategy. Some efforts have been levels of pro-inflammatory cytokines IL-1β, IL-6, and made to inhibit MCP-1 over-production and ameliorate TNF-α [59, 60], inhibit T lymphocyte proliferation obesity-related syndromes, such as insulin resistance, [61], downregulate TNF-α, IL-6, iNOS, COX-2 and diabetic nephropathy and type 2 diabetes, and an im- upregulate IL-10 by inhibition of the expression of toll- portant portion of the studies was on plant metabolites, like receptors and activation of NF-κB, and inhibit most of them phenolic in nature, and plant-based ex- ICAM-1 and VCAM-1 activity [62, 63]. The effect of tracts. Here we present data confirming the activity of plant-derived phenolic compounds on MCP-1 was also several selected components, from different classes of described, and in the aspect of involvement in type 2 chemical compounds – phenolic acids, flavonoids, al- diabetes is described below. Furthermore, plant phe- kaloids – as well as some data on crude plant extract nolics are involved in the development of the micro- activity (Table 1). 1458 Current Medicinal Chemistry, 2017, Vol. 24, No. 14 Czemplik et al.

Table.1 Chemical structures of chosen plant metabo- 6.1. Phenolic Acids and their Derivatives lites interacting with MCP-1 activity. Caffeic acid phenethyl ester (CAPE) is a known active component of propolis characterized by antibacte- Plant Structure rial, anticancer, and anti-inflammatory properties [68- metabolite/s 70]. It was reported that CAPE can suppress the differentiation of 3T3-L1 into adipocytes and inhibit the production of adipocytokines during adipogenesis [71, 72]. Phenolic Moreover, its interaction with MCP-1 was reported by acids Juman et al., who studied its suppressive effect on LPS-induced production of pro-inflammatory cytokines in a macrophage cell line, RAW264.7, and found that

CAPE inhibits gene expression of key pro- inflammatory cytokines, MCP-1, IL-1-beta and TNF-α. Additionally, secretion of these pro-inflammatory cy- Flavonoids tokines from RAW264.7 macrophages also decreased with CAPE pre-treatment [73]. It is therefore suggested that CAPE is able to attenuate chronic and low-grade inflammation occurring via macrophage infiltration in Stilbenes obesity.

The cardiac protective effects of caffeic acid (CA) and ellagic acid (EA) in diabetic mice were studied. Anthocyan- Dietary supplementation of these compounds in dia- ins betic mice resulted in a significant decrease in glucose level and reduced the levels of pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha as well as MCP-1 levels. Additionally, CA or EA treatment significantly Capsaicin up-regulated mRNA expression of catalase, SOD and GPX1, and down-regulated IL-1beta, IL-6, TNF-alpha

and MCP-1 in cardiac tissue of diabetic mice [74]. Thus these plant metabolites could protect cardiac tis- Alkaloids sue against the progression of diabetic cardiomyopathy via these triglyceride-lowering, anti-oxidative, and (Nicotine) anti-inflammatory effects. Ferulic acid (FA) was studied regarding its protective effect in the development of diabetic nephropathy Plant sterols in type 2 diabetic rats. Diabetic nephropathy is a major complication associated with type 2 diabetes and is a leading cause of end-stage renal disease [75]. It was demonstrated that FA treatment in diabetic rats effec- tively improved blood glucose levels, increased insulin Saponins sensitivity and insulin secretion of beta cells. As MCP- 1 plays a crucial role in mesangial cell proliferation, glomerulosclerosis and renal fibrogenesis [76], the treatment with FA significantly reduced MCP-1 level in FA-treated diabetic rats compared to the diabetic Terpenes control group [77]. Moreover, FA treatment reduced ROS production and suppressed MCP-1 expression in cultured podocytes, which indicates strong antioxidant Polyunsatu- and anti-inflammatory effects of FA in diabetic neph- rated fatty acids (Linoleic acid) ropathy. Hence it is suggested that FA may be a potent (Limonen) Therapeutic Strategies of Plant-derived Compounds Current Medicinal Chemistry, 2017, Vol. 24, No. 14 1459 new therapeutic drug for diabetic nephropathy in type 2 lin with glucose transporters on the cell membrane or diabetic patients by indirectly affecting insulin action and the levels of Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)- gene expression of glucose transporters. Luteolin was 1,6-heptadien-3,5-dione, is thought to be the main ac- shown to significantly reduce gene expression of MCP- tive ingredient derived from the root of turmeric. Cur- 1 and other pro-inflammatory cytokines such as cumin exists as a mixture of two tautomeric structures, TNF-α, IL-6, cyclooxygenase-2 and resistin in a dose- the diketone and keto–enol form. The enol form is dependent manner. Moreover, it enhanced the mRNA more energetically stable in the solid phase and in solu- levels of gene expression for two key adipokines, leptin tion. Many therapeutic activities of curcumin are re- and adiponectin, in 3T3-L1 adipocytes and primary ported due to its structure, and thus there is a wide mouse adipose cells [91, 92]. Adiponectin levels are range of molecular targets. Curcumin can modulate reported to be negatively correlated with obesity and several transcription factors, cytokines, growth factors, insulin resistance, due to its anti-inflammatory function and kinases [78-80]. However, its wide biological ac- [93]. Addition of luteolin to a high-fat diet increases tivities are limited due to poor bioavailability. Curcu- these levels. Therefore luteolin inhibits pro- min is an unstable molecule that decomposes rapidly in inflammatory cytokines and adipokines implicated in neutral and basic conditions and has been reported to the development of insulin resistance [94]. Addition- undergo extensive metabolism through oxidation, re- ally, it was suggested that luteolin increased the ex- duction, glucuronidation, and sulfation [81-83] . Cur- pression of IRS-1/2, a molecule participating in the cumin is able to inhibit macrophage accumulation in insulin signaling cascade, in a dose-dependent manner adipose tissue [84] and can stimulate human adipocyte [92]. differentiation [85]. The putative mechanism is due to Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid the suppression of NF-κB activation, which results in abundantly present in common fruits and vegetables. It reducing TNF-α and nitric oxide (NO) and inhibits the possesses health-promoting activities due to its low release of MCP-1 from 3T3-L1 adipocytes [86]. Cur- toxicity and high chemopreventive effects [95]. Api- cumin is suggested to possess anti-inflammatory prop- genin inhibits the LPS-induced increase of pro- erties. Curcumin supplementation decreased blood lev- inflammatory cytokines, such as IL-1β, IL-6 and MCP- els of MCP-1, IL-6, and TNF-α, hyperglycemia, and 1, and the two adhesion molecules ICAM-1 and oxidative stress in U937 monocytes and in a diabetic VCAM-1. Moreover, it prevents an LPS-induced de- rat model in response to high glucose (35 mM) treat- crease of the anti-inflammatory cytokine IL-10 [96]. ment [87]. Moreover curcumin inhibits degradation of The regulatory effects of apigenin and other flavonoids, IκBα and NF-κB activity, which might reduce macro- chrysin and quercetin were evaluated on adhesion phage infiltration and prevent proinflammatory cytoki- molecules and pro-inflammatory cytokine expression nes (TNF-α and IL-1β) from releasing and downregu- in endothelial cells. High glucose and TNF-α resulted lating ICAM-1, MCP-1, and TGF-β1 protein synthesis in the augmented expression of ICAM-1, VCAM-1 and in diabetic nephropathy. MCP1. The subsequent incubation with examined flavonoids resulted in strong inhibition of expression of 6.2. Flavonoids the above-mentioned VCAM-1 and MCP1 genes. Api- Luteolin, (3′,4′,5,7-tetrahydroxyflavone) is one of genin and chrysin significantly inhibited the gene ex- the most common flavonoids present in edible plants pression of VCAM-1 and MCP1 at 50 μM, quercetin and in plants used in traditional medicine to treat a inhibited the expression of ICAM1 and MCP1 at 50 wide variety of pathologies [88]. Lutoelin possesses μM (but enhanced that of VCAM-1 at 30 μM), and anti-inflammatory properties in the obesity-associated kaempferol inhibited the expression of MCP1 and inflammatory response due to its ability to regulate VCAM-1. From the structure and inhibitory activity of obesity-induced inflammation. Luteolin anti- these flavonoids, it was suggested that a double bond in inflammatory activity results from its structural fea- the C-ring of flavonoids and the third hydroxyl group tures – a double bond at positions C2–C3 of the C ring in the A-ring were required for the inhibition of gene and OH groups at positions 3′ and 4′ of the B ring [89, expression [97]. 90]. Luteolin exhibits anti-insulin-resistance properties Naringenin (49,5,7-trihydroxyflavanone), an agly- in adipocytes as it significantly increased the response cone of naringin, is produced in several plants, espe- of glucose uptake to insulin stimulation in these cells cially in grapefruit, and has been reported to possess [91]. The putative mechanism is an interaction of luteo- various pharmacological effects, such as antioxidant, 1460 Current Medicinal Chemistry, 2017, Vol. 24, No. 14 Czemplik et al. anti-inflammatory, and anti-proliferative activities. It tion by altering the gene expression of this chemokine was shown that naringenin ameliorates obesity-related in 3T3-L1 adipocytes in a dose-dependent manner diseases such as atherosclerosis in disease-model ani- [111]. Moreover, the regulatory effect of resveratrol on mals [98, 99]. It is also known that naringenin exhibits MCP-1 transcription was examined by promoter lu- anti-inflammatory effects in adipocytes, as it inhibited ciferase activity analysis. The HEK293 cells were TNF-α-induced adipocyte lipolysis [100]. Naringenin transfected with the MCP-1 promoter that was fused to suppressed high-fat-diet-induced accumulation of the luciferase gene as a reporter. It was revealed that macrophages during the 14-day administration period resveratrol inhibited TNF-α-induced luciferase expres- and also caused suppression of MCP-1 expression in sion in a dose-dependent manner ranging from 10 to 50 adipose tissue [101]. Naringenin was also shown to µM [111]. It was also assumed that these effects were regulate fat deposition in adipose tissues via MCP-1 mediated by directly repressing NF-κB binding activ- action, as it inhibited the production of TNF-α, MCP-1, ity, and also indirectly inhibiting NF-κB dependent and nitric oxide in a dose-dependent manner in transcription activity through activation of Sirt1 RAW264 macrophages and co-culture of 3T3-L1 adi- (NAD(+)-dependent protein deacetylase). These litera- pocytes and RAW264 macrophages stimulated by LPS ture data indicate that resveratrol might be an important [102]. Therefore, naringenin may be beneficial for plant metabolite in preventing obesity-related patholo- ameliorating the inflammatory changes in the obese gies. adipose tissue. 6.4. Anthocyanins Puerarin is a isoflavone glycoside, abundantly present in root of Pueraria lobata, a native plant in South- Anthocyanins belong to the family of phenolic east Asia. It is known to have antioxidant, anticancer compounds and are the largest group of water-soluble and antihyperglycemic properties [103-105]. Puerarin pigments in plants. The basic structures of the antho- could significantly increase glucose tolerance in cyanins are anthocyanidins, which consist of an aro- C57BL/6J-ob/ob mice, an animal model of type 2 dia- matic ring bonded to a heterocyclic ring containing betes mellitus [106]. This metabolite could also inhibit oxygen, which is then bonded by a carbon–carbon the upregulation of MCP-1 gene expression, which was bond to a third aromatic ring [112]. Their glycoside induced by high glucose treatment in vascular endothe- forms are known as anthocyanins. They are known to lial cells. Moreover, the epigenetic mechanism of this possess strong antioxidative, anti-inflammatory and inhibitory effect was examined. It was found that a few anti-hyperlipidemia effects [113]. key epigenetic chromatin markers such as H3K4me2/3, A study of the effect of anthocyanins (cyanidin-3- H3K4 HMTs and LSD1 of the MCP-1 gene promoter, O-β-glucoside chloride [C3G] and cyanidin chloride which are involved in high-glucose-induced up- [Cy], an aglycon of C3G;) on hyperglycemia-mediated regulation of MCP-1 gene expression in endothelial cholesterol accumulation and inflammation, as well as cells, could be modulated by puerarin [107]. on their molecular mechanism of action in HK-2 cells, was performed. It revealed that these anthocyanins are 6.3. Stilbenes able to inhibit high-glucose-induced cholesterol accu- Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a mulation and also reduced the inflammatory process by stilbenoid, a naturally occurring polyphenol present in inhibiting the production of MCP1, ICAM1, and red wine and berries. The main bioactive effect of res- TGFβ1, both intracellularly and extracellularly. It was veratrol is associated with its heart-protective effect, also suggested that the anthocyanin-mediated inhibition but other biological effects have also been well docu- of high glucose-induced cytokine production was likely mented in the literature, such as anti-oxidative, anti- mediated by the NFκB pathway [114]. Similarly, the inflammatory, anti-aging, anti-cancer, and anti-viral anti-diabetic properties of purple corn anthocyanins activity [108-110]. It is also implicated in the health- were reported by Kang et al. The anthocyanin-rich promoting effects in diabetes and obesity. Oral admini- purple corn extract (PCA) could suppress monocyte stration of resveratrol was shown to improve insulin activation and macrophage infiltration. In the diabetic sensitivity in mice fed a high-fat diet. The favorable kidney, high glucose promotes mesangial production of roles of resveratrol in improving insulin sensitivity and MCP-1, IL-6, and TNF-α, which, together with adhe- preventing atherosclerosis are suggested to be at least sion molecules, leads to the recruitment of leukocytes in part due to altering MCP-1 expression. It was shown and their adhesion to endothelial cells. This interaction that resveratrol inhibited TNF-α-induced MCP-1 secre- is crucial in activating monocytes to migrate from the Therapeutic Strategies of Plant-derived Compounds Current Medicinal Chemistry, 2017, Vol. 24, No. 14 1461 circulation to the kidney in the early stages of diabetic lism in diabetic patients. Several studies have demon- nephropathy [115]. PCA lowered the expression level strated that the beneficial effects of berberine on meta- of MCP-1 and chemokine macrophage inflammatory bolic disorders including cholesterol-lowering and hy- protein 2, both involved in monocyte chemotaxis and poglycemic effects [120, 121] are associated with acti- macrophage infiltration, in diabetic kidney, and thus vation of AMP-activated protein kinase (AMPK). The antagonized the infiltration and accumulation of adipogenic/lipogenic gene expression in the white adi- macrophages [116]. It is therefore considered that an- pose tissue of obese db/db mice fed with berberine was thocyanins might contribute to the prevention of renal decreased. Moreover, the mRNA levels of pro- vascular diseases in type 2 diabetes. inflammatory genes, including MCP-1, TNF-α, IL-β, IL-6, iNOS, and cyclooxygenase-2 (COX-2), were de- 6.5. Capsaicin creased in the white adipose tissue upon berberine Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a treatment [122]. It is also concluded that berberine capsaicinoid and is the most abundant metabolite pro- suppresses pro-inflammatory responses in macrophages duced by pepper plants. It is an important ingredient in by inhibition of MAPK signaling and cellular ROS spicy foods consumed throughout the world. The fa- through AMPK activation. These reports indicate that vorable role of this metabolite has been widely de- berberine exhibits advantageous effects on metabolic scribed, especially its role in oxidative stress and can- disorders by, inter alia, attenuating the inflammatory cer. It also plays a crucial role in inflammation. It was state via MCP-1 regulation. demonstrated that capsaicin significantly lowered the 6.7. Plant Sterols expressions of MCP-1 and IL-6 mRNAs and protein release in the mesenteric adipose tissues of obese mice. Plant sterols are plant metabolites that have a Moreover, it enhanced the expression of adiponectin chemical structure similar to cholesterol, but with the mRNA and protein release. It exhibited an inhibitory presence of an extra methyl or ethyl group. The most effect of capsaicin on macrophage migration induced abundant plant sterols in the human diet are β- by obese mice mesenteric adipose tissue-conditioned sitosterol, campesterol and stigmasterol, while plant medium or MCP-1 [117]. Additionally, the anti- stanols are less abundant and consist mainly of sitosta- diabetic effect was investigated in in vivo experiments nol and campestanol [123]. Plant sterols are known to on C57BL/6 obese mice fed a high-fat diet. It was re- reduce circulating levels of cholesterol in humans and vealed that dietary capsaicin protected against obesity- thus reduce the risk of coronary heart disease [124]. It induced glucose intolerance, as it significantly in- is generally known that a daily intake of 2.5 g of plant creased the mRNA expression of insulin receptor sub- sterols or stanols lowers serum cholesterol concentra- strate-1 and glucose transporter-4. Furthermore, it tions up to 10% [125]. It is suggested that they have a markedly decreased the levels of TNF-α, MCP-1 and positive effect on obesity-associated metabolic disor- interleukin IL-6 mRNAs and proteins in adipose tissue ders. Two phytosterols from Aloe vera, namely lophe- and liver. Additionally, capsaicin was reported to in- nol and cycloartanol, were suggested to diminished hibit macrophage infiltration into obese adipose tissue glucose levels in Zucker diabetic fatty rats. Treatment by ~25% [118]. with those phytosterols was shown to reduce the serum MCP-1 level and increase the serum adiponectin level. 6.6. Alkaloids Additionally, lophenol and cycloartanol decreased serum and hepatic lipid concentrations (triglyceride, non- Berberine is an isoquinoline alkaloid (C20H19NO5) and constitutes the main component of the ancient Chi- esterified fatty acid, and total cholesterol) and lowered nese herb Coptis chinensis Franch, but also is present the expression levels of hepatic genes encoding glu- in Hydrastis canadensis (goldenseal), Cortex Phello- coneogenic enzymes and lipogenic enzymes [126]. dendri (huangbai), and Rhizoma Coptidis (huanglian). 6.8. Saponins It has been used to treat diabetes for thousands of years, as it exhibits antihyperglycemic effects. Berber- Saponins are polycyclic aglycones that are attached ine significantly reduced levels of serum triglyceride to one or more sugar residues. The aglycone part is and total cholesterol, as well as high- and low-density called sapogenin, and can be a steroid (C27) or a triter- lipoprotein cholesterol (HDL-C and LDL-C) [119]. pene (C30). The aglycone may have steroid or triterpe- Such activity was similar to that reported elsewhere in noid structure according to which saponins are classi- vivo [120]. Thus it regulates glucose and lipid metabo- fied. Steroidal compounds are less common and usually 1462 Current Medicinal Chemistry, 2017, Vol. 24, No. 14 Czemplik et al. found among the monocotyledons, while triterpenoid oxidation protein product-induced MCP-1 expression saponins are more widely distributed and typical of the in podocytes, and these effects were likely to be medi- dicotyledons. Many studies have illustrated the benefi- ated by their anti-inflammatory properties through in- cial effects of these metabolites on blood cholesterol hibition of the IKK/NF-κB pathway [134]. These find- levels, cancer, and stimulation of the immune system ings suggest that sesquiterpene lactones can exert a [29, 127, 128]. The soybean saponins possess anti- beneficial role in the therapy of diabetic nephropathy. inflammatory properties as they are able to inhibit the release of MCP-1 and other pro-inflammatory media- 6.10. Polyunsaturated Fatty Acids (PUFA) tors by LPS-stimulated peritoneal macrophages in a The beneficial effects of PUFA have been broadly dose-dependent manner [129]. Saponins are the main investigated, and the results suggest that diets rich in active compounds of Panax notoginseng, which is used PUFA are beneficial to health, providing a protective to promote the circulation of blood in Chinese medi- role against a range of diseases [135], but also play an cine [130]. Saponins derived from Panax notoginseng important role in metabolic syndrome, which is an in- were found to reduce the glucose and lipid levels in dicator of risk of type 2 diabetes and obesity [136]. blood and also to attenuate the damage of diabetic kid- Plant oils such as soybean oil, peanut oil and corn oil ney in a diabetic rat model. These effects were sug- are a rich source of PUFA. Corn oil has one of the gested to be a result of, among other things, regulation highest PUFA levels, and is composed of 59% polyun- of inflammation via MCP-1. It was shown that sapon- saturated, 24% monounsaturated and 13% saturated ins suppressed the expression of MCP-1 by up- fatty acid. A high intake of corn oil, with 58.6% fat- regulating Sirt1 to deacetylate NF-κB and inhibit NF- derived calories, improved health and longevity of ag- κB signaling transduction in rat mesangial cells. ing mice. It also significantly reduced pro-inflam- Moreover, saponins reduced oxidative stress and sup- matory cytokines including MCP-1, IL-1β and IL-6 in pressed renal fibrosis and inflammation in the kidney the blood. Moreover, it lowered serum triglyceride, caused by high activity of MCP-1 [114]. total cholesterol and LDL-C [137]. The effect of fish oil-derived n-3 PUFA on adipocytes in obese mice was 6.9. Terpenes investigated. It was observed that fish oil derived n-3 Terpenes are biosynthesized from isoprene units PUFA reduced secreted protein concentrations of (molecular formula C5H8) and are classified by the MCP-1 (223%), IL-6 (242.6%), TNF-α (267%), number of isoprene units in the molecule. They are macrophage inflammatory protein (MIP) (252%), MIP- volatile compounds produced by many plants, which 1b (262%), and MCP-3 (219%). They also reduced ac- often possess odors and flavors. Sesquiterpenes consist tivation of the inflammatory transcription factor NF- of three isoprene units and have the molecular formula κB. Thus, a beneficial effect of n-3 PUFA on the obese C15H24. Sesquiterpene lactones were shown to inhibit inflammatory phenotype was reported [138]. inflammatory cytokines, such as MCP-1, IL-1β, IL-18 and MIP-1α, in human renal mesangial cells under hy- 6.11. Plant-derived Extracts perglycemic conditions. Another study revealed that Procyanidins belong to flavonoids, and are oli- synthesized sesquiterpene lactones could be a putative gomeric forms of catechins. They are abundant in red drug in treatment of diabetic nephropathy, as they wine, grapes, cocoa, tea and apples. They are strong could significantly decrease the high glucose-induced antioxidants and exhibit anti-inflammatory actions secretion of MCP-1, TGF-β1 and fibronectin at the [139, 140]. It was demonstrated that grapeseed procya- concentration of 1 and 10 μM. In addition, the expres- nidin extract has a protective role in obesity and insulin sion levels of MCP-1, TGF-β1 and FN were also di- resistance and has a regulatory role in lipid synthesis, minished [131]. Other studies have demonstrated that lipid degradation, glucose uptake, and adipocyte differ- parthenolide, a sesquiterpene which possesses anti- entiation [141]. The exposure of adipocytes and inflammatory activities in vitro, blocks MCP-1 mRNA macrophage-like cells to increasing doses of grapeseed and protein expression by inhibiting NF-κB activity in procyanidin extract followed by an inflammatory experimental glomerulonephritis [132]. Wang et al. stimulus was found to modulate IL-6 and MCP-1 ex- reported that sesquiterpene lactones could inhibit MCP- pression levels. Grapeseed procyanidin extract at 100 1 expression induced by advanced oxidation protein mg/L concentration and higher caused a linear reduc- products by increasing ROS-mediated activation of the tion of MCP-1 mRNA. Lower concentration was found NF-κB pathway in rat mesangial cells [133]. Similarly, not significant for this activity [142]. Grapeseed pro- sesquiterpene lactones were able to inhibit advanced Therapeutic Strategies of Plant-derived Compounds Current Medicinal Chemistry, 2017, Vol. 24, No. 14 1463 cyanidin extract could also modulate adiponectin gene cluding interleukins 1β and 6, cyclooxygenase 2, and expression in vitro at the concentration of 100 mg/L, activation of the expression of suppressor of cytokine but leptin mRNA induction was not detected [142]. and chemokine signaling 1, which is a known anti- An ethanol/water extract from fresh leaves and inflammatory gene. The altered expression of other small branches of the bamboo Phyllostachys edulis was genes showed a similar direction of extract activity, shown to lower MCP-1 concentration in mice fed a lowering migration, and adhesion of leukocytes (MCP1 high-fat diet. Mice were fed a standard (10% energy and ICAM1), and these changes were correlated with from fat) or high-fat (60% energy from fat) diet with or the cannabidiol concentration in the extract [149]. without bamboo extract supplement (11 g dry mass per CONCLUSION 17,000 kJ) for 6 months of treatment. The study showed that bamboo extract supplementation decreased In conclusion, this article reviews the significance the weight of mesenteric fat by 0.52 g, and could sig- and involvement of the chemokine MCP-1 in the de- nificantly attenuate MCP-1 secretion from this tissue velopment of obesity, type 2 diabetes, and diabetic and subsequently contribute to the decrease of MCP-1 complications, with an emphasis on the role of plant in the circulation by 49% [143]. metabolites in the regulation of this chemokine and thus the role in the prevention or therapy of diabetes. In Unripe kiwi fruit methanol extract was applied to these studies, the downregulation of MCP-1 production 3T3-L1 pre-adipocyte cells. It was found that kiwi ex- was found to result in improvement of the symptoms of tract could regulate gene and protein expression of diabetes-related pathologies. MCP-1 and IL-6 by treatment with 30 and 100 µg/ml [144]. Moreover, the kiwi extract promoted differentia- CONFLICT OF INTEREST tion of 3T3-L1 adipocytes, which contributes to lowering of the glucose level in the hyperglycemic/diabetic The authors confirm that this article content has no state. This was proved by the intracellular triglyceride conflict of interest. content and activity of glycerol-3-phosphate dehydro- genase, an enzyme of adipogenesis. ACKNOWLEDGEMENTS Mulberry (Morus alba L.) leaf extract, which con- This work was supported by grant 2012/06/A/ tains flavonoids including rutin, quercetin, isoquercitrin NZ1/00006 from the National Science Center and pro- and quercetin 3-(6-malonylglucoside), exhibits a hypo- gramme The Leading National Research Centre glycemic effect [145]. It was demonstrated that mul- (KNOW) for years 2014-2018. Authors would like to berry leaf extract could reduce atherosclerotic lesions thank Dr. Kamil Kostyn for his assistance with Table 1 in apolipoprotein E-deficient mice by inhibiting lipo- preparation. protein oxidation [146] and inhibit TNF-α-induced nu- REFERENCES clear factor κB activation and lectin-like oxidized low- density lipoprotein receptor-1 expression in vascular [1] Yoshimura, T.; Robinson, E. A.; Tanaka, S.; Appella, E.; Leonard, E. J. Purification and amino acid analysis of two endothelial cells [147]. 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