Frontiers in Clinical Drug Research - Anti-Allergy Agents: Volume 5 E-Book
45,60 €
Mehr erfahren.
- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Clinical Drug Research - Anti-Allergy Agents
- Sprache: Englisch
Frontiers in Clinical Drug Research - Anti-Allergy Agents is a book series comprising of a selection of updated review articles relevant to the recent development of pharmacological agents used for the treatment of allergies. The scope of the reviews includes clinical trials of anti-inflammatory and anti-allergic drugs, drug delivery strategies used to treat specific allergies (such as inflammation, asthma and dermatological allergies), lifestyle dependent modes of therapies and the immunological or metabolic mechanisms that are of interest to researchers as targets for new drugs. The fifth volume of this series brings 5 reviews which cover the following topics: - Resistin: an irresistible therapeutic target for inflammatory diseases, allergy-related disorders, and cancer- Asthma in adults: evaluation, prevalence, and its clinical management- Nitrogen-containing heterocycles as anti-allergy agents- Experimental and clinical studies on the effects of nigella sativa and its constituents on allergic and immunological disorders- Aspirin desensitization/challenge in patients with cardiovascular diseases: current trends and advances Frontiers in Clinical Drug Research - Anti-Allergy Agents will be of interest to immunologists and drug discovery researchers interested in anti-allergic drug therapy as the series provides relevant cutting edge reviews written by experts in this rapidly expanding field
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 337
Veröffentlichungsjahr: 2001
Ähnliche
BENTHAM SCIENCE PUBLISHERS LTD.
End User License Agreement (for non-institutional, personal use)
This is an agreement between you and Bentham Science Publishers Ltd. Please read this License Agreement carefully before using the ebook/echapter/ejournal (“Work”). Your use of the Work constitutes your agreement to the terms and conditions set forth in this License Agreement. If you do not agree to these terms and conditions then you should not use the Work.
Bentham Science Publishers agrees to grant you a non-exclusive, non-transferable limited license to use the Work subject to and in accordance with the following terms and conditions. This License Agreement is for non-library, personal use only. For a library / institutional / multi user license in respect of the Work, please contact: [email protected].
Usage Rules:
All rights reserved: The Work is the subject of copyright and Bentham Science Publishers either owns the Work (and the copyright in it) or is licensed to distribute the Work. You shall not copy, reproduce, modify, remove, delete, augment, add to, publish, transmit, sell, resell, create derivative works from, or in any way exploit the Work or make the Work available for others to do any of the same, in any form or by any means, in whole or in part, in each case without the prior written permission of Bentham Science Publishers, unless stated otherwise in this License Agreement.You may download a copy of the Work on one occasion to one personal computer (including tablet, laptop, desktop, or other such devices). You may make one back-up copy of the Work to avoid losing it.The unauthorised use or distribution of copyrighted or other proprietary content is illegal and could subject you to liability for substantial money damages. You will be liable for any damage resulting from your misuse of the Work or any violation of this License Agreement, including any infringement by you of copyrights or proprietary rights.Disclaimer:
Bentham Science Publishers does not guarantee that the information in the Work is error-free, or warrant that it will meet your requirements or that access to the Work will be uninterrupted or error-free. The Work is provided "as is" without warranty of any kind, either express or implied or statutory, including, without limitation, implied warranties of merchantability and fitness for a particular purpose. The entire risk as to the results and performance of the Work is assumed by you. No responsibility is assumed by Bentham Science Publishers, its staff, editors and/or authors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products instruction, advertisements or ideas contained in the Work.
Limitation of Liability:
In no event will Bentham Science Publishers, its staff, editors and/or authors, be liable for any damages, including, without limitation, special, incidental and/or consequential damages and/or damages for lost data and/or profits arising out of (whether directly or indirectly) the use or inability to use the Work. The entire liability of Bentham Science Publishers shall be limited to the amount actually paid by you for the Work.
General:
Any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims) will be governed by and construed in accordance with the laws of Singapore. Each party agrees that the courts of the state of Singapore shall have exclusive jurisdiction to settle any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims).Your rights under this License Agreement will automatically terminate without notice and without the need for a court order if at any point you breach any terms of this License Agreement. In no event will any delay or failure by Bentham Science Publishers in enforcing your compliance with this License Agreement constitute a waiver of any of its rights.You acknowledge that you have read this License Agreement, and agree to be bound by its terms and conditions. To the extent that any other terms and conditions presented on any website of Bentham Science Publishers conflict with, or are inconsistent with, the terms and conditions set out in this License Agreement, you acknowledge that the terms and conditions set out in this License Agreement shall prevail.Bentham Science Publishers Pte. Ltd. 80 Robinson Road #02-00 Singapore 068898 Singapore Email: [email protected]
PREFACE
Frontiers in Clinical Drug Research - Anti Allergy Agents (Volume 5) comprises five comprehensive chapters on various treatment strategies for allergic conditions.
In chapter 1, Ozkan and Bakar Ates have doscussed the multi-faceted roles of resistin in cellular events as well as its contribution to allergic and inflammatory diseases. Khan et al., in chapter 2 of the book have focused on asthma in adults, its evaluation, prevalence, and clinical management. In the next chaptet, Ameta et al., discuss the role of nitrogen-containing heterocycles as anti-allergy agents. Boskabady et al., in chapter 4, present the experimental and clinical studies on the effects of Nigella sativa and its constituents on allergic and immunologic disorders. In the last chapter, Rezabakhsh and Soleimanpour summarize the new achievements and novel findings of recent clinical advances related to the desensitization approaches following aspirin consumption in patients with coronary artery diseases (CADs).
I hope that this volume will be of great interest to the scientific community and will play a vital role in the development of more effective therapeutic agents to combat various pulmonary ailments.
I would like to thank all the authors for their contributions and the excellent team of Bentham Science Publishers, particularly Mr. Mahmood Alam (Editorial Director) and Ms. Asma Ahmed (Senior Manager Publications), for their support and hard work.
List of Contributors
Resistin: An Irresistible Therapeutic Target for Inflammatory Diseases, Allergy-Related Disorders, and Cancer
Erva Ozkan1,*,Filiz Bakar Ates1Abstract
Resistin is a cytokine that has gained popularity over the last decade for its roles in allergic and inflammatory reactions. It is a cysteine-rich protein secreted mostly by macrophages in humans and adipocytes in mice. It was first identified as a small molecule that mediates insulin resistance in rodents. Following the discovery of resistin, many researchers have started investigating its activity in a wide range of pathological conditions where inflammation is present. Findings from these studies have revealed that resistin serves a major function in almost all inflammatory diseases. Elevated serum resistin levels have been associated with allergic contact dermatitis, atherosclerosis, osteoarthritis, obesity, neurological and cognitive disorders, and cancer. Therefore, it is critically important to understand the exact role of resistin in these pathological conditions to develop an effective therapeutic approach. So far, four receptors are known to interact with resistin. Two of these receptors, toll-like receptor 4 (TLR4) and adenylyl cyclase-associated protein 1 (CAP1), are present on the membrane of human macrophages. The other two receptors, receptor tyrosine kinase-like orphan receptor 1 (ROR1) and decorin (DCN), are found in mice. Even though it is possible that ROR1 exists in humans, too, there is still an open question regarding other receptors that interact with resistin in humans. However, accumulated data suggest that resistin is involved in multiple signaling pathways via binding to TLR4 and CAP1. This chapter aims to elaborate on the multi-faceted roles of resistin in cellular events as well as its contribution to allergic and inflammatory diseases with a focus on cancer formation based on the current and most recent findings.
INTRODUCTION
In 2001, a group of researchers discovered a unique peptide while investigating adipocyte-derived factors that cause insulin resistance. They named this unique compound 'resistin' because it was highly expressed in obese mice with insulin resistance, and its downregulation improved insulin sensitivity [1]. Following the identification of resistin, the same research group did further analyses to find its homologs based on its unique structure and discovered a family of resistin-like molecules (RELMs) in both humans and rodents. Each identified member of this family (resistin, RELMα, RELMβ) was found in different tissues with possible different functions [2]. Interestingly, a different research group discovered the same family of proteins simultaneously while screening for molecules associated with allergic inflammation in mice with ovalbumin-induced asthma, and they named these novel compounds 'found in inflammatory zone' or FIZZ in short [3].
In the decade following the discovery of resistin, numerous studies were conducted in order to illuminate its roles and functions in the pathogenesis of various inflammatory disorders. Data obtained so far have demonstrated a potential benefit in targeting resistin in metabolic diseases in which immune cells are most active. This chapter aims to present current findings regarding the role of resistin in inflammatory and allergic disorders as well as its association with cancer development.
RESISTIN
Structure and Function
Resistin is a 12.5 kDa polypeptide that consists of 108 amino acids in humans and 114 in mice. It was the first identified member of the RELM family. The other members, RELMα, RELMβ, and RELMγ, are found in different tissues with diverse functions. Among these, only resistin and RELMβ exist in humans [4].
The general structure of resistin, as well as the other RELM proteins, consists of 3 main domains: a cleavable N-terminal signal sequence, a variable middle section, and a cysteine-rich conserved C-terminal region (Fig. 1) [2, 5]. The C-terminal, which constitutes almost half of the entire molecule, is the signature sequence that makes RELM members unique peptides and is responsible for stabilizing the structure as well as binding to receptors [2, 6]. It has been reported that resistin and RELMβ contain an additional cysteine residue in N-terminal, which is necessary for multimerization. Due to this extra cysteine, resistin can have a trimer and a hexamer form by disulfide bonding, both of which can be found in serum [7]. The diversity of RELM proteins can be attributed to different coding genes (RETN) present in different species. For instance, mice have four different RETN genes (Retn, Retn1a, Retn1b, Retn1g), while humans have two (Retn and Retn1b) [4]. Furthermore, single nucleotide polymorphisms of RETN have been reported in humans and are associated with varying impacts on metabolic disorders such as obesity and diabetes [8].
Fig.(1)) A representation of the structure of resistin in monomer, trimer, and hexamer forms.Current data on the function of RELM proteins are very limited. However, resistin has received much attention and has been well-studied in recent years due to its close relationship with inflammation and diverse roles in various pathologies. So far, 4 receptors have been reported to interact with resistin: toll-like receptor 4 (TLR4), adenylyl cyclase-associated protein 1 (CAP1), receptor tyrosine kinase-like orphan receptor 1 (ROR1), and decorin (DCN). In humans, mainly TLR4 and CAP1 receptors are expressed, while the other two are predominantly found in mice [4]. These receptors and their downstream signaling pathways have been explored in numerous studies and are still being investigated for their potential to develop new treatment strategies. The binding of resistin to TLR4 stimulates TNF receptor-associated factor 6 (TRAF6) via the MyD88-dependent signaling pathway, leading to the phosphorylation and activation of p38mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Resistin can also activate p38-MAPK and NF-κB via binding to CAP1, which then upregulates cyclic AMP (cAMP) concentration and protein kinase A (PKA) [9]. Additionally, it has been demonstrated that resistin suppresses the insulin signaling pathway, inhibits AMP-activated protein kinase (AMPK), and indirectly interferes with several other signaling pathways via upregulating various mediators such as cytokines and chemokines [10]. As the functions of resistin are tissue and disease-specific, each will be addressed in a separate section.
THE ROLE OF RESISTIN IN DISEASES
Inflammatory Diseases
Obesity
For many years, adipose tissue was considered merely an energy store. However, currently, it is recognized as a major endocrine organ that secretes various hormones and inflammatory cytokines; hence, it is not surprising that chronic inflammation often accompanies obesity, where immune cells infiltrate in adipose tissue, leading to the production of proinflammatory molecules [11].
Obesity is one of the major risk factors for developing metabolic abnormalities, from insulin resistance to diabetes, cardiovascular diseases, and eventually metabolic syndrome or even cancer [12, 13]. In general, obesity is defined as the accumulation of overly enlarged adipocytes caused by insufficient energy expenditure as opposed to a high amount of energy intake. The enlargement of adipose tissue results in a disruption of its functions, leading to increased secretion of pro-inflammatory mediators. These mediators, especially monocyte chemoattractant protein-1 (MCP-1), attract macrophages to the region, causing an immune cell infiltration. In obese patients, M2-type macrophages, which display anti-inflammatory functions in healthy individuals, polarize to M1 and adopt a pro-inflammatory role. Both enlarged adipocytes and M1-type macrophages continue producing a range of pro-inflammatory molecules such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), C-C chemokine receptor type 2 (CCR-2), C-C chemokine receptor type 5 (CCR-5), reactive oxygen species (ROS), leptin and resistin, creating a state of chronic, low-grade systemic inflammation [11]. Most of these mediators are involved in several cell signaling pathways, altering various cellular functions. For instance, TNF-α inhibits insulin action by downregulating the glucose transporter type-4 (GLUT4) [14]. Moreover, c-jun N-terminal kinase (JNK), inhibitor of κ kinase (IKK), mitogen-activated protein kinase (MAPK), protein kinase R (PKR) as well as toll-like receptors (TLRs) and NF-κB are also activated, contributing to the inflammatory processes. The activation of JNK or IKK pathways can target insulin receptor substrate 1 (IRS-1), inhibit the insulin receptor signaling, and cause a loss in insulin sensitivity [15].
In light of the data mentioned above, resistin seems to play a multifunctional role in obesity. As it was previously pointed out, resistin is secreted mostly from macrophages in humans; therefore, it is expected to observe a high level of its expression in obese individuals with increased pro-inflammatory macrophages. It has been reported that resistin stimulates the production of various inflammatory factors, including TNF-α, IL-6, IL-8, and MCP-1 [16]. Enhanced IL-6 promotes JAK/STAT signaling and increases the expression of suppressors of cytokine signaling-1 (SOCS-1) and SOCS-3, which also prevent the interaction between the insulin receptor and its substrate IRS [17, 18]. IL-6 also promotes TLR4 gene expression via STAT3 activation [19]. Apart from impaired glucose metabolism, all these obesity-induced, resistin-related mediators along with NF-κB participate in creating a vicious circle by intensifying and aggravating one another, thereby helping the inflammation gain a chronic state and eventually lead to other metabolic disorders, such as cardiovascular diseases, rheumatoid arthritis and even cancer [13, 16].
It is important to note that findings in the literature regarding resistin levels in obesity are not always consistent [20]. However, it is necessary to consider the context as well as the experimental conditions. For instance, Wu et al. reported that resistin levels are higher in healthy individuals compared to both obese and obese plus hypertensive patients [21]. However, their study included a limited number of patients and lacked test results of inflammatory markers or any information on their physical activities. Multiple investigations have reported that long-term exercise reduces resistin levels in obese patients [22, 23]. One interesting mechanism of the negative correlation between physical activity and resistin levels is that exercising attenuates the polarization of M2-type macrophages to M1 type, which is a major source of resistin expression [24, 25]. Additionally, catecholamines secreted with exercise contribute to the reduction of resistin through β-adrenergic receptors [26]. On the other hand, resistin was found elevated in metabolically unhealthy obese patients compared to healthy individuals [27]. Similarly, obese patients with polycystic ovary syndrome (PCOS) display a higher level of resistin than non-obese PCOS patients [28]. Overall data support the notion that increased resistin levels follow obesity and adipose tissue-derived inflammation. Therefore, resistin could be a potential candidate to prevent the development of obesity-induced disorders, including metabolic syndrome and cancer.
Insulin Resistance and Type-2-Diabetes
Type-2-diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR) and impaired insulin production. Various genetic and environmental factors are involved in the development of T2D [29]. One of the major risk factors is indeed obesity. In the UK alone, around 85% of patients with T2D are overweight [30]. In Europe, the prevalence of obesity in T2D is reported to be between 50.9% and 98.6% [31]. As mentioned in the previous section, enlarged adipose tissue promotes inflammatory reactions via secreting an array of mediators, including adipokines, which prevent insulin from functioning properly. The pathophysiological events involved in T2D include inflammation, adipokine dysregulation, disruption in gut microbiota as well as the immune system [32]. In this section, the molecular mechanisms of IR and T2D will be explored in the context of inflammation and their association with resistin.
Under normal circumstances, glucose is taken up by cells upon activation of the insulin signaling pathway. To summarize, insulin binds to its receptor and then activates it by autophosphorylation, leading to the activation of its substrate, IRS. When IRS is enabled, it binds to phosphoinositide 3-kinase (PI3K), which converts phosphatidylinositol bisphosphate (PIP2) to PIP3. PIP3 then recruits phosphoinositide-dependent kinase-1 (PDK1), and PDK1 enables Akt (also known as protein kinase B). The activation of Akt allows GLUT4 to translocate to the plasma membrane, which then takes up glucose. It also leads to the activation of mTORC1, an inhibitor of IRS in the negative feedback loop of the insulin signaling pathway [33]. In T2D, however, the binding of insulin does not induce this pathway properly. When the interaction between insulin and its receptor is compromised, the downstream stages cannot be carried out, hence, the relevant cellular functions get interrupted. The occurrence of insulin resistance can be observed predominantly in adipose tissue, liver and skeletal muscle. Following a high-fat diet or lipid infusion, accumulated diacylglycerols (DAG) in muscle tissues induce the activation of protein kinase C (PKC). Activated PKC inhibits the interaction between the insulin receptor and IRS. As a result, GLUT4 cannot translocate to the plasma membrane and glucose uptake gets halted while lipolysis is induced. Extracellular glucose is then diverted to the liver, where it is used for de novo lipogenesis, thereby increasing both liver and plasma triglyceride levels [32]. In a cohort study, it has been reported that hepatic DAG concentrations and PKC activation were the most significant predictors of insulin sensitivity in patients undergoing bariatric surgery [34]. In line with these data, a more recent study has reported that resistin can activate PKC via its receptor TLR4 [35], indicating its potential role in the development of IR (Fig. 2).
The discovery of resistin was initially made while investigating the link between IR and increased adiposity in mice. An anti-diabetic class of drugs known as thiazolidinediones was able to improve insulin sensitivity in obese mice while downregulating resistin levels. Additionally, the administration of resistin caused an impairment in insulin function, whereas anti-resistin antibody restored insulin sensitivity [1]. Following this study, numerous investigations were performed in order to illuminate the role of resistin in the development and progression of IR and T2D.
Fig.(2)) The effects of resistin on the insulin signaling pathway. The binding of resistin to CAP1 or TLR4 upregulates NF-κB and MAPK, resulting in the expression of several proinflammatory mediators such as TNF-α, SOC3 and IL-6. These molecules inhibit insulin signaling either by preventing the interaction between the insulin receptor and IRS-1 or by blocking glucose uptake of GLUT4 via suppressing the PI3K/Akt pathway. Resistin also increases PKC activation, which is another mediator that inhibits insulin receptor and IRS-1 interaction. Res: Resistin, CAP1: Adenylyl cyclase-associated protein 1, TLR4: Toll-like receptor 4, GLUT4: Glucose transporter 4, TIRAP: Toll-interleukin 1 receptor domain containing adaptor protein, MyD88: Myeloid differentiation primary response 88, TRAF6: TNF receptor-associated factor 6, IKK: Inhibitor of κ kinase, MAPK: p38-mitogen-activated protein kinase, JNK: c-jun N-terminal kinase, NF-κB: Nuclear factor-κB, AP-1: Activator protein-1, cAMP: Cyclic AMP, PKA: Protein kinase A, PKC: Protein kinase C, IRS-1: Insulin receptor substrate 1, PI3K: Phosphoinositide 3-kinase, PIP2/3: Phosphatidylinositol bisphosphate 2/3, PDK1: Phosphoinositide-dependent kinase-1, SOCS3: Suppressor of cytokine signaling-3, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor-αIn this regard, several studies confirmed a positive correlation between resistin levels and IR in humans [36, 37], while a number of studies stated otherwise [38, 39]. The conflicting data may be due to the small sample size in most studies. Furthermore, multiple other factors are likely to cause the varying findings. For instance, gender and age have been reported to associate with resistin levels, where females displayed a higher level of resistin than males, which was significantly positively correlated with age [38]. Different ethnicities and RETN gene polymorphisms were also reported to significantly impact resistin levels in patients with T2D [8]. However, according to a meta-analysis, accumulated data predominantly support a correlation between resistin and diabetes [20]. A recent review of randomized controlled trials presented by Dludla et al. was in line with this analysis, reporting that metformin use in diabetic patients reduces pro-inflammatory markers such as IL-6 and TNF-α as well as resistin levels [37].
Pro-inflammatory adipokines contribute to the development of insulin resistance through inhibiting the interaction of insulin receptor and its substrate IRS, activating JNK or IKKβ/NF-κB pathways [40]. Elevated glucose or resistin activates MAPK [10] and NF-κB, leading to TNF-α secretion. TNF-α participates in the pathogenesis of insulin resistance through several different routes. Firstly, it can inhibit the activation of IRS directly [41]. Secondly, it alters adipocyte differentiation by downregulating PPARγ, which also contributes to insulin resistance by counteracting anti-diabetic drugs [42]. Furthermore, by inhibiting the insulin signaling pathway, it promotes lipolysis and free fatty acid (FFA) release, which enhances hepatic glucose production [43]. Interestingly, TNF-α also activates its own activator NF-κB [11]. The elevated NF-κB activity in high-fat diet animals has been reported to activate mTORC1 which deactivates IRS-1 [44].
In all these cellular events, resistin is involved either directly or indirectly. For instance, the activation of NF-κB enhances resistin levels, leading to the promotion of TNF-α [11]. The increase in resistin levels leads to the production of IL-6, IL-8 and MCP-1; all of which play significant roles in insulin resistance [19]. IL-6 upregulates one of the insulin signaling inhibitors, SOCS3, and reduces the expression of GLUT4, as well as IRS-1, via JAK/STAT signaling. It also promotes a direct receptor of resistin, TLR4 [45]. On the other hand, MCP-1, which has significant roles in both obesity-related inflammation and diabetes, is upregulated by increased resistin. In T2D, enhanced expression of MCP-1 in adipose tissue promotes gluconeogenesis and increases insulin resistance via its receptor CCR-2 [46]. Additionally, it has been reported that resistin inhibits AMP-activated protein kinase (AMPK), which is involved in glucose uptake [10]. More importantly, resistin can downregulate IRS at both protein expression level and the phosphorylation stage, thereby interrupting the interaction between the insulin receptor and IRS [47, 48].
Altering the expression or the function of any of these mediators may assist in downregulating resistin and/or related inflammatory pathways in T2D. For instance, the shift towards the pro-inflammatory macrophage M1 is maintained by TLR4 receptor ligands such as saturated fatty acids or resistin [14], and it has been reported that knockdown of TLR4 protects against insulin resistance by improving IRS activation, glucose uptake and decreasing JNK1 phosphorylation in skeletal muscle [49]. It has also been reported that the inhibition of NF-κB results in downregulation of high glucose-induced resistin [50] and improves insulin sensitivity. Moreover, in human monocytic cells, high glucose upregulated the gene expression and protein production of resistin via MAPK, ERK1/2 and JNK pathways, which were suppressed by PI3K activation [50]. Interestingly, Lee et al. showed that binding of resistin to CAP1 receptor upregulates NF-κB expression as well as cAMP and protein kinase A (PKA), whereas, in contrast, PKA inhibitors lead to a blockage of resistin-induced NF-κB activation [51]. Similarly, JNK inhibition also improves glucose uptake while reducing TNF-α and MCP-1 [45].
It is important to note that even though increased resistin was detected mostly in patients with both obesity and diabetes, Bu et al. demonstrated higher levels in T2D patients, regardless of their state of obesity [39]. Hence, resistin may have diabetes-specific roles that require further investigation. Despite the doubts in the literature regarding the role of resistin in the development of IR or T2D, it is evident that resistin is a significant mediator in inflammatory processes. Therefore, by targeting resistin-related pathways, the ensuing complications can be minimized or slowed down.
Atherosclerosis
Atherosclerosis is a cardiovascular disease characterized by a lipid-filled plaque formation and inflammation in the endothelium of arteries. Risk factors include smoking, sedentary lifestyle, unhealthy diet, obesity, diabetes, hypertension and a high level of low-density lipoprotein (LDL), as opposed to a low level of high-density lipoprotein (HDL) [52].
Under healthy conditions, endothelial cells tightly line up and form a monolayer in order to cover the inner walls of blood vessels and prevent circulating compounds such as LDL from permeating underneath, while also regulating blood clotting by expressing antiplatelet agents. Irritants, such as chronic hyperglycemia, hypertension, toxins of cigarettes or hyperlipidemia, can disturb this protective barrier, causing endothelial cells to deteriorate and lose their functionality [53]. This allows LDL particles to easily go into the subendothelial space. Additionally, damaged endothelial cells initiate the production of certain adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), causing platelets to aggregate and monocytes to attach. These cells pass through the endothelium to the subendothelial space where LDLs accumulate. Then, monocytes transform into M1-type macrophages and begin to secrete several inflammatory mediators such as IL-6, IL-12, IL-1β and TNF-α. They also produce ROS which oxidize LDL particles. The oxidized LDLs exhibit chemoattractant properties and call in more monocytes to the region. These white blood cells begin to collect the oxidized LDLs through their receptors, such as scavenger receptor-A (SR-A) or CD36, and become foam cells [54]. However, excessive amounts of LDL cause them to die off and release their contents including signaling molecules such as MCP-1, which then brings in more and more monocytes to the region, turning the situation into a positive feedback loop [55]. Dead cell fragments, oxidized LDLs, damaged endothelial cells and accumulated foam cells constitute a growing plaque on the surface of the wall of arteries. Over time, this plaque slows down the blood flow by narrowing the vessel. Meanwhile, smooth muscle cells (SMCs) beneath the endothelium also migrate out of their own layer into the built-up plaque material. Both SMCs and macrophages secrete pro-coagulant tissue factors which confer thrombogenic properties to the plaque. As a last defensive line for arterial lumen, SMCs form a protective shield called a fibrous cap, consisting of collagens, elastin fibers and the like, which covers the thrombogenic plaque and protects it from exposure to blood. However, macrophages also express a group of proteinases known as matrix metalloproteinases (MMP) that degrade the fibrous cap and make it unstable. If and when the plaque fractures, the blood will be exposed to thrombogenic factors and clots will form. These clots may block off the arteries and then cause several complications like ischemia, stroke or myocardial infarction [55].
In this context, data in the literature show that the functions of resistin in the formation of atheromatous plaque are diverse. Hsu et al. treated endothelial cell lines (HUVEC) with resistin and found that the expression of adhesion molecules VCAM-1 and ICAM-1, as well as monocyte attachment, increased significantly, and this increase was blocked by the inhibition of p38/MAPK [56]. In another study conducted in the same year, the contribution of resistin was demonstrated to be immense. Both in vitro and in vivo experiments indicated that resistin induces VCAM-1 expression from the vascular smooth muscle cells and enhances macrophage infiltration to the subendothelial space as well as the expression of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in the arterial walls. It has also been reported that resistin enhances atherosclerotic lesions by 2.5-fold and weakens the fibrous cap by triggering apoptosis in vascular smooth muscle cells [57, 58]. Additionally, it induces the conversion of macrophages into the proinflammatory phenotype via TLR4/NF-κB signaling pathway [7]. Furthermore, activated resistin/ERK1/2 pathway causes M1 macrophages to infiltrate into the fibrous cap and produce MMPs that degrade the collagen and create a risk of plaque rupture and thrombosis [59].
As it was indicated previously, elevated LDL cholesterol is a major risk factor for atherosclerosis. One of the mechanisms by which circulating LDL increases is the reduction in liver uptake via LDL receptors (LDLR). Decreased expression of this receptor will lessen the clearance of LDL and contribute to lipid accumulation in the arteries. Cho et al. reported that resistin treatment in hepatocytes diminished the LDLR protein levels by 40%. It also decreased statin-mediated upregulation of LDLR by 80% [60]. Moreover, Costandi et al. reported that treating hepatocytes with resistin enhanced apolipoprotein B, which is necessary for LDL production, by 10-fold via activating microsomal triglyceride transfer protein (MTP). Enhanced apolipoprotein B led to VLDL overproduction, and this was reversed by the removal of serum resistin with an antibody. Resistin also increased the lipid content of hepatocytes by stimulating de novo lipogenesis [61]. On the other hand, experiments have revealed that resistin upregulates SR-A and CD36 on macrophages, which are the two main receptors responsible of internalizing the oxidized LDLs, and promotes the formation of foam cells via activating the activator protein-1 (AP-1) and PPARγ [62]. Additionally, it downregulates the expression of cholesterol efflux regulatory protein ABCA1, which contributes to increased cholesterol build-up [62].
These findings suggest that resistin accelerates the atherosclerotic plaque progression by affecting various mediators and aggravating the inflammatory conditions. A recent study provided evidence that enhanced activation of PPARγ downregulates resistin expression and causes a significant increase in HDL levels [63]. Therefore, resistin may be a promising target in preventing atherosclerosis and its associated cardiovascular complications.
Rheumatoid Arthritis and Osteoarthritis
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in synovial joints and degradation of synovial fluid as well as cartilage. Although the exact cause of RA has not yet been discovered, several genetic and environmental factors are thought to play an important role in the initiation of the disease [64]. Current treatment options can only slow the progression of the present inflammation, but not cure it. Therefore, there is a great need to design novel treatment strategies for RA.
Multiple immune cells and mediators are involved in the pathogenesis of RA. One of the major events observed is the citrullination process of endogenous proteins such as collagen or fibrin. Exposure to RA-initiating factors, including joint injury, acute inflammation or bacterial infection in individuals who are susceptible to RA development (such as those who carry HLA DR-B1 gene [64]), may promote the conversion of arginine residue of proteins into citrulline, causing them to be recognized as foreign antigens by the immune cells, which then trigger a chain of inflammatory reactions. The citrullinated proteins are bound by antigen presenting cells (APC) and carried to lymph nodes, where they activate the CD4+ T helper cells (Th). Activated Th cells then initiate B cell proliferation and differentiation into plasma cells which produce antigen-specific antibodies. In RA, there are two main identified antibodies: rheumatoid factor (RF) and anti-cyclic citrullinated protein antibody (anti-CCP). These antibodies target and bind to the modified auto-antigens and form an immune complex that triggers an inflammatory response [65].
On the other hand, Th cells migrate to the synovial space of joints, where they secrete cytokines such as interferon gamma (IFNγ) and IL-17, and recruit macrophages to the region, which also begin to produce several pro-inflammatory cytokines including TNF-α, IL-1β and IL-6. These mediators stimulate the proliferation of synovial cells (especially fibroblast-like synoviocytes) and promote thickening of the synovial membrane. Stimulated synoviocytes produce proteases which break down the cartilage [65]. Meanwhile, cytokines increase the expression of the receptor activator of nuclear factor kappa-Β ligand (RANKL) on the surface of Th cells. RANKL allows Th cells to bind RANK receptor on osteoclasts which start breaking down the bone tissue [66]. Additionally, neutrophils that are present in the synovial fluid also produce proteases and ROS, contributing to the inflammatory process and the degradation of cartilage. Another role of cytokines in RA is to increase vascular permeability and the expression of adhesion molecules as well as angiogenesis. This allows more immune cells to migrate to the joints, while enabling activated synoviocytes to escape to other joints and spread the disease throughout the body [64].
Although adipokines are mainly secreted by adipocytes and immune cells, they can also be produced by synoviocytes, osteoclasts, osteoblasts and chondrocytes in joints and participate in the development of rheumatic disorders [67]. Considering the important roles of adipokines in inflammatory diseases, it is expected to encounter resistin involvement at the crossroad of inflammation and RA. Hence, many researchers investigated the potential role of resistin in patients with RA and demonstrated an apparent relationship between the disease progression and resistin levels. For instance, in a study conducted with 20 patients with RA, resistin levels were found significantly higher in the synovium. Moreover, macrophages, B lymphocytes and plasma cells displayed colocalization with resistin. Additionally, serum resistin, but not synovial resistin, positively correlated with C-reactive protein (CRP) levels [68]. On the other hand, a different study with 42 patients reported that serum resistin levels are higher in patients with RA, and it correlates with circulating TNF-α, CRP and RA-related markers [69]. These results were confirmed by another study and indicated that resistin is associated with the expression of IL-1R antagonist (IL-1Ra), CRP and TNF-α in post-menopausal women with RA. Interestingly, resistin levels also correlated with increased osteoclast activity and reduced bone mineral density, indicating an important role of resistin in the degeneration of joints [70]. Additionally, Nagaev et al. reported that the inhibition of TNF-α caused a significant downregulation in resistin gene expression in CD4+ Th cells in RA [71]. Furthermore, resistin was reported to directly promote VEGF expression in endothelial progenitor cells (EPC), which participate in angiogenesis in the synovium, while the blockade of resistin prevented EPC from navigating to the synovial fluid and inducing angiogenesis in vivo [72].
More importantly, the association of resistin levels with two RA-specific biomarkers, RF and anti-CCP antibodies, was investigated in 25 patients. Results have indicated that resistin levels in the synovial fluid, but not serum resistin levels, correlated with both RF and anti-CCP, suggesting that resistin may be associated with poor prognosis in RA [73]. Similar to other metabolic disorders, some researchers reported no significant correlation between resistin and RA [74]. Data in the literature, however, predominantly suggest a significant link between resistin and disease progression. A recent meta-analysis of 8 studies confirmed that serum resistin levels are significantly higher in patients with RA compared to healthy individuals [75
