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Review

Regulatory Effects of Curcumin on Platelets: An Update and Future Directions

by
Yaseen Hussain
1,
Abdullah
2,
Fazlullah Khan
3,
Khalaf F. Alsharif
4,
Khalid J. Alzahrani
4,
Luciano Saso
5 and
Haroon Khan
6,*
1
Lab of Controlled Release and Drug Delivery System, College of Pharmaceutical Sciences, Soochow University, Suzhou 215000, China
2
Department of Pharmacy, University of Malakand, Chakdara 18800, Pakistan
3
Faculty of Pharmacy, Capital University of Science & Technology, Islamabad 44000, Pakistan
4
Department of Clinical Laboratory, College of Applied Medical Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
5
Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University, 00185 Rome, Italy
6
Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
*
Author to whom correspondence should be addressed.
Biomedicines 2022, 10(12), 3180; https://doi.org/10.3390/biomedicines10123180
Submission received: 14 October 2022 / Revised: 29 November 2022 / Accepted: 1 December 2022 / Published: 8 December 2022
(This article belongs to the Section Drug Discovery, Development and Delivery)
Browse Figures
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Abstract

:
The rhizomatous plant turmeric, which is frequently used as a spice and coloring ingredient, yields curcumin, a bioactive compound. Curcumin inhibits platelet activation and aggregation and improves platelet count. Platelets dysfunction results in several disorders, including inflammation, atherothrombosis, and thromboembolism. Several studies have proved the beneficial role of curcumin on platelets and hence proved it is an important candidate for the treatment of the aforementioned diseases. Moreover, curcumin is also frequently employed as an anti-inflammatory agent in conventional medicine. In arthritic patients, it has been shown to reduce the generation of pro-inflammatory eicosanoids and to reduce edema, morning stiffness, and other symptoms. Curcumin taken orally also reduced rats’ acute inflammation brought on by carrageenan. Curcumin has also been proven to prevent atherosclerosis and platelet aggregation, as well as to reduce angiogenesis in adipose tissue. In the cerebral microcirculation, curcumin significantly lowered platelet and leukocyte adhesion. It largely modulated the endothelium to reduce platelet adhesion. Additionally, P-selectin expression and mice survival after cecal ligation and puncture were improved by curcumin, which also altered platelet and leukocyte adhesion and blood–brain barrier dysfunction. Through regulating many processes involved in platelet aggregation, curcuminoids collectively demonstrated detectable antiplatelet activity. Curcuminoids may therefore be able to prevent disorders linked to platelet activation as possible therapeutic agents. This review article proposes to highlight and discuss the regulatory effects of curcumin on platelets.

1. Introduction

The chemical name of curcumin, a phenolic molecule, is (1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione [1]. It is also known as diferuloylmethane. It has been classified as both a PAINS (pan assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate [2]. The rhizome and roots of the turmeric plant contain significant levels of this biologically active chemical (Curcuma longa) [3]. Demethoxycurcumin and bis-demethoxycurcumin are two more curcuminoids found in this plant in addition to curcumin (Figure 1). It has been found that 2–4 percent of the dry turmeric root powder is made up of curcuminoids. Curcumin is a yellow substance that has a variety of uses, including herbal dietary supplements and culinary coloring and flavoring agents in various preparations [4].
Curcumin was first isolated in an impure form in 1815. Curcumin demonstrates keto-enol tautomerism in its position as a bis-α, β-unsaturated β-diketone. While curcumin’s keto form is more common in acidic and naturally occurring pH, the enol form is more common in alkaline solutions [5,6]. It is important to note that Curcumin is employed in the food, pharmaceutical, and textile industries. According to evidence dating back 2500 years, curcumin has long been used to cure different diseases in traditional Indian medicine and throughout Asia. Curcumin has been considered a potent remedy for various ailments, including rheumatism, dyspepsia, and irritable bowel syndrome as well as infection treatments for eye and skin conditions [7,8].
Since 1937, when the first study on curcumin’s medicinal effects was published, much effort has gone into illuminating the compound’s unique pharmacological properties [9]. According to reports, curcumin has beneficial biological and therapeutic properties including antioxidant, hepatoprotective, cardioprotective, neuroprotective, anti-microbial, anti-tumor and improvement of dyslipidemia and ischemia-reperfusion [10]. In oil-based solutions, curcumin is very soluble. Curcumin is soluble at alkaline pH despite being insoluble in water at acidic and neutral pH levels. As was already established, although having outstanding therapeutic effects, curcumin’s effectiveness has been significantly constrained by several factors [11]. Its limited solubility in aqueous environments and quick conversion into an inactive metabolite are the biggest obstacles. Due to this, numerous studies have focused on improving the solubility of curcumin or encapsulating it to create targeted drug delivery systems for biological uses [12].
Platelets are non-nucleated cells of the blood generated continuously by the human body (1011 cells daily) from megakaryocytes via differentiation, maturation, and fragmentation [13]. Usually, their normal life span ranges from 8 to 10 days in the blood [14].
Thrombopoiesis (the formation of platelets) occurs in bone marrow that involve the formation of megakaryocytes (50–100 μm in diameter) from hematopoietic stem cells [15]. The mature megakaryocytes shed long-branching cytoplasmic protrusions, called proplatelets [16]. When the platelet count is reduced, thrombopoietin is secreted by the liver that activates thrombopoietin receptor of megakaryocytes resulting in the proplatelets generation [17]. Situations requiring thrombopoiesis, for instance during inflammation, IL-6 increases the thrombopoietin level, thereby increasing the formation of proplatelets [18]. The generation of proplatelets involves the redistribution of granules, vesicular structures, and organelles from the cell body of megakaryocytes into proplatelets. The proplatelets subsequently give rise to platelets. It has been found that proplatelet formation is inhibited by collagen I (via glycoprotein VI (GPVI) and integrin α2β1) and stimulated by fibrinogen, type IV collagen, and fibronectin [19].
Platelets contain different cell organelles, including ribosomes, mitochondria, microtubules, glycogen granules, occasional Golgi elements and enzyme systems for aerobic as well as anaerobic respiration [20,21]. In addition, one of the important organelles is their granules, which are of three types known as α-granules, δ-granules (dense granules), and lysosomes. The α-granules are the largest and most abundant (50–80 α-granules/platelet) [22], heterogenous in content and function that contain adhesive proteins including von Willebrand Factor (vWF), platelet factor 4 (PF4), fibronectin, fibrinogen, platelet derived growth factor (pdGF), tetraspanins (e.g., CD 9) and immunoglobulin family receptors (e.g., PECAM, GPVI) [23]. The δ-granules are smaller, less in number (3–8/platelet), electron-dense, containing non-protein molecules involved in platelet activation and vasoconstriction such as calcium, serotonin, histamine, ATP, and ADP [24,25], while the lysosomes are scanty, membrane-bound vesicles containing lysosomal enzymes (e.g., hexosaminidase and cathepsins). These act in the digestion of cytosolic components and extracellular functions, such as degradation of extracellular matrix, cleavage of receptors and fibrinolysis [26]. Recently, a novel, electron-dense, secretory granule designated as T granule has been reported [27], which behaves similar to the Toll-like receptors (TLR). Defects or deficiency in platelet granules have been linked to several bleeding disorders, such as Hermansky-Pudlak Syndrome (dense granule deficiency) and Grey Platelet Syndrome (α-granule deficiency) [28].
Platelets form a platelet plug, thus blocking bleeding during vascular injury [29]. It plays an important role in infection, tumor growth, vascular repair and constriction, inflammation, and tissue homeostasis [30,31,32,33]. Platelets help to regulate the tone of blood vessels, re-formation of neointima after injury to wall of the vessels, and pathological processes such as atherosclerosis, cancer metastasis, and thrombosis [34]. Oxidative stress has been implicated in the modulation of platelet function resulting in platelet aggregation [35]. The elevated ROS concentration reduce the amount of NO., an antiplatelet and vasorelaxant agent, forming a cytotoxic substance, peroxynitrite [36]. Oxidative stress and the subsequent chronic inflammation are involved in several diseases including cardiovascular disorders (CVDs), and cancer.
It has been observed that curcumin prevent platelet activation and aggregation, most likely through inhibition of lipoxygenase and cyclo-oxygenase pathway (thus blocking thromboxane B2 and 12-HETE production) [37], interfering with cytosolic Ca2+ which is necessary for platelet activation and aggregation [38]. Other mechanisms of curcumin mediated platelets inhibition involve reduction of mitochondrial membrane potential, microparticle formation, and increased annexin-V binding [39]. According to some reports, curcumin prevents its formation of fibrinogen and thus, lowers plasma levels of fibrinogen. Thus, curcumin administration to HFD-rats resulted in lower fibrinogen and platelet counts, indicating a physiological response to preventing thrombosis and lowering CVD risk [40]. In the present review, we aimed to highlight the regulatory effects of curcumin on platelets.

2. Functions of Platelets

2.1. Hemostasis

Hemostasis is the ability to prevent bleeding from an injured blood vessel. It may be primary, secondary, or fibrinolysis [41]. Primary hemostasis involves stopping of blood loss via formation of platelets plug [27]. Secondary hemostasis involves the deposition of insoluble fibrin produced through coagulation cascade. Fibrinolysis is the breakdown of fibrin clot through several enzymes that occur during wound healing [41]. In normal healthy vessels, the endothelium is intact and offers a non-adhesive surface to platelets, while in case of damage, the platelets adhere to the extracellular matrix of the exposed endothelial surface and thus form a platelet plug, which is a three-step process including platelet adhesion, platelet activation and secretion, and platelet aggregation [42].

2.2. Platelet’s Role beyond Hemostasis

a.
Inflammation and immunity
Platelets play an important role in immunity and inflammation by interacting with immune cells [43]. The α- and dense granules contain proinflammatory mediators including growth factors, TGF-β, P-selectin, and CD40L. These cause stimulation of other cells to secrete proinflammatory chemokines and cytokines such as TNFα, IL-8, IL-1β, and CCL2 [44]. Platelets contain several Toll-like receptors (TLR) ranging from TLR1-9 that identify molecular motifs known as pathogen-associated molecular patterns (PAMPs) and thus stimulate immune system [45]. Bacteria, via TLR2 stimulation, initiate a pro-inflammatory response through the PI3K signaling pathway [22]. Likewise, TLR9 stimulation is linked to oxidative stress and thrombosis [27].
Recently, a link between immune system and platelets has been found that involve the interaction of platelets with complement system [46,47,48]. Platelets bind C3b, a key complement component, via P-selectin and activates the formation of membrane attack complex and anaphylatoxin C5a, that is responsible the lysis of pathogen cells [49].
Platelets have the intrinsic ability to store and release significant quantities of chemokines and cytokines involved in inflammation [50]. Platelets are the first cells to reach at the infection site in blood vessels. They are also indispensable players in infection and immune response to viral and bacterial infections [51]. Deficiency of platelets (thrombocytopenia) occur in sepsis, and it has been proved that platelets exhibit important role in multiorgan failure and sepsis [52].
b.
Cancer
Platelets play an important role in the pathogenesis of metastasis [53]. It has been observed in the in vitro studies that platelets adhere to metastatic cells, thus forming a “cloak” around the circulating tumor cells and hence, acting as a shield for immune clearance. This has resulted in epithelia-mesenchymal transition, pro-angiogenic, and pro-survival effects in cancer cells [54]. Moreover, platelets have been found as the culprits behind the enhanced tumor growth by secretion of PDGF and VEGF [55].
c.
Wound healing
It has been found that platelets are relevant mediators of tissue regeneration and wound healing. It involves the release of growth factors and several other mediators of repair and regeneration, including cytokines, fibronectin, vitronectin, and sphingosine 1-phosphate. The different steps involved in wound healing includes hemostasis, inflammation, proliferation, and remodeling/maturation. Platelets are key players in these steps [56]. As the tissue is injured, platelets quickly form fibrin clot that halts bleeding [57]. Platelets and neutrophils help to resolve inflammation by secreting several pro-resolving mediators and polarizing macrophages towards a repair phenotype [58]. Furthermore, platelets play important role in the proliferative phase of repair by releasing angiogenic and growth factors. Angiogenesis: an important step to cope with increased metabolic needs of the healing tissues; is induced by VEGF, Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF); platelets activate the recruitment of CD34+ bone marrow derived endothelial progenitors [59]. Moreover, platelets release PDGF and TGF-b that act on fibroblasts so that the initial provisional fibrin scaffold is replaced with a granulation tissue rich in immature collagens, proteoglycans, and fibronectin [60]. Finally, platelets help to remodel the extracellular matrix by releasing matrix metalloproteinase and hydrolases. Platelets-rich plasma (PRP) gels are available that is applied in clinics for healing diabetic ulcers and skin wounds [61].
d.
Infection
Platelets play an important role in infection ranging from directly killing bacteria to increasing the differentiation of immune cells [32,62]. Platelets granules contain proteins, such as thrombocidin 1 and 2 which kill a broad range of bacteria by direct microbicidal effect [63,64]. It has been proved that platelets detect lipopolysaccharides of bacteria by toll-like receptor 4 and activate the neutrophil extracellular traps (NET) formation in neutrophils [65]. NET is composed of neutrophilic proteins, histones, and DNA that traps and eliminates fungi and bacteria [66,67]. Moreover, platelets contain β1-defensins that stimulate the production of NET and stop bacterial growth [68]. P-selectin in platelets stimulates platelets-dependent NET formation [69]. Likewise, platelets contain a ligand for leucocyte triggering receptor expressed on myeloid cells 1 (TREM-1). Bacterial structures upregulate these receptors that enhance the secretion of IL-8 by the neutrophils and enhance TREM-1-induced respiratory burst [70]. Furthermore, T-lymphocytes are the main players in modulation of immune response by platelets. In an acute viral hepatitis model, platelets have been found to trigger cytotoxic T-cells response, resulting in hepatic injury [71]. Moreover, the interaction of cytotoxic T-cells and platelets depend on platelets CD154 [72,73]. Similarly, in chronic viral hepatitis model, the serotonin derived from platelets exacerbated hepatocytes damage by reducing cytotoxic T-cells recruitment and sinusoidal blood flow [74]. It is noteworthy that serotonin stimulate T-cells through 5-HT receptors [75]. In addition, a chemokine, Regulated And Normal T cell Expressed and Secreted (RANTES), released by platelets has been found to play pivotal role in cytotoxic T-cells function in viral infections [76].

3. Pharmacological Effects of Curcumin

Many in vivo and in vitro model systems were used in past decades to identify the pharmacological effects of curcumin. However, its poor pharmacokinetics has led to its limited use in humans following clinical applications. Curcumin exhibits many versatile pharmacological effects that are schematically shown in Figure 2.
Curcumin exhibits promising antioxidant activity. It has been shown that curcumin mimics the level of oxidative stress markers systemically thus leads to the modulation of enzymes responsible for free radical neutralization such as catalase, superoxide dismutase, glutathione etc. [77] in addition, curcumin also exhibit free radical scavenging activity and scavenge nitrogen and oxygen reactive species [78]. Results of a recent meta-analysis study showed that curcumin significantly decreased malondialdehyde concentration in participant subjects and increased the total antioxidant capacity showing the antioxidant potential of pure curcumin [79]. In another study, curcumin loaded Zein/carboxymethyl dextrin nanoparticles were evaluated and results showed impressive antioxidant potential of curcumin from nanotechnology platform [80]. Results from reducing power assay and DPPH radical scavenging analysis showed a high in vitro antioxidant activity for curcumin loaded whey protein micro gels [81]. Curcumin is a well-known anti-inflammatory agent. In this regard, using ovalbumin-induced allergic asthma mouse model, curcumin was administered to BALB/c mice in a dose of 20 mg and 100 mg/kg dose. From results, it was concluded that curcumin showed an anti-inflammatory effect through suppression of pro inflammatory cytokines and elevation in the expression levels of aquaporin [82]. Glucan particles extracted from yeast were used for loading curcumin and were delivered in vitro to evaluate its anti-inflammatory potential. The secretion of pro-inflammatory cytokines, TNF-α and IL-1β, showed the effective anti-inflammatory response of the delivered curcumin [83].
Defensive mechanisms of the immune system combat infections [84]. The activity of the immune system is modulated by immunomodulators that in turn reduce inflammation through normalization of the immune system [85]. The normal function of the immune system is affected by many flavonoids posing their pharmacological action [86]. The expression of proinflammatory cytokines and chemokines was down regulated by curcumin via NF-kB inactivation [87]. At low doses curcumin showed modulation of immune system and showed its pharmacological effect in various ailments, i.e., cancer, heart diseases, asthma, and diabetes [88]. In an experimental multiple sclerosis animal model, curcumin resulted in decreased production of IL-2 as well as STAT4 activation and showed an immunomodulatory effect [89]. In addition, data from pre-clinical and clinical trials have shown the curcumin immunomodulatory actions focusing mediators and immune cells involved in immune responses [90,91]. Curcumin has a versatile immunomodulatory action and affects different immune cells, showing its future use in immune diseases therapy.
The pathological process of neuronal killing is called excitotoxicity [92]. Excessive glutamate induces calcium influx and neuronal injury [93]. Eventually, excitotoxicity associated neurodegeneration and depressive disorders are triggered [94]. In such major depressive disorders, curcumin has shown antidepressant effect [95]. Curcumin also decreases calcium influx along with inhibition of A-kinase anchoring protein 79 translocation from cytomembrane to cytoplasm [96]. Another study showed that curcumin significantly elevated the expression of brain-derived neurotrophic factor along with cell viability [97]. Similarly, curcumin suppressed the neuroprotective effect and enhanced the expression of brain-derived neurotrophic factor with retardation of the TrkB signaling pathway [98]. Programmed cell death is achieved through a regulated mechanism known as apoptosis [99]. Curcumin exhibited anticancer and chemo preventive potential through cell cycle arrest and eventually leads to apoptosis using various intrinsic and extrinsic pathways [100]. In neuronal cells, β-amyloid results in the induction of apoptosis and curcumin significantly showed antiapoptotic activity in such cells [101].

4. Effects of Curcumin on Platelets

Curcumin exerts antiplatelet activity in several pathological conditions, including inflammatory diseases, atherthrombosis, and thromboembolism, thus playing a pivotal role in cardiovascular diseases (CVDs). Effects of curcumin on platelets is shown in Table 1.

4.1. Coagulation and Angiogenesis

Platelets can promote coagulation by exposure of phosphatidylserine (phospholipid) [102] and also promote critical process including angiogenesis and metastasis in caner [103]. Inflammation activates the procoagulant molecules and alters the coagulation system. Platelets secrete IL-1β consequently secreting cytokines dependent on IL-1β such as IL-4, 6 and 8, which are among the main pro-inflammatory cytokines of inflammation [104]. Moreover, thrombin mediates platelet activation via P-selectin expression [105]. In rats, intraperitoneal administration of curcumin (60 mg/kg) reduced mortality in lipopolysaccharide (LPS)-induced intravascular coagulation by decreasing TNF-α level. This research study demonstrated the beneficial potential of curcumin in coagulopathy induced by infections [106]. Furthermore, it has been shown that curcumin inhibits platelets aggregation induced by collagen, adrenaline, and arachidonic acid. It also causes suppression of thromboxane B2 production and elevate 12-lipoxygenase (LOX) enzyme. Curcumin inhibits the expression of platelet/endothelial cell adhesion molecule 1, netrin G1, delta-like 1, and plasma cell endoplasmic reticulum protein 1, which cause cell adhesion and migration [107].
Table
Table 1. Effects of curcumin on platelets.
Table 1. Effects of curcumin on platelets.
S.No.ParameterEffect/MechanismReferences
1CoagulationInhibit coagulation, ↓ TNF[106]
2Platelet aggregationInhibit platelet aggregation and platetlet plug formation, ↓ cell adhesion molecule 1, netrin G1, delta-like 1, and plasma cell endoplasmic reticulum protein-1[107]
3Platelets activationInhibit activation of platelets to form thrombosis/embolism, ↓ P-selectin, E-selectin, and GP IIb/IIIa [108]
4Autophagyinhibition of PKB, and activation of AMP kinase [109]
5Antioxidant effect↑ antioxidant enzymes, ↓ oxidative stress parameters, ↑ platelet factor-3-like activity[110,111]
6Platelet count↑ platelets level [112]
7PDGF Ameliorated lung fibrosis, liver fibrosis, and cirrhosis, Inhibit PDGF[113]
8Platelet aggregation and hyperlipidemia↓ cholesterol, ↑ antioxidant activity[114]
9AtherosclerosisThromboxane inhibition, ↑ prostacyclin activity[115]
10Arachidonic acid-mediated platelet aggregationInhibition of TXA2 and mobilization of intracellular Ca2+[116]

4.2. Activation of Platelets

Coagulation cascade and platelets activity are linked with each other. Glycoprotein IIb (GPIIb)/IIIa receptor activation play key role in the aggregation of platelets [117]. The procoagulant platelet response is also facilitated by the adhesive complexes glycoprotein Ib-V-IX and integrin αIIbβ3 [118]. The key pathway for platelet activation is via activation of receptor GP IIb/IIIa that cause cross-linking of von Willebrand factor or fibrinogen between receptors leading to platelets aggregation [117]. Administration of curcumin inhibits platelets adhesion and elevation of GP IIb/IIIa mediated platelet activation that is associated with decreased expression of P-selectin, E-selectin, and GP IIb/IIIa on platelets as shown in Figure 3 [108]. Curcumin also inhibits platelet activation by interfering with spleen tyrosine kinase and subsequent activation of phospholipase C gamma [119]. Curcumin has shown anticoagulant activity in vitro [120]. Moreover, in-vivo study exhibited that curcumin inhibited platelet aggregation in monkeys. This implies that patients suffering from arterial thrombosis may take benefit from curcumin [121].
In another in vitro study, eight natural products including curcumin, were compared to prednisolone regarding anti-inflammatory potential. Several pathways of inflammatory response (such as IL-6, IL-8, and TNF-α, ROS production) were investigated along with platelet activation in the blood. Besides curcumin, epigallocatechin gallate and berberine chloride also displayed good anti-inflammatory potential that suggested these compounds were alternatives to prednisolone [122].
Curcumin has been found to inhibit arachidonic acid, adrenaline, and collagen-induced aggregation of platelets. It blocked the formation of thromboxane B2 (Conversion of A2 into B2) and increased the production of 12-LOX. Furthermore, the anti-inflammatory effect of curcumin is mediated via multiple mechanisms including its impact on eicosanoids biosynthesis [121], increasing the expression of PPAR-α, IL-4, platelet/endothelial cell adhesion molecule 1, netrin G1, plasma cell endoplasmic reticulum protein 1, and delta-like 1, which have been correlated with cell adhesion and migration [107].
Curcumin reduces platelets adhesion in cerebral microcirculation mainly via endothelium modulation. PDGF-βR in phosphorylated form, extracellular signal regulated kinase (ERK-1/2) epidermal growth factor receptor (EGFR), and c-Jun N-terminal kinase (JNK1/2) levels were decreased by curcumin due to increase in the activity of PPARγ [123]. Curcumin attenuated cigarette smoke-induced elevation in AMP, ATP, and decreased ADP hydrolysis in rats. These effects of curcumin are due to modulation of purinergic signaling, platelet aggregation, and thrombus formation regulation [124].

4.3. Autophagy

Curcumin cause autophagy induction in platelets indicated by inhibition of PKB, and activation of AMP kinase [109]. Cellular autophagy is linked with cell death and survival [125,126]. Autophagy in platelets is observed during activation and play an important role in hemostasis and thrombosis [127,128]. Increased autophagy reduces apoptosis and increase platelets viability in immune thrombocytopenia [129], and oxidative stress in platelets of diabetic patients [130]. In one study, curcumin potentiated platelets apoptosis in a low concentration (5 µM) and inhibited apoptosis in a high concentration (50 µM). At a low concentration, the viability of platelets was unaffected, but at a high concentration it was reduced by 17%. Moreover, curcumin inhibited the activity of P-glycoprotein in platelets [39].

4.4. Oxidative Status of Platelets

Several studies have shown the antioxidant effects of curcumin in platelets. Oxidative stress leads to the development of several disorders including CVDs [131]. In an in vitro study, curcumin inhibited the formation of thiobarbituric acid reactive substances (TBARS) formation in platelets in peroxynitrite-induced oxidative stress model. A 50% reduction in the level TBARS was observed at 50 mg/mL concentration of curcumin in platelets. It was concluded that curcumin display antioxidant and protective effect against damage to platelets caused by ROS/RNS [132]. In humans, administration of curcumin also exhibited antioxidant potential. Signaling pathways of ROS elicit epigenetic and transcriptional dysregulation, causing activation of platelets, chronic inflammation, and endothelial dysfunction [131]. It has been observed in several studies that curcumin display antioxidant activity in platelets facing oxidative stress.
In another study conducted in humans, curcuminoids were administered (at 500 mg/day) to thalassemic patients for one year. Curcuminoid administration elevated the plasma level of some proteins and reduced their oxidative effects. Similarly, antioxidant enzymes, oxidative stress parameters, and platelet factor-3-like activity were improved. Curcuminoids have been demonstrated to inhibit cyclo-oxygenase and 12-lipoxygenase activities in human platelets, thus showing antioxidant activity [110,111]. Moreover, curcumin inhibited damage to the cells as it is powerful antioxidant and free radicals scavenger [115].

4.5. Platelets Count

The effect of curcumin on platelets count has been demonstrated in several studies. One study reported that profenofos-induced reduction in platelets count was attenuated by administration of curcumin (120 mg/kg) to mice for 30 days [112]. In another study, curcumin displayed anti-inflammatory effect, however no effect on platelets count was observed, so that is a controversial scenario that needs further investigations [133]. Another study also reported increase in platelets levels by curcumin [112]. In rats administered a high fat diet (HFD), the level of total cholesterol, total lipids, C-reactive protein, TNF-α, platelet count and fibrinogen contents were elevated. Administration of curcumin (20 mg/kg, for 3 months, p.o) countered all these changes. Therefore, curcumin could be a possible choice in HFD-associated CVDs; however, it needs future exploration in humans [134]. Nanocurcumin has exhibited more effective activity in preventing chemotherapy-induced thrombocytopenia in mice. Nanocurcumin administration could preserve bone marrow integrity and increase the number of circulating platelets [135].

4.6. Effect on Platelet Derived Growth Factor (PDGF)

Growth factors, such as PDGF, are secreted by platelets during vascular damage and play a key role in the remodeling of vessels during extracellular and cellular response to injury [136]. PDGF is responsible for the migration, proliferation, and collagen synthesis in vascular smooth muscle cells [136]. Atherosclerosis is characterized by over expression of PDGF in arteries after inflammatory-fibroproliferative response [137]. The over-expression of PDGF also occur in fibrosis of several other organs, including liver, and lungs [136]. PDGF control platelet aggregation by a feedback mechanism on vascular system. Activation of PDGF decrease the aggregation of platelets [138]. The Stat molecules family has been demonstrated to bind to the activated PDGF-βR and to be phosphorylated following PDGF stimulation. Curcumin inhibit PDGF-mediated effects of smooth muscle cells, thus ameliorating atherosclerosis and fibrosis [136].
Studies have shown that curcumin is a beneficial drug for the treatment of PDGF related diseases. For instance, curcumin has attenuated fibrotic injury and sinusoidal angiogenesis induced by carbon tetrachloride in rats by inhibition of expression of vascular endothelial growth factor (VEGF) in hepatic stellate cells (HSCs), which is mediated by disruption of the mTOR and PDGF-βR/ERK pathways. Moreover, in conclusion, HSCs targeting is mediated via activation of the PPAR-γ dependent mechanism. Therefore, pathological angiogenesis in liver fibrosis may be reduced by targeting PPAR-γ [113].

5. Discussion

This review focused on regulatory effects of curcumin on platelets. Curcumin (Diferuloylmethane), a bioactive compound isolated from the roots and rhizome of Curcuma longa is extensively used in spices in the subcontinent and for the treatment of several diseases. Curcumin belongs to the curcuminoids class of phytochemicals and has been approved as “Generally recognized as safe” by the FDA [139]. It has good tolerability and a wide margin of safety at 4–8 g/day [140]. The emergence of curcumin as an important functional food is linked with several studies that demonstrated its antioxidant potential, anti-tumor, antidiabetic, anti-atherosclerotic, and usefulness in colitis, pancreatic, and hepatic diseases [141,142,143,144]. Its effectiveness in cancer is mediated by inhibition of COX-2, MMP-9, and NF-kB [145,146].
Although curcumin exhibited pleiotropic activity on the platelet regulation, its poor solubility and low bioavailability mainly due to hepatic and intestinal glucoronidation limits its usefulness [147]. It was reported in 2004 that oral administration of curcumin (450–3600 mg per day) to human results in undetectable plasma concentration. Therefore, several techniques have been developed to enhance plasma concentration of curcumin including nano-formulations, concurrent administration with pepper, etc. [5], the details of which are beyond the scope of this review.
Curcumin caused blockade of lipoxygenase, cyclo-oxygenase, Syk kinase, followed by activation of PLCΥ and mobilization of calcium [37,119,121,148]. The inhibition of platelet activation involves stimulation of A2A receptor that in turn activates protein kinase A (PKA). Another mechanism for curcumin-mediated inhibition of platelet activation involves potentiation of inhibitory effect of P2Y12ADP receptor inhibitor cangrelor [149].
Curcumin has been found to be an agonist of A2A receptor that activates the PKA/cAMP/AC pathway in thrombocytes. Blockade of A2A receptor resulted in the inhibition of PKA, which denotes that this receptor is the key player the involvement of curcumin-induced activation of PKA in thrombocytes [150].
Curcumin has been used for the treatment of many diseases either alone or in combination with other drugs. It has demonstrated anti-thrombotic activity [148] at least in part via inhibition of platelet activation. Nonetheless, procoagulant activity and pro-apoptotic potential [151,152] also inhibit platelet activation. Moreover, curcumin exposes the anionic phospholipids phosphatidyl serine (PS) on platelets surface, which indicates procoagulant and apoptotic effect in platelets [39].

6. Conclusions and Future Directions

In conclusion, curcumin inhibits platelet activation and aggregation and improves platelet count. Thus, curcumin is bestowed with anti-inflammatory properties; it inhibits thrombo-embolism, atherothrombosis and leukemia potential in several diseases. These diseases are major contributors of death; therefore, it is vital to understand the therapeutic impact of phytochemicals.
Curcumin exhibited anti-platelet activity in several ways including platelet activation, aggregation, and adhesion. Currently available anti-platelet drugs are based on natural products that include aspirin, snake venom-based peptides, molecules irreversibly blocking P2Y12 [39], warfarin, heparin [153], clopidogrel and abciximab [154]. Despite the development of several anti-thrombotic drugs, their effects on morbidity and mortality are not completely known [155]. In future, this scenario will be more challenging with a persistent increase in the incidence of metabolic syndrome, thromboembolism, and CVDs. The sub-optimal activity of these drugs is due to side effects (GIT dysfunction, bleeding) and drug resistance [156]. Hence, novel therapeutics are urgently needed to reduce the adverse effects of these drugs without reducing efficacy. Curcumin shows pleiotropic activities and affects the coagulation pathway through multiple mechanisms, exhibits synergistic potential, and reduces the adverse effects associated with current drugs [157,158,159]. Thus, clinical trials must be conducted to fully evaluate the untapped potential of curcumin on platelets and offer better treatment to patients suffering from thromboembolic, leukemia and cardiovascular disease.

Author Contributions

Y.H., A., F.K., K.F.A. and K.J.A. have written different chapters. L.S. and H.K. have designed the study and supervised the overall revision. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Baldi, A.; De Luca, A.; Maiorano, P.; D’Angelo, C.; Giordano, A. Curcumin as an anticancer agent in malignant mesothelioma: A review. Int. J. Mol. Sci. 2020, 21, 1839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Parsamanesh, N.; Moossavi, M.; Bahrami, A.; Butler, A.E.; Sahebkar, A. Therapeutic potential of curcumin in diabetic complications. Pharmacol. Res. 2018, 136, 181–193. [Google Scholar] [PubMed]
  3. Hesari, A.; Azizian, M.; Sheikhi, A.; Nesaei, A.; Sanaei, S.; Mahinparvar, N.; Derakhshani, M.; Hedayt, P.; Ghasemi, F.; Mirzaei, H. Chemopreventive and therapeutic potential of curcumin in esophageal cancer: Current and future status. Int. J. Cancer 2019, 144, 1215–1226. [Google Scholar] [CrossRef] [PubMed]
  4. Aggarwal, B.B.; Sundaram, C.; Malani, N.; Ichikawa, H. Curcumin: The Indian solid gold. Adv. Exp. Med. Biol. 2007, 595, 1–75. [Google Scholar] [CrossRef]
  5. Mehanny, M.; Hathout, R.M.; Geneidi, A.S.; Mansour, S. Exploring the use of nanocarrier systems to deliver the magical molecule; Curcumin and its derivatives. J. Control Release 2016, 225, 1–30. [Google Scholar] [CrossRef]
  6. Aggarwal, B.B.; Harikumar, K.B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int. J. Biochem. Cell Biol. 2009, 41, 40–59. [Google Scholar] [CrossRef] [Green Version]
  7. Unlu, A.; Nayir, E.; Dogukan Kalenderoglu, M.; Kirca, O.; Ozdogan, M. Curcumin (Turmeric) and cancer. J. Buon 2016, 21, 1050–1060. [Google Scholar]
  8. Funamoto, M.; Shimizu, K.; Sunagawa, Y.; Katanasaka, Y.; Miyazaki, Y.; Kakeya, H.; Yamakage, H.; Satoh-Asahara, N.; Wada, H.; Hasegawa, K.; et al. Effects of Highly Absorbable Curcumin in Patients with Impaired Glucose Tolerance and Non-Insulin-Dependent Diabetes Mellitus. J. Diabetes Res. 2019, 2019, 8208237. [Google Scholar] [CrossRef]
  9. Zhou, H.; Beevers, S.C.; Huang, S. The targets of curcumin. Curr. Drug Targets 2011, 12, 332–347. [Google Scholar] [CrossRef]
  10. Salehi, B.; Stojanović-Radić, Z.; Matejić, J.; Sharifi-Rad, M.; Kumar, N.V.A.; Martins, N.; Sharifi-Rad, J. The therapeutic potential of curcumin: A review of clinical trials. Eur. J. Med. Chem. 2019, 163, 527–545. [Google Scholar] [CrossRef]
  11. Radomska-Leśniewska, D.M.; Osiecka-Iwan, A.; Hyc, A.; Góźdź, A.; Dąbrowska, A.M.; Skopiński, P. Therapeutic potential of curcumin in eye diseases. Cent. Eur. J. Immunol. 2019, 44, 181–189. [Google Scholar] [CrossRef] [PubMed]
  12. Moeini, A.; Pedram, P.; Makvandi, P.; Malinconico, M.; d’Ayala, G.G. Wound healing and antimicrobial effect of active secondary metabolites in chitosan-based wound dressings: A review. Carbohydr. Polym. 2020, 233, 115839. [Google Scholar] [CrossRef] [PubMed]
  13. Xu, X.R.; Zhang, D.; Oswald, B.E.; Carrim, N.; Wang, X.; Hou, Y.; Zhang, Q.; LaValle, C.; McKeown, T.; Marshall, A.H.; et al. Platelets are versatile cells: New discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond. Crit. Rev. Clin. Lab. Sci. 2016, 53, 409–430. [Google Scholar] [CrossRef]
  14. Wachowicz, B.; Morel, A.; Miller, E.; Saluk, J. The physiology of blood platelets and changes of their biological activities in multiple sclerosis. Acta Neurobiol. Exp. 2016, 76, 269–281. [Google Scholar] [CrossRef] [Green Version]
  15. Lefrançais, E.; Ortiz-Muñoz, G.; Caudrillier, A.; Mallavia, B.; Liu, F.; Sayah, D.M.; Thornton, E.E.; Headley, M.B.; David, T.; Coughlin, S.R.; et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 2017, 544, 105–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Stegner, D.; Vaneeuwijk, J.M.M.; Angay, O.; Gorelashvili, M.G.; Semeniak, D.; Pinnecker, J.; Schmithausen, P.; Meyer, I.; Friedrich, M.; Dütting, S.; et al. Thrombopoiesis is spatially regulated by the bone marrow vasculature. Nat. Commun. 2017, 8, 127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Grozovsky, R.; Giannini, S.; Falet, H.; Hoffmeister, K.M. Regulating billions of blood platelets: Glycans and beyond. J. Am. Soc. Hematol. 2015, 126, 1877–1884. [Google Scholar]
  18. Kaser, A.; Brandacher, G.; Steurer, W.; Kaser, S.; Offner, F.A.; Zoller, H.; Theurl, I.; Widder, W.; Molnar, C.; Ludwiczek, O. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: Role in inflammatory thrombocytosis. J. Am. Soc. Hematol. 2001, 98, 2720–2725. [Google Scholar] [CrossRef] [Green Version]
  19. Semeniak, D.; Kulawig, R.; Stegner, D.; Meyer, I.; Schwiebert, S.; Bösing, H.; Eckes, B.; Nieswandt, B.; Schulze, H. Proplatelet formation is selectively inhibited by collagen type I through Syk-independent GPVI signaling. J. Cell Sci. 2016, 129, 3473–3484. [Google Scholar]
  20. Coppinger, J.A.; Cagney, G.; Toomey, S.; Kislinger, T.; Belton, O.; McRedmond, J.P.; Cahill, D.J.; Emili, A.; Fitzgerald, D.J.; Maguire, P.B. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 2004, 103, 2096–2104. [Google Scholar] [CrossRef] [Green Version]
  21. Wijten, P.; van Holten, T.; Woo, L.L.; Bleijerveld, O.B.; Roest, M.; Heck, A.J.; Scholten, A. High precision platelet releasate definition by quantitative reversed protein profiling—Brief report. Arter. Thromb. Vasc. Biol. 2013, 33, 1635–1638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Blair, P.; Flaumenhaft, R. Platelet α-granules: Basic biology and clinical correlates. Blood Rev. 2009, 23, 177–189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Italiano, J.E., Jr.; Battinelli, E.M. Selective sorting of alpha-granule proteins. J. Thromb. Haemost. 2009, 7, 173–176. [Google Scholar] [CrossRef] [PubMed]
  24. Morrell, C.N.; Aggrey, A.A.; Chapman, L.M.; Modjeski, K.L.J.B. Emerging roles for platelets as immune and inflammatory cells. J. Am. Soc. Hematol. 2014, 123, 2759–2767. [Google Scholar] [CrossRef] [Green Version]
  25. Ruiz, F.A.; Lea, C.R.; Oldfield, E.; Docampo, R.; Gande, R.; Gibson, K.J.C.; Brown, A.K.; Krumbach, K.; Dover, L.G.; Sahm, H.; et al. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J. Biol. Chem. 2004, 279, 44250–44257. [Google Scholar] [CrossRef] [Green Version]
  26. Heijnen, H.; Van Der Sluijs, P.J. Platelet secretory behaviour: As diverse as the granules… or not? J. Thromb. Haemost. 2015, 13, 2141–2151. [Google Scholar] [CrossRef]
  27. Thon, J.N.; Peters, C.G.; Machlus, K.R.; Aslam, R.; Rowley, J.; MacLeod, H.; Devine, M.T.; Fuchs, T.A.; Weyrich, A.S.; Semple, J.W.; et al. T granules in human platelets function in TLR9 organization and signaling. J. Cell Biol. 2012, 198, 561–574. [Google Scholar] [CrossRef]
  28. Nurden, A.T.; Nurden, P. The gray platelet syndrome: Clinical spectrum of the disease. Blood Rev. 2007, 21, 21–36. [Google Scholar] [CrossRef]
  29. Gerrits, A.J.; Frelinger III, A.L.; Michelson, A.D. Whole blood analysis of leukocyte-platelet aggregates. Curr. Protoc. Cytom. 2016, 78, 6.15.1–6.15.10. [Google Scholar]
  30. Habets, K.L.; Huizinga, T.W.; Toes, R.E. Platelets and autoimmunity. Eur. J. Clin. Investig. 2013, 43, 746–757. [Google Scholar] [CrossRef]
  31. Jenne, C.N.; Kubes, P. Platelets in inflammation and infection. Platelets 2015, 26, 286–292. [Google Scholar] [CrossRef]
  32. Kapur, R.; Zufferey, A.; Boilard, E.; Semple, J.W. Nouvelle cuisine: Platelets served with inflammation. J. Immunol. 2015, 194, 5579–5587. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Salamanna, F.; Maglio, M.; Sartori, M.; Landini, M.P.; Fini, M. Vitamin D and platelets: A menacing duo in COVID-19 and potential relation to bone remodeling. Int. J. Mol. Sci. 2021, 22, 10010. [Google Scholar] [CrossRef] [PubMed]
  34. Patrono, C.; Coller, B.; FitzGerald, G.A.; Hirsh, J.; Roth, G. Platelet-active drugs: The relationships among dose, effectiveness, and side effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Comp. Study 2004, 126, 234S–264S. [Google Scholar]
  35. Cammisotto, V.; Baratta, F.; Simeone, P.G.; Barale, C.; Lupia, E.; Galardo, G.; Santilli, F.; Russo, I.; Pignatelli, P. Proprotein convertase subtilisin kexin type 9 (PCSK9) beyond lipids: The role in oxidative stress and thrombosis. Antioxidants 2022, 11, 569. [Google Scholar] [CrossRef] [PubMed]
  36. da Silva, G.M.; da Silva, M.C.; Nascimento, D.V.G.; Lima Silva, E.M.; Gouvêa, F.F.F.; de França Lopes, L.G.; Araújo, A.V.; Ferraz Pereira, K.N.; de Queiroz, T.M. Nitric oxide as a central molecule in hypertension: Focus on the vasorelaxant activity of new nitric oxide donors. Biology 2021, 10, 1041. [Google Scholar] [CrossRef]
  37. Maheswaraiah, A.; Jaganmohan Rao, L.; Naidu, K.A. Anti-platelet activity of water dispersible curcuminoids in rat platelets. Phytother. Res. 2015, 29, 450–458. [Google Scholar] [CrossRef]
  38. Heemskerk, J.; Sage, S. Calcium signalling in platelets and other cells. Platelets 1994, 5, 295–316. [Google Scholar] [CrossRef]
  39. Rukoyatkina, N.; Shpakova, V.; Sudnitsyna, J.; Panteleev, M.; Makhoul, S.; Gambaryan, S.; Jurk, K. Curcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis. Int. J. Mol. Sci. 2021, 22, 5405. [Google Scholar] [CrossRef]
  40. Kim, M.; Kim, Y. Hypocholesterolemic effects of curcumin via up-regulation of cholesterol 7a-hydroxylase in rats fed a high fat diet. Nutr. Res. Pract. 2010, 4, 191–195. [Google Scholar] [CrossRef] [Green Version]
  41. Gale, A.J. Continuing education course# 2: Current understanding of hemostasis. Toxicol Pathol. 2011, 39, 273–280. [Google Scholar] [PubMed] [Green Version]
  42. Clemetson, K.J. Platelets and primary haemostasis. Thromb. Res. 2012, 129, 220–224. [Google Scholar] [CrossRef] [PubMed]
  43. Herter, J.M.; Rossaint, J.; Zarbock, A. Platelets in inflammation and immunity. J. Thromb. Haemost. 2014, 12, 1764–1775. [Google Scholar] [CrossRef] [PubMed]
  44. Schrör, K.; Huber, K. Platelets, inflammation and anti-inflammatory drugs in ACS and CAD. Thromb. Haemost. 2015, 114, 446–448. [Google Scholar] [CrossRef]
  45. Cognasse, F.; Nguyen, K.A.; Damien, P.; McNicol, A.; Pozzetto, B.; Hamzeh-Cognasse, H.; Garraud, O. The inflammatory role of platelets via their TLRs and Siglec receptors. Front. Immunol. 2015, 6, 83. [Google Scholar] [CrossRef]
  46. Patzelt, J.; Verschoor, A.; Langer, H.F. Platelets and the complement cascade in atherosclerosis. Front. Physiol. 2015, 6, 49. [Google Scholar] [CrossRef] [Green Version]
  47. Nording, H.; Langer, H.F. Complement links platelets to innate immunity. Semin. Immunol. 2018, 37, 43–52. [Google Scholar] [CrossRef]
  48. Langer, H.F.; Verschoor, A. Crosstalk between platelets and the complement system in immune protection and disease. Thromb. Haemost. 2013, 110, 910–919. [Google Scholar] [CrossRef]
  49. Del Conde, I.; Crúz, M.A.; Zhang, H.; López, J.A.; Afshar-Kharghan, V. Platelet activation leads to activation and propagation of the complement system. J. Exp. Med. 2005, 201, 871–879. [Google Scholar] [CrossRef] [Green Version]
  50. Boilard, E.; Nigrovic, P.A.; Larabee, K.; Watts, G.F.M.; Coblyn, J.S.; Weinblatt, M.E.; Massarotti, E.M.; Remold-O’Donnell, E.; Farndale, R.W.; Ware, J.; et al. Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production. Science 2010, 327, 580–583. [Google Scholar] [CrossRef] [Green Version]
  51. Pate, K.A.M.; Lyons, C.; Dorsey, J.L.; Queen, S.E.; Adams, R.J.; Morrell, C.N.; Mankowski, J.L. TGFβ-Mediated Downregulation of Thrombopoietin Is Associated with Platelet Decline in Asymptomatic SIV Infection. JAIDS J. Acquir. Immune Defic. Syndr. 2014, 65, 510–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Guclu, E.; Durmaz, Y.; Karabay, O. Effect of severe sepsis on platelet count and their indices. Afr. Health Sci. 2013, 13, 333–338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Labelle, M.; Begum, S.; Hynes, R.O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011, 20, 576–590. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Cooke, N.M.; Spillane, C.D.; Sheils, O.; O’Leary, J.; Kenny, D. Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion. BMC Cancer 2015, 15, 627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Erpenbeck, L.; Schön, M.P. Deadly allies: The fatal interplay between platelets and metastasizing cancer cells. J. Am. Soc. Hematol. 2010, 115, 3427–3436. [Google Scholar] [CrossRef] [PubMed]
  56. Wilkinson, H.N.; Hardman, M.J. Wound healing: Cellular mechanisms and pathological outcomes. Open Biol. 2020, 10, 200223. [Google Scholar] [CrossRef] [PubMed]
  57. Rodrigues, M.; Kosaric, N.; Bonham, C.A.; Gurtner, G.C. Wound Healing: A Cellular Perspective. Physiol. Rev. 2019, 99, 665–706. [Google Scholar] [CrossRef]
  58. Uchiyama, R.; Toyoda, E.; Maehara, M.; Wasai, S.; Omura, H.; Watanabe, M.; Sato, M. Effect of platelet-rich plasma on M1/M2 macrophage polarization. Int. J. Mol. Sci. 2021, 22, 2336. [Google Scholar] [CrossRef]
  59. Ho-Tin-Noé, B.; Demers, M.; Wagner, D.D. How platelets safeguard vascular integrity. J. Thromb. Haemost. 2011, 9, 56–65. [Google Scholar] [CrossRef] [Green Version]
  60. EEisinger, F.; Patzelt, J.; Langer, H.F. The Platelet Response to Tissue Injury. Front. Med. 2018, 5, 317. [Google Scholar] [CrossRef] [Green Version]
  61. Arora, G.; Arora, S. Platelet-rich plasma—Where do we stand today? A critical narrative review and analysis. Dermatol. Ther. 2021, 34, e14343. [Google Scholar] [CrossRef] [PubMed]
  62. Semple, J.W.; Italiano, J.E.; Freedman, J. Platelets and the immune continuum. Nat. Rev. Immunol. 2011, 11, 264–274. [Google Scholar] [CrossRef] [PubMed]
  63. Krijgsveld, J.; Zaat, S.A.J.; Meeldijk, J.; van Veelen, P.A.; Fang, G.; Poolman, B.; Brandt, E.; Ehlert, J.E.; Kuijpers, A.J.; Engbers, G.H.M.; et al. Thrombocidins, Microbicidal Proteins from Human Blood Platelets, Are C-terminal Deletion Products of CXC Chemokines. J. Biol. Chem. 2000, 275, 20374–20381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Kwakman, P.H.; Krijgsveld, J.; de Boer, L.; Nguyen, L.T.; Boszhard, L.; Vreede, J.; Dekker, H.L.; Speijer, D.; Drijfhout, J.W.; Velde, A.A.T.; et al. Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements. J. Biol. Chem. 2011, 286, 43506–43514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Clark, S.R.; Ma, A.C.; Tavener, S.A.; McDonald, B.; Goodarzi, Z.; Kelly, M.M.; Patel, K.D.; Chakrabarti, S.; McAvoy, E.; Sinclair, G.D.; et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 2007, 13, 463–469. [Google Scholar] [CrossRef] [PubMed]
  66. Martinod, K.; Wagner, D.D. Thrombosis: Tangled up in NETs. J. Am. Soc. Hematol. 2014, 123, 2768–2776. [Google Scholar] [CrossRef] [PubMed]
  67. Brinkmann, V.; Zychlinsky, A. Beneficial suicide: Why neutrophils die to make NETs. Nat. Rev. Genet. 2007, 5, 577–582. [Google Scholar] [CrossRef]
  68. Kraemer, B.F.; Campbell, R.A.; Schwertz, H.; Cody, M.J.; Franks, Z.; Tolley, N.D.; Kahr, W.H.A.; Lindemann, S.; Seizer, P.; Yost, C.C.; et al. Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation. PLOS Pathog. 2011, 7, e1002355. [Google Scholar] [CrossRef]
  69. Etulain, J.; Martinod, K.; Wong, S.L.; Cifuni, S.M.; Schattner, M.; Wagner, D.D. P-selectin promotes neutrophil extracellular trap formation in mice. J. Am. Soc. Hematol. 2015, 126, 242–246. [Google Scholar] [CrossRef] [Green Version]
  70. Haselmayer, P.; Grosse-Hovest, L.; von Landenberg, P.; Schild, H.; Radsak, M.P. TREM-1 ligand expression on platelets enhances neutrophil activation. J. Am. Soc. Hematol. 2007, 110, 1029–1035. [Google Scholar] [CrossRef] [Green Version]
  71. Iannacone, M.; Sitia, G.; Isogawa, M.; Marchese, P.; Castro, M.G.; Lowenstein, P.R.; Chisari, F.; Ruggeri, Z.M.; Guidotti, L.G. Platelets mediate cytotoxic T lymphocyte–induced liver damage. Nat. Med. 2005, 11, 1167–1169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Elzey, B.D.; Tian, J.; Jensen, R.J.; Swanson, A.K.; Lees, J.; Lentz, S.; Stein, C.S.; Nieswandt, B.; Wang, Y.; Davidson, B.L.; et al. Platelet-Mediated Modulation of Adaptive Immunity: A Communication Link between Innate and Adaptive Immune Compartments. Immunity 2003, 19, 9–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Elzey, B.D.; Schmidt, N.W.; Crist, S.A.; Kresowik, T.P.; Harty, J.T.; Nieswandt, B.; Ratliff, T.L. Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge. Blood 2008, 111, 3684–3691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Lang, P.A.; Contaldo, C.; Georgiev, P.; El-Badry, A.M.; Recher, M.; Kurrer, M.; Cervantes-Barragan, L.; Ludewig, B.; Calzascia, T.; Bolinger, B.; et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat. Med. 2008, 14, 756–761. [Google Scholar] [CrossRef] [PubMed]
  75. León-Ponte, M.; Ahern, G.P.; O’Connell, P.J. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood 2007, 109, 3139–3146. [Google Scholar] [CrossRef] [PubMed]
  76. Crawford, A.; Angelosanto, J.M.; Nadwodny, K.L.; Blackburn, S.D.; Wherry, E.J. A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection. PLoS Pathog. 2011, 7, e1002098. [Google Scholar] [CrossRef]
  77. El-Desoky, G.E.; Wabaidur, S.M.; AlOthman, Z.A.; Habila, M.A. Regulatory Role of Nano-Curcumin against Tartrazine-Induced Oxidative Stress, Apoptosis-Related Genes Expression, and Genotoxicity in Rats. Molecules 2020, 25, 5801. [Google Scholar] [CrossRef]
  78. Zheng, Q.-T.; Yang, Z.-H.; Yu, L.-Y.; Ren, Y.-Y.; Huang, Q.-X.; Liu, Q.; Ma, X.-Y.; Chen, Z.-K.; Wang, Z.-B.; Zheng, X. Synthesis and antioxidant activity of curcumin analogs. J. Asian Nat. Prod. Res. 2017, 19, 489–503. [Google Scholar] [CrossRef]
  79. Jakubczyk, K.; Drużga, A.; Katarzyna, J.; Skonieczna-Żydecka, K. Antioxidant potential of curcumin—A Meta-analysis of randomized clinical trials. Antioxidants 2020, 9, 1092. [Google Scholar] [CrossRef]
  80. Meng, R.; Wu, Z.; Xie, Q.-T.; Cheng, J.-S.; Zhang, B. Preparation and characterization of zein/carboxymethyl dextrin nanoparticles to encapsulate curcumin: Physicochemical stability, antioxidant activity and controlled release properties. Food Chem. 2021, 340, 127893. [Google Scholar] [CrossRef]
  81. Mohammadian, M.; Salami, M.; Momen, S.; Alavi, F.; Emam-Djomeh, Z. Fabrication of curcumin-loaded whey protein microgels: Structural properties, antioxidant activity, and in vitro release behavior. LWT 2019, 103, 94–100. [Google Scholar] [CrossRef]
  82. Shahid, H.; Shahzad, M.; Shabbir, A.; Saghir, G. Immunomodulatory and anti-inflammatory potential of curcumin for the treatment of allergic asthma: Effects on expression levels of pro-inflammatory cytokines and aquaporins. Inflammation 2019, 42, 2037–2047. [Google Scholar] [CrossRef] [PubMed]
  83. Plavcová, Z.; Šalamúnová, P.; Saloň, I.; Štěpánek, F.; Hanuš, J.; Hošek, J. Curcumin encapsulation in yeast glucan particles promotes its anti-inflammatory potential in vitro. Int. J. Pharm. 2019, 568, 118532. [Google Scholar] [CrossRef] [PubMed]
  84. Lauridsen, C. From oxidative stress to inflammation: Redox balance and immune system. Poult. Sci. 2019, 98, 4240–4246. [Google Scholar] [CrossRef] [PubMed]
  85. Cristofori, F.; Dargenio, V.N.; Dargenio, C.; Miniello, V.L.; Barone, M.; Francavilla, R. Anti-inflammatory and immunomodulatory effects of probiotics in gut inflammation: A door to the body. Front. Immunol. 2021, 12, 178. [Google Scholar] [CrossRef]
  86. Ginwala, R.; Bhavsar, R.; Chigbu, D.G.I.; Jain, P.; Khan, Z.K. Potential role of flavonoids in treating chronic inflammatory diseases with a special focus on the anti-inflammatory activity of apigenin. Antioxidants 2019, 8, 35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Rahimi, K.; Hassanzadeh, K.; Khanbabaei, H.; Haftcheshmeh, S.M.; Ahmadi, A.; Izadpanah, E.; Mohammadi, A.; Sahebkar, A. Curcumin: A dietary phytochemical for targeting the phenotype and function of dendritic cells. Curr. Med. Chem. 2021, 28, 1549–1564. [Google Scholar] [CrossRef] [PubMed]
  88. Fu, Y.-S.; Chen, T.-H.; Weng, L.; Huang, L.; Lai, D.; Weng, C.-F. Pharmacological properties and underlying mechanisms of curcumin and prospects in medicinal potential. Biomed. Pharmacother. 2021, 141, 111888. [Google Scholar] [CrossRef]
  89. Chamani, S.; Moossavi, M.; Naghizadeh, A.; Abbasifard, M.; Majeed, M.; Johnston, T.P.; Sahebkar, A. Immunomodulatory effects of curcumin in systemic autoimmune diseases. Phytother. Res. 2022, 36, 1616–1632. [Google Scholar] [CrossRef]
  90. Forouzanfar, F.; Majeed, M.; Jamialahmadi, T.; Sahebkar, A. Curcumin: A Review of Its Effects on Epilepsy. Stud. Biomark. New Targets Aging Res. Iran 2021, 1291, 363–373. [Google Scholar]
  91. Momtazi-Borojeni, A.A.; Haftcheshmeh, S.M.; Esmaeili, S.-A.; Johnston, T.P.; Abdollahi, E.; Sahebkar, A. Curcumin: A natural modulator of immune cells in systemic lupus erythematosus. Autoimmun. Rev. 2018, 17, 125–135. [Google Scholar] [CrossRef] [PubMed]
  92. Hoque, A.; Williamson, N.A.; Ameen, S.S.; Ciccotosto, G.D.; Hossain, M.I.; Oakhill, J.S.; Ng, D.C.; Ang, C.-S.; Cheng, H.-C. Quantitative proteomic analyses of dynamic signalling events in cortical neurons undergoing excitotoxic cell death. Cell Death Dis. 2019, 10, 213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Park, D.H.; Park, J.Y.; Kang, K.S.; Hwang, G.S. Neuroprotective effect of gallocatechin gallate on glutamate-induced oxidative stress in hippocampal ht22 cells. Molecules 2021, 26, 1387. [Google Scholar] [CrossRef] [PubMed]
  94. Olloquequi, J.; Cornejo-Córdova, E.; Verdaguer, E.; Soriano, F.X.; Binvignat, O.; Auladell, C.; Camins, A. Excitotoxicity in the pathogenesis of neurological and psychiatric disorders: Therapeutic implications. J. Psychopharmacol. 2018, 32, 265–275. [Google Scholar] [CrossRef] [PubMed]
  95. Zhang, Y.; Li, L.; Zhang, J. Curcumin in antidepressant treatments: An overview of potential mechanisms, pre-clinical/clinical trials and ongoing challenges. Basic Clin. Pharmacol. Toxicol. 2020, 127, 243–253. [Google Scholar] [CrossRef]
  96. Farooqui, T.; Farooqui, A.A. Curcumin: Historical background, chemistry, pharmacological action, and potential therapeutic value. In Curcumin for Neurological and Psychiatric Disorders; Academic Press: Cambridge, MA, USA, 2019; pp. 23–44. [Google Scholar]
  97. Numakawa, T.; Odaka, H.; Adachi, N. Actions of brain-derived neurotrophin factor in the neurogenesis and neuronal function, and its involvement in the pathophysiology of brain diseases. Int. J. Mol. Sci. 2018, 19, 3650. [Google Scholar] [CrossRef]
  98. Ma, W.; Xu, D.; Zhao, L.; Yuan, M.; Cui, Y.-L.; Li, Y. Therapeutic role of curcumin in adult neurogenesis for management of psychiatric and neurological disorders: A scientometric study to an in-depth review. Crit. Rev. Food Sci. Nutr. 2022, 1–13. [Google Scholar] [CrossRef]
  99. Mishra, A.P.; Salehi, B.; Sharifi-Rad, M.; Pezzani, R.; Kobarfard, F.; Sharifi-Rad, J.; Nigam, M. Programmed cell death, from a cancer perspective: An overview. Mol. Diagn. Ther. 2018, 22, 281–295. [Google Scholar] [CrossRef]
  100. Agarwal, A.; Kasinathan, A.; Ganesan, R.; Balasubramanian, A.; Bhaskaran, J.; Suresh, S.; Srinivasan, R.; Aravind, K.; Sivalingam, N. Curcumin induces apoptosis and cell cycle arrest via the activation of reactive oxygen species–independent mitochondrial apoptotic pathway in Smad4 and p53 mutated colon adenocarcinoma HT29 cells. Nutr. Res. 2018, 51, 67–81. [Google Scholar] [CrossRef]
  101. Du, S.; Zhang, Y.; Yang, J.; Liu, X.; Wang, Y.; Xu, B.; Jia, J. Curcumin alleviates β amyloid-induced neurotoxicity in HT22 cells via upregulating SOD2. J. Mol. Neurosci. 2019, 67, 540–549. [Google Scholar] [CrossRef]
  102. Neubauer, K.; Zieger, B. Endothelial cells and coagulation. Cell Tissue Res. 2021, 387, 391–398. [Google Scholar] [CrossRef] [PubMed]
  103. Stoiber, D.; Assinger, A. Platelet-leukocyte interplay in cancer development and progression. Cells 2020, 9, 855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Kaplanski, G.; Farnarier, C.; Porat, R.; Shapiro, L.; Bongrand, P.; Dinarello, C. Interleukin-1 induces interleukin-8 secretion from endothelial cells by a juxtacrine mechanism. Blood 1994, 84, 4242–4248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Tunjungputri, R.N.; Li, Y.; de Groot, P.G.; Dinarello, C.A.; Smeekens, S.P.; Jaeger, M.; Doppenberg-Oosting, M.; Cruijsen, M.; Lemmers, H.; Toenhake-Dijkstra, H. The inter-relationship of platelets with interleukin-1β-mediated inflammation in humans. Thromb. Haemost. 2018, 118, 2112–2125. [Google Scholar] [CrossRef] [PubMed]
  106. Chen, H.-W.; Kuo, H.-T.; Chai, C.-Y.; Ou, J.-L.; Yang, R.-C. Pretreatment of curcumin attenuates coagulopathy and renal injury in LPS-induced endotoxemia. J. Endotoxin Res. 2007, 13, 15–23. [Google Scholar] [CrossRef] [PubMed]
  107. Karlstetter, M.; Lippe, E.; Walczak, Y.; Moehle, C.; Aslanidis, A.; Mirza, M.; Langmann, T. Curcumin is a potent modulator of microglial gene expression and migration. J. Neuroinflamm. 2011, 8, 125. [Google Scholar] [CrossRef] [PubMed]
  108. Zhang, L.; Gu, Z.L.; Qin, Z.h.; Liang, Z.Q. Effect of curcumin on the adhesion of platelets to brain microvascular endothelial cells in vitro. Acta Pharmacol. Sin. 2008, 29, 800–807. [Google Scholar] [CrossRef] [Green Version]
  109. Pourbagher-Shahri, A.M.; Farkhondeh, T.; Ashrafizadeh, M.; Talebi, M.; Samargahndian, S. Curcumin and cardiovascular diseases: Focus on cellular targets and cascades. Biomed. Pharmacother. 2021, 136, 111214. [Google Scholar] [CrossRef]
  110. Ammon, H.; Safayhi, H.; Mack, T.; Sabieraj, J. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J. Ethnopharmacol. 1993, 38, 105–112. [Google Scholar] [CrossRef]
  111. Weeraphan, C.; Srisomsap, C.; Chokchaichamnankit, D.; Subhasitanont, P.; Hatairaktham, S.; Charoensakdi, R.; Panichkul, N.; Siritanaratkul, N.; Fucharoen, S.; Svasti, J.; et al. Role of curcuminoids in ameliorating oxidative modification in β-thalassemia/Hb E plasma proteome. J. Nutr. Biochem. 2013, 24, 578–585. [Google Scholar] [CrossRef]
  112. Singh, J.K.; Roy, A.K. Research. Role of curcumin and cumin on hematological parameters of profenofos exposed mice-Mus Musculus. Int. J. Curr. Pharm. Rev. Res. 2014, 4, 120–127. [Google Scholar]
  113. Zhang, F.; Zhang, Z.; Chen, L.; Kong, D.; Zhang, X.; Lu, C.; Lu, Y.; Zheng, S. Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells. J. Cell. Mol. Med. 2014, 18, 1392–1406. [Google Scholar] [CrossRef] [PubMed]
  114. Liu, Y. Curcumin: An Ingredient that Reduces Platelet Aggregation and Hyperlipidemia, and Enhances Antioxidant and Immune Functions; ACS Publications: London, UK, 1997. [Google Scholar]
  115. Olszanecki, R.; Jawień, J.; Gajda, M.; Mateuszuk, L.; Gebska, A.; Korabiowska, M.; Chłopicki, S.; Korbut, R. Effect of curcumin on atherosclerosis in apoE/LDLR-double knockout mice. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 2005, 56, 627–635. [Google Scholar]
  116. Shah, B.H.; Nawaz, Z.; Pertani, S.A.; Roomi, A.; Mahmood, H.; Saeed, S.A.; Gilani, A.H. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor-and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biol. Chem. Biochem. Pharmacol. 1999, 58, 1167–1172. [Google Scholar] [CrossRef]
  117. Yun, S.-H.; Sim, E.-H.; Goh, R.-Y.; Park, J.-I.; Han, J.-Y. Platelet Activation: The Mechanisms and Potential Biomarkers. BioMed Res. Int. 2016, 2016, 9060143. [Google Scholar] [CrossRef] [Green Version]
  118. Swieringa, F.; Spronk, H.M.; Heemskerk, J.W.; van der Meijden, P.E. Integrating platelet and coagulation activation in fibrin clot formation. Res. Pract. Thromb. Haemost. 2018, 2, 450–460. [Google Scholar] [CrossRef]
  119. Mayanglambam, A.; Dangelmaier, C.A.; Thomas, D.; Reddy, C.D.; Daniel, J.L.; Kunapuli, S.P. Curcumin inhibits GPVI-mediated platelet activation by interfering with the kinase activity of Syk and the subsequent activation of PLCγ2. Platelets 2010, 21, 211–220. [Google Scholar] [CrossRef]
  120. Jiaju, T.; Jin, W.; Changjiang, P.; Yajun, W.; Nan, H. Anticoagulation and drug release behavior of Curcumin-Loaded PLGA films. Key Eng. Mater. 2007, 342, 343. [Google Scholar]
  121. Srivastava, K.; Bordia, A.; Verma, S. Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets. Prostaglandins Leukot. Essent. Fat. Acids 1995, 52, 223–227. [Google Scholar] [CrossRef]
  122. Allijn, I.E.; Vaessen, S.F.; Quarles van Ufford, L.C.; Beukelman, K.J.; De Winther, M.P.; Storm, G.; Schiffelers, R.M. Head-to-head comparison of anti-inflammatory performance of known natural products in vitro. PLoS ONE 2016, 11, e0155325. [Google Scholar] [CrossRef] [Green Version]
  123. Lin, J.; Chen, A. Activation of peroxisome proliferator-activated receptor-γ by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells. Lab. Investig. 2008, 88, 529–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Jaques, J.A.D.S.; Ruchel, J.B.; Schlemmer, K.B.; Pimentel, V.C.; Bagatini, M.; Souza, V.D.C.G.; Moretto, M.B.; Morsch, V.M.; Schetinger, M.R.C.; Leal, D.B.R. Effects of curcumin on the activities of the enzymes that hydrolyse adenine nucleotides in platelets from cigarette smoke-exposed rats. Cell Biochem. Funct. 2011, 29, 630–635. [Google Scholar] [CrossRef]
  125. Maiuri, M.C.; Zalckvar, E.; Kimchi, A.; Kroemer, G. Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 2007, 8, 741–752. [Google Scholar] [CrossRef] [PubMed]
  126. Bergmann, A. Autophagy and cell death: No longer at odds. Cell 2007, 131, 1032–1034. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Ouseph, M.M.; Huang, Y.; Banerjee, M.; Joshi, S.; MacDonald, L.; Zhong, Y.; Liu, H.; Li, X.; Xiang, B.; Zhang, G.J.B. Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis. J. Am. Soc. Hematol. 2015, 126, 1224–1233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Feng, W.; Chang, C.; Luo, D.; Su, H.; Yu, S.; Hua, W.; Chen, Z.; Hu, H.; Liu, W. Dissection of autophagy in human platelets. Autophagy 2014, 10, 642–651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Wang, C.-Y.; Ma, S.; Bi, S.-J.; Su, L.; Huang, S.-Y.; Miao, J.-Y.; Ma, C.-H.; Gao, C.-J.; Hou, M.; Peng, J. Enhancing autophagy protects platelets in immune thrombocytopenia patients. Ann. Transl. Med. 2019, 7, 134. [Google Scholar] [CrossRef]
  130. Lee, S.H.; Du, J.; Stitham, J.; Atteya, G.; Lee, S.; Xiang, Y.; Wang, D.; Jin, Y.; Leslie, K.L.; Spollett, G.; et al. Inducing mitophagy in diabetic platelets protects against severe oxidative stress. EMBO Mol. Med. 2016, 8, 779–795. [Google Scholar] [CrossRef]
  131. Santilli, F.; Guagnano, M.; Vazzana, N.; Barba, S.; Davi, G. Oxidative Stress Drivers and Modulators in Obesity and Cardiovascular Disease: From Biomarkers to Therapeutic Approach. Curr. Med. Chem. 2015, 22, 582–595. [Google Scholar] [CrossRef]
  132. Kolodziejczyk-Czepas, J.; Olas, B.; Saluk-Juszczak, J.; Wachowicz, B. Antioxidative properties of curcumin in the protection of blood platelets against oxidative stress in vitro. Platelets 2011, 22, 270–276. [Google Scholar] [CrossRef]
  133. Megid, A.-E.; Osman, E.; Khamis, T.; Arisha, A. Curcumin Effect on Rats Hepato-Renal Functions, Hematological Parameters, and Inflammatory Markers in Comparison with Celecoxib and Prednisolone. Zagazig Vet. J. 2021, 49, 390–399. [Google Scholar] [CrossRef]
  134. El-Habibi, E.; El-Wakf, A.; Mogall, A. Efficacy of curcumin in reducing risk of cardiovascular disease in high fat diet-fed rats. J. Bioanal. Biomed. 2013, 5, 66–70. [Google Scholar] [CrossRef] [Green Version]
  135. Mortazavi Farsani, S.S.; Sadeghizadeh, M.; Gholampour, M.A.; Safari, Z.; Najafi, F. Nanocurcumin as a novel stimulator of megakaryopoiesis that ameliorates chemotherapy-induced thrombocytopenia in mice. Life Sci. 2020, 256, 117840. [Google Scholar] [CrossRef]
  136. Heldin, C.-H.; Westermark, B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. 1999, 79, 1283–1316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Ross, R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 1993, 362, 801–809. [Google Scholar] [CrossRef] [PubMed]
  138. Bryckaert, M.; Rendu, F.; Tobelem, G.; Wasteson, Å. Collagen-induced binding to human platelets of platelet-derived growth factor leading to inhibition of P43 and P20 phosphorylation. J. Biol. Chem. 1989, 264, 4336–4341. [Google Scholar] [CrossRef]
  139. Gupta, S.C.; Patchva, S.; Aggarwal, B.B. Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials. AAPS J. 2013, 15, 195–218. [Google Scholar] [CrossRef] [Green Version]
  140. Basnet, P.; Skalko-Basnet, N. Curcumin: An anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules 2011, 16, 4567–4598. [Google Scholar] [CrossRef] [Green Version]
  141. Chainani-Wu, N. Safety and anti-inflammatory activity of curcumin: A component of tumeric (Curcuma longa). J. Altern Complement Med. 2003, 9, 161–168. [Google Scholar] [CrossRef]
  142. Kao, N.-J.; Hu, J.-Y.; Wu, C.-S.; Kong, Z.-L. Curcumin represses the activity of inhibitor-κB kinase in dextran sulfate sodium-induced colitis by S-nitrosylation. Int. Immunopharmacol. 2016, 38, 1–7. [Google Scholar] [CrossRef]
  143. Pan, M.-H.; Chen, J.-W.; Kong, Z.-L.; Wu, J.-C.; Ho, C.-T.; Lai, C.-S. Attenuation by Tetrahydrocurcumin of Adiposity and Hepatic Steatosis in Mice with High-Fat-Diet-Induced Obesity. J. Agric. Food Chem. 2018, 66, 12685–12695. [Google Scholar] [CrossRef] [PubMed]
  144. Hatcher, H.; Planalp, R.; Cho, J.; Torti, F.; Torti, S. Curcumin: From ancient medicine to current clinical trials. Cell. Mol. Life Sci. 2008, 65, 1631–1652. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Soudamini, K.; Kuttan, R. Inhibition of chemical carcinogenesis by curcumin. J. Ethnopharmacol. 1989, 27, 227–233. [Google Scholar] [CrossRef] [PubMed]
  146. Kurup, V.P.; Barrios, C.S. Immunomodulatory effects of curcumin in allergy. Mol. Nutr. Food Res. 2008, 52, 1031–1039. [Google Scholar] [CrossRef]
  147. Tsai, Y.-M.; Jan, W.-C.; Chien, C.-F.; Lee, W.-C.; Lin, L.-C.; Tsai, T.-H. Optimised nano-formulation on the bioavailability of hydrophobic polyphenol, curcumin, in freely-moving rats. Food Chem. 2011, 127, 918–925. [Google Scholar] [CrossRef]
  148. Tabeshpour, J.; Hashemzaei, M.; Sahebkar, A. The regulatory role of curcumin on platelet functions. J. Cell. Biochem. 2018, 119, 8713–8722. [Google Scholar] [CrossRef]
  149. Rukoyatkina, N.; Shpakova, V.; Bogoutdinova, A.; Kharazova, A.; Mindukshev, I.; Gambaryan, S. Curcumin by activation of adenosine A2A receptor stimulates protein kinase a and potentiates inhibitory effect of cangrelor on platelets. Biochem. Biophys. Res. Commun. 2021, 586, 20–26. [Google Scholar] [CrossRef]
  150. Chen, G.-L.; Cai, H.-Y.; Chen, J.-P.; Li, R.; Zhong, S.-Y.; Jia, X.-J.; Liu, X.-F.; Song, B.-B. Chitosan/Alginate Nanoparticles for the Enhanced Oral Antithrombotic Activity of Clam Heparinoid from the Clam Coelomactra antiquata. Mar. Drugs 2022, 20, 136. [Google Scholar] [CrossRef]
  151. Rukoyatkina, N.; Butt, E.; Subramanian, H.; Nikolaev, V.O.; Mindukshev, I.; Walter, U.; Gambaryan, S.; Benz, P.M. Protein kinase A activation by the anti-cancer drugs ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition and apoptosis. Cell Death Dis. 2017, 8, e2898. [Google Scholar] [CrossRef]
  152. Vogler, M.; Hamali, H.A.; Sun, X.-M.; Bampton, E.T.; Dinsdale, D.; Snowden, R.T.; Dyer, M.J.; Goodall, A.H.; Cohen, G.M. BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood J. Am. Soc. Hematol. 2011, 117, 7145–7154. [Google Scholar] [CrossRef] [Green Version]
  153. Mladenović, M.; Mihailović, M.; Bogojević, D.; Vuković, N.; Sukdolak, S.; Matić, S.; Nićiforović, N.; Mihailović, V.; Mašković, P.; Vrvić, M.M. Biochemical and pharmacological evaluation of 4-hydroxychromen-2-ones bearing polar C-3 substituents as anticoagulants. Eur. J. Med. Chem. 2012, 54, 144–158. [Google Scholar] [CrossRef] [PubMed]
  154. Becattini, C.; Agnelli, G. Aspirin for prevention and treatment of venous thromboembolism. Blood Rev. 2014, 28, 103–108. [Google Scholar] [CrossRef] [PubMed]
  155. Collaboration, A.T. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002, 324, 71–86. [Google Scholar] [CrossRef] [Green Version]
  156. Barrett, N.; Holbrook, L.; Jones, S.; Kaiser, W.; Moraes, L.; Rana, R.; Sage, T.; Stanley, R.; Tucker, K.; Wright, B. Future innovations in anti-platelet therapies. Br. J. Pharmacol. 2008, 154, 918–939. [Google Scholar] [CrossRef] [Green Version]
  157. Fuentes, E.; Palomo, I. Antiplatelet effects of natural bioactive compounds by multiple targets: Food and drug interactions. J. Funct. Foods 2014, 6, 73–81. [Google Scholar] [CrossRef]
  158. Gui, L.; Guo, L.; Xu, X. Effect of Kang Naoxueshuan tablet on protecting ischemic brain injury in rats. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi = Chin. J. Integr. Tradit. West. Med. 2006, 26, 7–10. [Google Scholar]
  159. Yasuda, T.; Takasawa, A.; Nakazawa, T.; Ueda, J.; Ohsawa, K. Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu-To, a traditional Chinese medicine, to rats. J. Pharm. Pharmacol. 2003, 55, 239–244. [Google Scholar] [CrossRef]
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Figure 1. Structures of curcumin, demethoxycurcumin and bis-demethoxycurcumin.
Figure 1. Structures of curcumin, demethoxycurcumin and bis-demethoxycurcumin.
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Figure 2. Pharmacological effects of curcumin.
Figure 2. Pharmacological effects of curcumin.
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Figure 3. Effects of curcumin on platelets and other blood cells.
Figure 3. Effects of curcumin on platelets and other blood cells.
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Hussain, Y.; Abdullah; Khan, F.; Alsharif, K.F.; Alzahrani, K.J.; Saso, L.; Khan, H. Regulatory Effects of Curcumin on Platelets: An Update and Future Directions. Biomedicines 2022, 10, 3180. https://doi.org/10.3390/biomedicines10123180

AMA Style

Hussain Y, Abdullah, Khan F, Alsharif KF, Alzahrani KJ, Saso L, Khan H. Regulatory Effects of Curcumin on Platelets: An Update and Future Directions. Biomedicines. 2022; 10(12):3180. https://doi.org/10.3390/biomedicines10123180

Chicago/Turabian Style

Hussain, Yaseen, Abdullah, Fazlullah Khan, Khalaf F. Alsharif, Khalid J. Alzahrani, Luciano Saso, and Haroon Khan. 2022. "Regulatory Effects of Curcumin on Platelets: An Update and Future Directions" Biomedicines 10, no. 12: 3180. https://doi.org/10.3390/biomedicines10123180

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