Javascript is currently disabled in your browser. When javascript is disabled, some functions of this website will not work.

Open access for scientific and medical research

From submission to the first editing decision.

From editor acceptance to publication.

Open access to peer-reviewed scientific and medical journals.

Dove Medical Press is a member of OAI.

Batch reprints for the pharmaceutical industry.

We provide authors with real benefits, including fast processing of papers.

Register your specific details and specific drugs of interest, and we will match the information you provide with articles in our extensive database and send you a PDF copy via email in a timely manner.

Back to Journal »Clinical Ophthalmology» Volume 15

New progress and controversy of curcumin in the treatment of retinal diseases

Author Nebbioso M, Franzone F, Greco A, Gharbiya M, Bonfiglio V, Polimeni A

Published on June 18, 2021, the 2021 volume: 15 pages 2553-2571

DOI https://doi.org/10.2147/OPTH.S306706

Single anonymous peer review

Editor who approved for publication: Dr. Scott Fraser

Marcella Nebbioso,1,* Federica Franzone,1,* Antonio Greco,1 Magda Gharbiya,1 Vincenza Bonfiglio,2 Antonella Polimeni3 1Department of Sense Organs, Sapienza University of Rome, Rome, 00185, Italy; 2Palermo University Experimental Biomedicine And Department of Clinical Neuroscience, Ophthalmology, Palermo, 90133, Italy; 3 Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Rome, 00185, Italy *These authors contributed equally to this work. Federica Franzone Department of Sensory Organs, Eye Electrophysiology Center, Umberto I Policlinic, Sapienza University of Rome, Viale del Policlinico 155, Rome, 00161, Italy Phone 39/06/49975422 Fax 39/06/49975426 Email [email protection] [email protection] Abstract: Turmeric Elements belong to the so-called group of plant compounds, which are biologically active molecules produced by plants and are beneficial to health. Curcumin shows a wide range of different properties and is an anti-inflammatory, antioxidant, antibacterial and anti-mutagenic molecule. The purpose of this review is to examine which literature reports the properties of curcumin, especially the beneficial and controversial aspects of this molecule, aimed at better treatment of retinal diseases. The retina is a constant target of oxidative stress. This tissue is characterized by cells and blood vessels rich in mitochondria. Obviously, photons continuously affect its layers. In particular, retinal ganglion cells and photoreceptors are extremely sensitive to oxidative stress damage. It is well known that the imbalance of reactive oxygen species is often associated with a variety of retinal diseases, such as uveitis, age-related macular degeneration, diabetic retinopathy, and central nervous system diseases. Serous chorioretinopathy, macular edema, retinal ischemia-reperfusion injury, proliferative vitreoretinopathy, hereditary tape retinal degeneration, and retinal and choroidal tumors. To date, several studies have shown that oral curcumin therapy is generally well tolerated in humans. In addition, it does not seem to have negative effects: therefore, curcumin is a promising treatment for retinal diseases. Unfortunately, the main limitation of curcumin is its poor bioavailability. In fact, only a very small part of this substance can enter the bloodstream in the form of biologically active compounds. However, many steps have been taken in many areas. It is expected that in the future, the strategies developed so far for curcumin to reach target tissues at a sufficient concentration can be improved. Most importantly, large-scale in vivo studies on the human body are required to prove the overall safety of these compounds and their compounds. The effect of different eye diseases. Keywords: anti-inflammatory properties, antioxidant properties, exosomes, miRNA, nanospheres, natural compounds

Curcumin (the IUPAC name is 1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione), also known as Diferuloylmethane, Natural Yellow 3 or E100, according to the European Code of Food Additives, 1 It is a herbal preparation with orange-yellow pigment, which is the characteristic shared by it and ginger. 2,3

It is the main polyphenolic substance derived from the turmeric plant (Curcuma longa), and due to its therapeutic properties, it is one of the most widely studied natural products in recent years. 4,5

For hundreds of years, curcumin has been widely used as a herbal medicine in Chinese medicine6 and Ayurvedic medicine7. It is a natural treatment for various diseases such as atherosclerosis, diabetes, liver disease, rheumatism and infectious diseases. essential elements. Oncological diseases. 8 Curcumin shows a wide range of different properties, especially as an anti-inflammatory, 9,10 anti-oxidant, anti-microbial and anti-mutagenic molecule. 11,12 However, it is necessary to emphasize that its biomedical potential is limited because of its poor digestive bioavailability. In fact, the absorption rate is very low, and the metabolism and elimination are extremely fast. 13,14 This topic will be discussed in the appropriate section later. In addition, curcumin is used as a spice in cooking and as a coloring agent in the cosmetics industry. 15

In ophthalmology, curcumin was first used as eye drops for patients with conjunctivitis and proved the same effect as soframycin. 16 Then, in 1996, Awasthi et al. reported its ability to prevent cataracts in rats, using curcumin (75 mg) for in vitro therapy/kg PO for 14 days). 17

Subsequently, curcumin was taken 3 times a day at a dose of 375 mg for 12 weeks to treat complicated cases of chronic anterior uveitis, and the symptoms improved. 18 In the past decade, researchers have used this natural medicine for a variety of eye diseases, especially in diabetic retinopathy (DR), glaucoma, and age-related macular degeneration (AMD). Potential candidates for the prevention and treatment of degenerative and inflammatory eye diseases. 19

This review aims to evaluate the literature reports on the properties of curcumin, with special attention to the beneficial and controversial aspects of the substance, in order to determine its application in the treatment of retinal diseases.

Curcumin is generally classified as a natural polyphenol with different functional groups: an aromatic ring system or methoxylated phenol is connected by two a, b-unsaturated carbonyl groups (Figure 1). Generally, curcumin exists in two tautomeric forms, namely keto-enol and di-keto tautomers. When curcumin is present in a polar organic solvent, the keto-enol tautomer is the main form. Its chemical formula is C21H20O6 (MW 368.38 g/mol)1, which is often solid at room temperature, with a melting point of 183 °C. 4 Vogel was extracted from dried rhizomes more than 140 years ago, in 1815. The traditional Indian herb turmeric, a perennial plant belonging to the Zinziberacee family, is also known as Indian saffron or turmeric. Lampe later synthesized it on 1913.20. Turmeric rhizomes are composed of curcumin (3–5%) and volatile components (2–7%): 21,22 Curcumin includes cinnamoyl methane derivatives such as curcumin and demethoxy Curcumin (DMC) and bis-demethoxycurcumin (BDMC), and the volatile part mainly contains characteristic terpene compounds, such as gingerene, curcumin and β-curcumin. 5 Figure 1 The chemical structure of curcumin.

Figure 1 The chemical structure of curcumin.

DMC and BDMC show similar biological properties to curcumin, and can inhibit the activity of enzymes responsible for NF-kB activation (such as COX-2). twenty three

All metabolites of curcumin, as well as hexahydrocurcumin (HHC), octahydrocurcumin (OHC), dihydrocurcumin and tetrahydrocurcumin (THC), all show anti-inflammatory and antioxidant effects. twenty four

The rhizomes of turmeric represent the most useful part of the plant: in fact, once the rhizomes are boiled and dried in the sun, they are crushed to produce a yellow-orange powder whose biologically active ingredient is curcumin. 25

Due to its biochemical properties, curcumin belongs to the so-called plant compound, that is, a biologically active molecule produced by plants, which is beneficial to health. Other types of plant compounds include β-carotene, lycopene, quercetin, and epigallocatechin gallate. 26

Inflammation is considered to be a physiological phenomenon, which usually occurs due to different pathological events: it is considered to be a protective mechanism of the body that appears when injury occurs, with the risk of damaging the body.

Curcumin can block many different pathways normally activated by the inflammatory process: for example, curcumin exerts a significant inhibitory effect on cyclooxygenase 2 (COX-2) and inhibits PGE2 synthase 1, which is responsible for prostaglandin E2 (PGE2) ) Synthesis and 5-Lipoxygenase (5-LOX). In addition, curcumin determines the reduction of IκBα gene expression and regulates the expression of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). The latter two are transcription factor genes that control a variety of cellular activities: in more detail, NF-κB is a trigger for inflammation, immune activity, and cell proliferation, while AP-1 stimulates cell proliferation. NF-κB mediates inflammation through the activation of cyclooxygenase-2 (COX-2), lipoxygenase (5-LOX) and xanthine oxidase. In addition, NF-κB and AP-1, which are also overexpressed in cancer cells, induce the expression of inducible nitric oxide synthase (iNOS), thereby enhancing the expression of nitric oxide (NO) and tumor necrosis factor (TNF)-α Produces, and prostaglandins.

All these pro-inflammatory factors lead to the expression of vascular endothelial growth factor (VEGF): therefore, VEGF triggers endothelial cell proliferation, and activation of matrix metalloproteinases (MMP) causes angiogenesis and extracellular matrix (ECM) degradation. 4

In addition, curcumin down-regulates the janus kinase, signal transducer and activator of transcription (JAK/STAT) pathway, thereby determining TNF-α and pro-inflammatory interleukins (IL-1, IL-2, IL-6, IL-8 and IL-12) deregulation. Among these cytokines, IL-8, which causes severe inflammation, is particularly inhibited by curcumin. Gupta et al. even demonstrated the ability of curcumin to inhibit p300/CREB ​​specific acetyltransferase, which usually prevents histone/non-histone acetylation from causing a decrease in TNF-α levels. 27 In addition, curcumin regulates IkB kinase activity by continuously down-regulating NF-κβ. 28

Other studies have shown that curcumin can also regulate gene transcription through the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR-γ plays an anti-inflammatory effect by binding to the peroxisome proliferator response element (PPRE) in the gene promoter sequence (Scheme 1). 5 Scheme 1 Pathways of eye diseases and biochemical properties of curcumin. Proliferation pathway: CDK4, cyclin D1, c-myc; cell survival pathway: Bcl-2, Bcl-xL; caspase activation pathway: caspase 8/3/9; molecular pathway containing protein kinase c-Jun N-terminal kinase: JNK; protein kinase B: PKB; reactive oxygen species: ROS; endothelial vascular cell adhesion molecule-1: VCAM-1; intracellular adhesion molecule-1: ICAM-1; leukocyte adhesion molecule-1: ELAM-1; metal Protease: MMP; Serine protease family: SP; Urokinase plasminogen activator system: uPA; Tumor suppressor pathway: p53, p21; Death receptor pathway: DR4, DR5; Cyclooxygenase-2: COX-2; 5-lipoxygenase: 5-LOX; prostaglandin E2: PGE2; nuclear factor-κB: NF-κB; activator protein-1: AP-1; xanthine oxidase: XO; janus kinase, signal transduction and transcription activation Factors: JAK/STAT; Tumor Necrosis Factor-α: TNF-α; Pro-inflammatory Interleukins: IL-1, IL-2, IL-6, IL-8 and IL-12; Peroxisome Proliferator Activated receptor-γ: PPAR-γ; vascular endothelial growth factor: VEGF; transforming growth factor: TGF-β1; stimulate fibroblasts to express fibronectin: FN; collagen.

Scheme 1 Pathways of eye diseases and biochemical properties of curcumin. Proliferation pathway: CDK4, cyclin D1, c-myc; cell survival pathway: Bcl-2, Bcl-xL; caspase activation pathway: caspase 8/3/9; molecular pathway containing protein kinase c-Jun N-terminal kinase: JNK; protein kinase B: PKB; reactive oxygen species: ROS; endothelial vascular cell adhesion molecule-1: VCAM-1; intracellular adhesion molecule-1: ICAM-1; leukocyte adhesion molecule-1: ELAM-1; metal Protease: MMP; Serine protease family: SP; Urokinase plasminogen activator system: uPA; Tumor suppressor pathway: p53, p21; Death receptor pathway: DR4, DR5; Cyclooxygenase-2: COX-2; 5-lipoxygenase: 5-LOX; prostaglandin E2: PGE2; nuclear factor-κB: NF-κB; activator protein-1: AP-1; xanthine oxidase: XO; janus kinase, signal transduction and transcription activation Factors: JAK/STAT; Tumor Necrosis Factor-α: TNF-α; Pro-inflammatory Interleukins: IL-1, IL-2, IL-6, IL-8 and IL-12; Peroxisome Proliferator Activated receptor-γ: PPAR-γ; vascular endothelial growth factor: VEGF; transforming growth factor: TGF-β1; stimulate fibroblasts to express fibronectin: FN; collagen.

Today, oxidative stress is defined as an imbalance between reactive oxygen species (ROS) and antioxidant defenses. 29 ROS is a normal product of cell metabolism, which may be beneficial or harmful to cells, depending on their concentration: in fact, low levels of ROS are essential for cell proliferation induction, intracellular signal transduction and apoptosis, but high levels Concentrations of oxidative active substances can interfere with the normal biological pathways of cells. 15 Specifically, ROS levels are the result of two mechanisms: endogenous ROS formation and exposure to exogenous ROS. Endogenous ROS is the product of mitochondrial oxidation and some enzymatic reactions catalyzed by certain oxidoreductases. 30

In some neurodegenerative diseases, 31 cardiovascular, endocrine, tumor and autoimmune diseases, which are common persistent oxidative stress, 32 can activate a large number of inflammatory molecular signaling pathways.

ROS can regulate nuclear factor-κβ (NF-κβ) and tumor necrosis factor α (TNF-α) pathways, which are usually involved in the inflammatory cascade. 29

In 2015, Deogade and Ghate6 emphasized the anti-inflammatory and antioxidant effects of curcumin, which may be attributed to its hydroxyl and methoxy groups: for example, this plant compound and its derivatives can be Polyunsaturated fatty acids block lipid peroxidation, in addition they act as ROS and NO scavengers. 4

Most natural antioxidants show phenolic or β-diketone groups. In view of the presence of both phenolic and β-diketone functional groups on the same molecule, curcumin and its analogs are considered unique molecules. 33

In particular, phenols seem to be responsible for the antioxidant properties of any plant phenolic compound. Therefore, some authors study the properties of curcumin, focusing on its phenol ring,33,34 while other authors insist that the β-diketone part of curcumin and its derivatives will exert antioxidant effects. 21,35

In the context of this debate, Jovanovic et al. thoroughly studied the physical and chemical properties of curcumin free radicals through laser flash photolysis and pulsed radiation decomposition, and gained great interest. In order to study the effects of phenolic hydroxyl and β-diketone moieties and determine the properties of curcumin free radicals, they synthesized two methylated curcumin derivatives, methyl curcumin and trimethyl curcumin. The universal curcumin radical is represented by phenoxy, which is obtained by transferring H atoms from any methoxyphenol ring molecule to β-oxoalkyl radicals or by direct one-electron oxidation of methoxyphenol groups of. Based on their results, the authors concluded that β-diketone alone does not have antioxidant properties, and that both β-diketone and phenol are necessary for curcumin’s antioxidant properties. 36

However, regarding antioxidant properties, not all authors agree that curcumin is an excellent antioxidant: Litwinienko et al. emphasized that since curcumin is a (bis)phenol, it can trap lipid peroxidation5,6 and The 1,1-diphenyl-2-picrylhydrazyl 7 free radical releases one of its phenolic H atoms, but this ability does not make it an antioxidant molecule. 37

In addition, they confirmed that, unlike what Jovanovic et al. 36 observed in the formation of ionized solvent radicals, it does not cause "rapid intramolecular H shift", but occurs after the loss of protons. According to Litwinienko et al., this discovery will resolve the CU antioxidant controversy. 37

ROS seem to play an important role in the regulation of angiogenesis homeostasis, and their role is mainly due to their concentration: as mentioned earlier, high ROS doses induce oxidative stress and subsequently inhibit angiogenesis, while low doses of ROS (mainly H2O2) Stimulate angiogenesis. 33,38

Several studies have shown that curcumin inhibits angiogenesis through different mechanisms: Chen et al. emphasized that curcumin can determine the isoforms 165 and 121 that inhibit VEGF secretion in U937 and Raji cells. 39 Millanta et al. observed that curcumin has an effect on angiogenesis. Inhibition, measured as the formation of a network of endothelial cells on Matrigel. The same phenomenon was also detected in the endothelial cell line-ECV304 cells. 40 Yoysungnoen et al. inoculated HepG2 cells into the upper layer of the skinfold chamber: these cells were then implanted into mice, and the mice were given curcumin orally. In this study, the angiogenesis process was evaluated as the tumor new capillary density, by using digital image analysis. Tumor angiogenesis was inhibited by curcumin 3000 mg/kg treatment by reducing VEGF and COX-2. 41 In addition, Li et al. found that the NF-κB pathway that works with liposomal curcumin is reduced.

Another mechanism that curcumin indirectly prevents angiogenesis involves the regulation of cell adhesion molecules such as endothelial vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and leukocyte adhesion molecules -1. ELAM-1). Curcumin can also reduce the activity of metalloprotease (MMP), serine protease family and urokinase plasminogen activator system (uPA). This special property of curcumin leads to the inhibition of endothelial cell migration and the release of transforming growth factor (TGF), TNF, hepatocyte growth factor (HGF) and VEGF. 42

In summary, all the properties described in this article indicate that curcumin can be used in several angiogenesis-related diseases, such as eye diseases that show these underlying processes. 15

Curcumin is a substance with multiple pleiotropic characteristics: as different in vivo and in vitro studies have shown, it even shows anticancer potential. In particular, curcumin inhibits carcinogenesis in three different stages: angiogenesis, tumor promotion and growth. It can regulate a variety of signal pathways, especially the tumor suppressor pathway (p53, p21), death receptor pathway (DR4, DR5), proliferation pathway (CDK4, cyclin D1, c-myc), cell survival pathway (Bcl- 2, Bcl-xL) and caspase activation pathways (caspase 8, 3 and 9), as well as molecular pathways containing protein kinase c-Jun N-terminal kinase (JNK) and protein kinase B (PKB). 43,44 Devassy et al. reported that curcumin can prevent a variety of cancer types, including breast, lung, colon, and pancreatic cancer, as well as multiple myeloma. 45

In addition to the features described above, curcumin’s ability to enhance the tissue repair process is also important: wound healing is a complex situation, including the inflammatory process associated with granulation and tissue remodeling. 44

A variety of growth factors and cytokines are involved: the first is transforming growth factor (TGF-β1), which plays a key role in the wound healing mechanism by stimulating the expression of fibroblasts of fibronectin (FN) and collagen. 46

The retina is a structure that occupies the posterior part of the eyeball, is in direct contact with the vitreous body, and is considered a part of the central nervous system (CNS). It is composed of several cell types. In more detail, two types of photoreceptors can be described: rod-shaped cells, which are located more on the periphery of the retina, work under dim light conditions (<0.1 lux, night vision), and are resistant to darkness. Particularly sensitive, and the cone cells, which are more concentrated in the macula, are very sensitive to fine shapes and light. They can distinguish colors and work under bright vision conditions (>10 lux). In addition to photoreceptors, there are retinal ganglion cells (RGC), bipolar cells, amacrine cells, horizontal cells, Müller cells, and retinal pigment epithelial cells (RPEC) in the retina. RPE is a layer of the retina that performs many key functions, such as digesting the damaged outer photoreceptor segment (POS) and maintaining the structure of the retina. Munia et al. evaluated the effects of resveratrol, lutein and curcumin on human retinal epithelial cells and proved that these cells can be protected from death by pretreatment with these nutrient compounds after being damaged by oxidative stress. 47

The retina is a constant target of oxidative stress, characterized by mitochondrial-rich cells and blood vessels, and it is clear that it is constantly being affected by photons that affect its layers.

This situation explains why most retinal pathological processes involve oxidative stress imbalance, large amounts of ROS, and reduced levels of antioxidant scavengers.

In addition, it is important to emphasize that in general, the retina shows a high content of polyunsaturated fatty acids (PUFA), especially, as mentioned above, higher oxygen and glucose uptake has been observed compared to other tissues; These characteristics make the retina extremely susceptible to oxidative stress.

In particular, RGC and photoreceptors are extremely sensitive to oxidative stress damage. It is well known that ROS imbalance is often associated with a variety of retinal diseases, such as uveitis, age-related macular degeneration (AMD), diabetic retinopathy (DR), and central retina Lesions. Serous chorioretinopathy (CSC), macular edema (ME), and retinal ischemia-reperfusion injury (RIRI) caused by rare causes, retinal and choroidal tumors, proliferative vitreoretinopathy (PVR), hereditary tape retinal degeneration And retinal and choroidal tumors. 1

As mentioned earlier, one of the earliest applications of curcumin in ophthalmology was in the field of uveitis: Lal et al. studied its clinical application in the treatment of chronic anterior uveitis (CAU). The enrolled patients were divided into two groups according to the severity of their manifestations: one group received curcumin treatment only, and the other group also received anti-tuberculosis treatment. Curcumin is administered in the form of capsules (one capsule, 3 times a day), each capsule contains 375 mg of molecules. In summary, the authors report a comparable efficacy between curcumin and corticosteroid therapy, the latter being the only accepted standard treatment for the disease. 48

A few years later, in addition to traditional therapies, patients with recurrent anterior atrial fibrillation were successfully followed up with oral phospholipid curcumin (iPhytoone, Indena SpA, Milan, Italy or Norflo®, Eye Pharma, Genoa, Italy). Uveitis of different origins (RUA): Three groups were identified as herpes, autoimmune and other types of uveitis. This study emphasized the anti-inflammatory properties of curcumin. In addition, it has a good effect in preventing any RUA recurrence. 49

Recently, oral phospholipid curcumin has been tried in patients with juvenile idiopathic arthritis-related uveitis, and promising results have been achieved in reducing chronic anterior chamber flares. 50

The protective effect of curcumin was also studied in AMD (Figure 2), where Mandal et al. observed the regulation of retinal inflammation gene expression in curcumin-fed Wistar rats (2000 ppm). NF-kB results were suppressed, and they also revealed the reduction of early growth response protein 1 (EGR1) and intercellular adhesion molecule 1 (ICAM1) in retinal cell lines 661W and ARPE-19.51, especially in AMD, Muangnoi et al. Tried a method called curcumin prodrug called diethyl disuccinate (CurDD), showing that this molecule is more effective in reducing oxidative stress in human ARPE-19 cells than curcumin. 52 Figure 2 Spectral domain optical coherence tomography degradation (AMD) of the right eye affected by the age-related macula. Macular neuroepithelial detachment (central thickness of 419 µm) and choroidal neovascular membrane (CNV).

Figure 2 Spectral domain optical coherence tomography of the right eye affected by age-related macular degeneration (AMD). Macular neuroepithelial detachment (central thickness of 419 µm) and choroidal neovascular membrane (CNV).

In all cases, CurDD is more effective than its parent drug against ARPE-19 cell damage induced by oxidative stress. These findings highlight that, compared with curcumin (Cur), CurDD is a more effective anti-oxidative stress drug, and shows that its protective effect is exerted by regulating key apoptosis and antioxidant molecular pathways. 52

Diabetic retinopathy (DR) is a metabolic chronic inflammatory disease characterized by ischemia, microaneurysms, hemorrhage, retinal edema, neovascularization, and neuronal degeneration. 53 It is considered to be a microvascular retinal disease, which consists of two different stages: the early and typical non-proliferative period (non-proliferative diabetic retinopathy or NPDR) and the later stage, which is more severe and characterized by vascular proliferation ( Proliferative diabetic retinopathy or PDR) 54.

Therefore, in addition to photoreceptors, these latter structures are more susceptible to the progress of DR. It has been recognized that when ROS imbalance exists, multiple metabolic pathways are involved: advanced glycation end products (AGE) pathway, polyol pathway, protein kinase C (PCK) and hexosamine pathway. 55

In particular, the accumulation of AGE determines the massive release of ROS, which makes the protein cross-link with continuous vascular and extravascular structural changes (Figure 3). Figure 3 Spectral domain optical coherence tomography of the right eye affected by diabetic macular edema (ME). The spongy appearance of the neural retina (with a central thickness of 520 µm) and the high reflectivity of the epiretinal membrane.

Figure 3 Spectral domain optical coherence tomography of the right eye affected by diabetic macular edema (ME). The spongy appearance of the neural retina (with a central thickness of 520 µm) and the high reflectivity of the epiretinal membrane.

In addition, Chiu et al. detected the activation of ribozyme poly(ADP-ribose) polymerase (PARP) after oxidative damage in PARP-/- mice and diabetic rats. In addition, they also observed the activation of NF-kB and endothelin-1 (ET-1). 56 In addition, vascular endothelial growth factor (VEGF) is a major angiogenic factor related to ocular neovascularization caused by ischemia, in DR eyes. 57

Wang et al. found that curcumin determines the reduction of TNF-α and VEGF by increasing the levels of antioxidant enzymes SOD and catalase. 58 Kumar et al. studied the effect of curcumin on streptozotocin-induced diabetic rats: they observed a reduction in oxidative stress and curcumin’s ability. 59 Under hyperglycemic conditions, curcumin can also inhibit VEGF in the retina. expression. 60 Khimmaktong et al. observed the process of retinal regeneration after curcumin treatment. In particular, they reported the normalization of the diabetic microvascular system with tortuosity, narrowing, and reduction of microaneurysms. 61 Then, curcumin may down-regulate the RPEC inflammatory damage induced by high glucose and regulate the ROS/PI3K/AKT/mTOR signaling pathway. 62

The efficacy of curcumin has also been studied in chronic diabetic ME. Mazzolani et al. administered the curcumin-phospholipid lecithin preparation (iPhytoone®) as a tablet (Norflo®) twice a day. After the treatment, the vision results improved and the macular edema was reduced. 63

Central serous chorioretinopathy (CSCR) is a well-known retinal disease characterized by a typical retinal serous neurosensory elevation (Figure 4). Usually, this disease is self-limiting, but sometimes photoreceptor and RPEC damage can be identified. Today, the pathogenesis of CSCR is still unclear, but changes in choroidal permeability are considered to be the main potential event. Figure 4 Right eye retinal angiography affected by recurrent central serous chorioretinopathy (CSC).

Figure 4 Right eye retinal angiography affected by recurrent central serous chorioretinopathy (CSC).

In a 12-month follow-up study, curcumin as a curcumin-phospholipid (lecithin) delivery system, administered in tablet form (Norflo®) was studied as a potential anti-inflammatory treatment for CSCR: all patients Both showed a significant reversal of vision loss. At present, there is no appropriate treatment plan for CSCR management. However, according to Mazzolani et al., treatment should be considered in acute and chronic CSCR cases. 63

ME, defined as intraretinal and/or subretinal macular effusion, is usually a common complication of several retinal diseases, such as AMD, DR, and retinal vein occlusion (RVO). However, sometimes ME is thought to be caused by uncommon causes, such as postoperative ME (Figure 5) or chronic CSC. Figure 5 Retinal angiography of the left eye affected by Irvine Gass syndrome. Patients with chronic glaucoma develop macular and paranipple (temporal border) edema after cataract surgery, accompanied by sunken and pale optic discs.

Figure 5 Retinal angiography of the left eye affected by Irvine Gass syndrome. Patients with chronic glaucoma develop macular and paranipple (temporal border) edema after cataract surgery, accompanied by sunken and pale optic discs.

A retrospective study evaluated the efficacy and tolerability of curcumin carriers in such patients. In more detail, subjects showing chronic and symptomatic ME of unknown cause were enrolled and then administered with polyvinylpyrrolidone hydrophilic carrier (CHC). The regimen consists of loading and maintenance phases, so the patient previously received two capsules per day for 1 month, and then received one capsule per day for the next 2 months. Each CHC capsule contains 60 mg CurcuWIN dry powder 20% (curcuminoids 20-34%, hydrophilic carrier 60-80% and natural antioxidants 1-5%). In both cases of ME, CHC has shown beneficial treatments, so curcumin can be considered as a potentially promising treatment for complex forms of ME. 64

In the case of pathological reperfusion injury after retinal ischemia due to decreased intraocular perfusion pressure, high intraocular pressure (Figure 6) or intraoperative/postoperative conditions, Wang et al. described the protective effect of curcumin on retinal neurons . They claim that curcumin can inhibit the nuclear factor kappa light chain enhancer (NF-kB) and signal transducer and activator of transcription (STAT3) that activate B cells. Therefore, curcumin can prevent or reduce the continuous overexpression of monocyte chemoattractant protein 1 (MCP-1) in Wistar rats. 65 Curcumin can also down-regulate the expression of c-Jun N-terminal kinase (JNK), such as that observed in retinal neurons and capillary stroke spontaneously hypertensive rats (SHR). 66 Figure 6 Figure 6 Retinal angiography of central venous thrombosis with ischemic edema and chorioretinal laser treatment.

Figure 6 Retinal angiography group with ischemic edema and central venous thrombosis treated with chorioretinal laser.

In addition, retinal ischemia due to central vascular occlusion, diabetes or retinal detachment can cause proliferative vitreoretinopathy (PVR). PVR is maintained by the proliferation and migration of RPEC, an event usually induced by epidermal growth factor (EGF). In this case, curcumin at an optimal concentration of 15 µg/mL can completely inhibit the proliferation of RPEC, and the positive effect of curcumin was evaluated. It was evaluated that the proliferative membrane and vitreous opacity were significant in the curcumin-treated patient group. Reduced situation. Compared with the control group. 67

The term Retinitis Pigmentosa (RP) (MIM#268000) refers to a wide range of inherited progressive and degenerative photoreceptor diseases that cause severe loss of vision or blindness. 68

Generally, the rod is the first photoreceptor to be severely affected, and the cone is only involved later (Figure 7). The degeneration of photoreceptors leads to their cell apoptosis, so the retina undergoes progressive and irreversible atrophy. 69 The prevalence of RP is about 1:4000, affecting more than 1 million people worldwide. 70 Figure 7 The left side of the spectral domain optical coherence tomography scan of the eye of a patient with retinitis pigmentosa. It can be observed: the epiretinal membrane between the optic disc and the macula; the photosensitive layer outside the fovea is lost; the central nuclear layer increases.

Figure 7 Spectral domain optical coherence tomography of the left eye of a patient with retinitis pigmentosa. It can be observed: the epiretinal membrane between the optic disc and the macula; the photosensitive layer outside the fovea is lost; the central nuclear layer increases.

Many different genes are involved in the same disease phenotype (genetic heterogeneity); different diseases can determine the mutation of each gene (allelic heterogeneity); different diseases are caused by different mutations in the same gene (phenotype Heterogeneity); despite having the same gene mutation, different individuals, even members of the same family, will show different clinical effects. 71,72

In genetics, it is important to emphasize that the disease spreads in different ways and has different phenotypic manifestations. For example, X-linked patients, who account for approximately 5-15% of all cases, generally tend to exhibit the most severe forms of RP, while subjects with autosomal recessive RP account for approximately 50-60% of all cases, and patients show autosomal In the dominant form of RP, 30-40% of cases are in good condition, especially in terms of disease progression and visual prognosis. In addition, they can keep central vision intact for longer. 69,73

In addition, RP exists in two forms: syndromes and non-syndromes: specifically, the syndrome form of retinitis pigmentosa refers to those conditions in which RP is not isolated, but it is related to a series of other diseases, such as developmental disorders or nerves. feeling abnormal. Usher syndrome is characterized by RP associated with congenital or early-onset deafness. In Bardet-Biedl syndrome (BBS), RP is accompanied by developmental delay, kidney disease, obesity, and polydactyly. Sometimes RP may also be related to mitochondria or degenerative cerebellar diseases. 71,74

Unfortunately, to date, there is no curative treatment for the disease: new treatment options, such as gene and cell therapy 75-77, are being developed to replace defective cells or their functions. 69

Various studies have been conducted to determine the effect of curcumin on patients with RP. At the same time, it is necessary to observe that the photoreceptor contains a kind of biological pigment called rhodopsin: most cases of autosomal dominant RP form are due to the P23H missense mutation of rhodopsin, which leads to abnormal folding of rhodopsin, leading to rhodopsin Preserve the endoplasmic reticulum. ER). The formation of insoluble aggregates of rhodopsin and its continuous cell storage end with cell death. 78-80 Khajavi et al. found that curcumin prevents the retention of myelin protein aggregates in the endoplasmic reticulum, so it may be a potential treatment for RP. 81 These curcumin effects have been demonstrated in extensive studies in transgenic rats affected by P23H rhodopsin mutations: rats treated with curcumin from the 30th day (P30) to the 60th day (P60) after birth In the photoreceptor core layer, photoreceptor outer core and inner core, the layer morphology was significantly improved. 82 Specifically, they administered curcumin at a dose of 100 mg/kg body weight and observed that the latter can cross the blood-brain barrier and blood-retinal barrier when taken orally. P23H-R rats showed improved retinal morphology and retained photoreceptors. In addition, the improvement in rod and cone specific gene expression levels was evaluated after the administration of curcumin. 82 The effect of curcumin induced by ROS generator methyl-N-nitrosourea (MNU) on photoreceptor cell apoptosis was also tested in Sprague-Dawley rats. The model of Emoto et al. In more detail, three days before MNU administration, they injected 100 or 200 mg/kg curcumin. It was observed that the reduction of retinal damage after 200 mg/kg curcumin treatment was limited to the central retinal section. In addition, the level of 8-hydroxy-2'-deoxyguanosine, which is a parameter of oxidative stress, was quantified, resulting in a number similar to that of the control group, demonstrating that oxidative damage was reduced. 83

Finally, Scott et al. studied the prenatal protection of curcumin in the Pro-23-His (P23H) rhodopsin mutant pig model. They fed 100 mg/kg body weight/day curcumin to the sows two days before farrowing. Then, Scott et al. enucleated the embryo: curcumin prevents the thinning of the outer nuclear layer (ONL) and inner nuclear layer (INL). In addition, consistent with Vasileddy, Scott et al. emphasized the properties of curcumin to prevent morphological changes of photoreceptors. 84

Optimal macular dystrophy (BD), also known as optimal yolk-like macular dystrophy (BVMD), is considered a form of macular degeneration, usually manifested as adolescent onset and characterized by loss of central vision. So far, there is no available treatment: In 2019, Lin et al. extracted dental pulp stromal cells from BD patients, and then induced them to dedifferentiate into pluripotent stem cells (BD-iPSC). Finally, these cells were stimulated to differentiate into Retinal Pigment Epithelial Cells (BD-RPEC). Compared with the RPEC of the control group, the expression of Bestrophin-1 (BEST1) and tight junction protein ZO-1 of BD-RPEC were lower. They observed that curcumin can significantly increase the mRNA expression level of BEST1 gene in RPEC derived from BD-iPSC. In addition, curcumin-loaded PLGA nanoparticles (Cur-NPs) can confirm the increase in the expression of antioxidant enzymes and the decrease in the production of ROS. 85

For retinal and choroidal tumors caused by the inactivation of the tumor suppressor gene RB1 gene, especially retinoblastoma, Li et al. found that curcumin can inhibit the proliferation and migration of RB cells and induce their apoptosis, even if curcumin has an effect on retinoblastoma The impact of (Rb) is still unclear. 86,87

In more detail, curcumin seems to determine the inactivation of the Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling pathway, thanks to microRNA-99, because it lacks microRNA-99a-silenced cells. Li et al. studied the effects of these on SO-Rb50 and Y79 cells and retinoblastoma cell lines, where the compound down-regulated the migration ability of retinoblastoma cells. 86

The main limitation of curcumin is its poor bioavailability. In fact, only a very small part of this substance can enter the bloodstream in the form of biologically active compounds: therefore, the greatest effort so far has been aimed at finding a remedy for this main limitation .

Numerous studies have shown that high doses (>3.6 g/day in humans) are required to obtain any therapeutic effect.88 Many different studies have proved this: Wahlstrom and Blennow reported the blood curcumin level in Sprague-Dawley rats in 1978. The minimal increase in the patient received oral curcumin (1 g/kg) due to its reduced intestinal absorption. 89 Similarly, Yang et al. mentioned that after intravenous injection of 10 mg/kg curcumin in rats, the maximum serum curcumin level was 0.36 μg/mL. 90 In order to improve the bioavailability of curcumin, different methods have been tried. For example, curcumin analogs and enhancers and delivery systems are synthesized. All these attempts to improve the bioavailability of curcumin will now be examined in detail.

Many curcumin analogues have been synthesized to improve the problems related to the molecular structure of curcumin. These problems are the reason for the decrease of its one-time performance, mainly related to the high reactivity of the β-diketone component in its structure. 91

Wang et al. developed the prodrug diphosphorylated curcumin (Cur-2p), followed by enzymatic activation: they achieved a significant improvement in molecular stability in aqueous media. 92 Similarly, Muannoi et al. compared the antioxidant properties of Cur prodrugs Curcumin diethyl disuccinate (CurDD) against curcumin is associated with the oxidative stress induced by human ARPE-19 cells: they mentioned that they can all regulate Different apoptosis signaling pathways such as p44/42 (ERK) play a protective role against oxidative damage. With the continuous down-regulation of the effector molecules Bcl2 and Bax, CurDD (the prodrug ester form of Cur) shows a better protective effect. So it may be an interesting alternative therapeutic agent, especially in the case of AMD. 52

Other analogs of curcumin have been tested in different fields: for example, curcumin derivative WZ35 shows stronger anti-tumor activity than curcumin, especially its ability to down-regulate glycolysis. Considering its ability to reduce tumor cell proliferation, it has been studied as a promising treatment for gastric cancer and breast cancer, so it may even become a potential molecule for the treatment of retinal and choroidal tumors. 93,94

"Bioavailability enhancers" refer to compounds that can improve the handleability of many substances: this is the case with piperine and curcumin. Specifically, piperine is a component of black pepper, and when administered with curcumin, it can increase its oral bioavailability. 95 Piperine exerts this effect by reducing curcumin liver and intestinal glucuronidation: 32 Shoba et al. observed that when curcumin was administered to rats alone at a dose of 2 g/kg, the curcumin serum concentration was moderate , And in addition to piperine 20 mg/kg, the blood concentration of curcumin increased. In humans, when there is no piperine, the curcumin serum concentration is undetectable. On the contrary, when combined with piperine 20 mg, the bioavailability increases by 2000%. 96

At present, researchers are trying to develop new curcumin carriers to take advantage of advances in the field of nanotechnology: especially nanocarrier delivery systems composed of nanoparticles, which can improve some molecular properties, such as bioavailability and solubility in aqueous media. And stability. 97 Table 1 Types and Authors of Curcumin (Cur) Delivery System (Bold)

Table 1 Types and authors of curcumin (Cur) delivery systems (in bold)

The first nanocarriers approved by the FDA are liposomes: 98 They are spherical double-layered vesicles with a water core in the center. Usually its size is about 25-1000 nm. 99,100

According to the molecular structure, liposomes are defined as unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs), showing great advantages of non-immunogenicity and non-toxicity.

Recently, the formulation of Cur-loaded liposomes has been realized: for example, Shi et al. synthesized curcumin-loaded liposomes (Lipo-cur) composed of cholesterol and lecithin. 101 In this case, the goal was to irradiate mice with the radioprotective properties of curcumin during the radiation process. In addition to liposomes, researchers developed polymer micelles in the late 1980s. 102 Structurally, micelles are composed of a hydrophilic part and a hydrophobic part: many amphiphilic polymers are used for this purpose, such as polyethylene glycol (PEG) and chitosan and polyvinylpyrrolidone (PVP). As a hydrophobic material, there are different possibilities. Polylactic acid (PLA), distearoyl phosphoethanolamine (DSPE), dioleoyl phosphatidylethanolamine (DOPE) and vitamin E can all be used to realize micellar cores. In ophthalmology, a curcumin mixed micellar in-situ gel system (Cur-MM-ISG) was prepared and showed the ability to remain on the surface of the cornea. 102-106,

In contrast, Alshamrani et al. used hydrogenated castor oil (HCO-40) and octoxynol-40 (OC-40) to develop curcumin water-based nanomicelle drops (CUR-NMF) to treat AMD. 107

Davis et al. used a nonionic surfactant called D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), which can form stable micelles when its concentration is greater than 0.02% w/w48 . TPGS is related to a copolymer surfactant called Pluronic F127. The latter substance is composed of hydrophobic and hydrophilic polyoxyethylene groups. They proved that these nanoparticles can protect RCG cells from high intraocular pressure in vivo, and therefore show neuroprotective effects. 108 Similarly, Duan et al. developed an ion-sensitive curcumin-loaded Pluronic P123 (P123)/Da-tocopherol polyethylene glycol succinate (TPGS) hybrid micellar in situ gel (CUR-MM-ISG) To ensure longer corneal permeability and retention time. 109

Recently, one of the most promising curcumin delivery systems is the new amphiphilic polymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG, Soluplus®). The carrier is composed of a hydrophilic part represented by a polyethylene glycol (PEG) main chain and a lipophilic part represented by a lipophilic structure represented by a vinyl caprolactam/vinyl acetate side chain. Therefore, curcumin is loaded onto PVCL-PVA-PEG nanomicelles, thanks to a special solvent evaporation/thin film hydration method. 96

Polymer nanoparticles, solid colloidal particles, represent another strategy: Several natural and synthetic polymers have been used to synthesize polymer nanoparticles, such as chitosan (CS), PLGA, polyvinyl alcohol (PVA) and Polybutylcyanoacrylate (PBCA). 96,110– 112

Lou et al. elaborated on a composite in-situ gel formulation composed of curcumin-loaded albumin nanoparticles (Cur-BSA-NPs-Gel). This is a useful method to optimize curcumin in aqueous humor. Bioavailability, as demonstrated in the eyes of rabbits and humans. 113

Recent porous materials, such as mesoporous silica nanoparticles (MSN), have also been used as curcumin carriers, as reported by several studies, 114-119 However, so far, they are still not used in the ophthalmology field .

In another study, some researchers combined alginate (AGT) with curcumin to develop a hydrogel-based system CCI/AGT that can anchor RPEC in it. They observed that the CCI/AGT system can enhance RPEC regeneration compared to pure AGT hydrogel. They propose to use this structure as a support for retinal tissue engineering implants. 120

Due to its biocompatibility, biodegradability and non-immunogenic properties, protein has become an effective choice for curcumin delivery nanoparticles, such as bovine serum albumin (BSA), ovalbumin (OVA), human serum albumin Protein (HSA) and silk fibroin. SF) Nanoparticles. 121–123

In addition, solid lipid nanoparticles (SLN) are a colloidal drug delivery system characterized by the presence of biodegradable solid lipids. Curcumin is embedded in the lipid core of SLN: this encapsulation has been widely used. 124

It is still worth remembering in the curcumin delivery system cyclodextrin that cyclodextrin is defined as a cyclic oligosaccharide with a special structure of hollow truncated cones, nanogels and nanocrystals. Regarding cyclodextrin, cyclodextrin was used in 2010 to ensure adequate administration of curcumin as eye drops, and it was found to be effective in determining the reduction of selenium-induced cataracts in rats. 125,126

Almost all of these final strategies have not been tested in the eye, so this may represent a future challenge for ophthalmologists. However, other methods have been tried: Zhang et al. developed a biodegradable curcumin scleral plug for the treatment of posterior ocular diseases. They experimented with the system in rabbit eyes and showed that it can be maintained in this way. High concentration of curcumin in vitro and in vivo. 127

Curcumin-phospholipid lecithin formulations represent another possibility. In addition to other strategies such as nanogels and nanocrystals, twice daily administration in the form of tablets seems to improve vision and reduce ME in DR patients. 128-132

So far, many studies have shown that oral curcumin therapy is generally well tolerated in humans, and no side effects have been observed.

This can be explained by considering that the dose of curcumin used in clinical trials is lower than the dose reported in in vitro/in vivo models, and the fact that the substance is generally metabolized extensively in the intestine and liver with low plasma. And tissue curcumin levels. 133

As mentioned earlier, some of the limitations of curcumin use are due to the reduced bioavailability of the molecule and its possible toxicity under certain conditions. For example, in in vitro and in vivo studies, curcumin appears to cause DNA changes when used at a concentration similar to that required to exert its beneficial effects. Therefore, in this regard, some authors emphasize that in the case where the safety of curcumin has not been clearly proven, it is necessary to be more cautious before considering it as safe. 133

Curcumin is a promising treatment for retinal diseases. These benefits are usually seen after a few weeks of treatment, especially in chronic eye diseases such as diabetic retinopathy, macular degeneration, ischemic retinopathy, glaucoma, etc. These effects are mainly due to its properties as antioxidants and antioxidants. Inflammatory molecules, although the exact mechanism of curcumin's beneficial effects on retinal diseases remains unclear. 5

However, as discussed earlier, the main problem that has been only partially solved so far relates to strategies that may be used to increase the bioavailability of the molecule. In this sense, many advances have been made in ophthalmology and other fields: Therefore, in the future, the strategies developed so far to make curcumin reach the target tissues in sufficient concentrations are expected to be improved, and, more than in short, require treatment on the human body. Conduct large-scale in vivo studies to prove the overall safety of these compounds and their effectiveness in different retinopathy and general eye diseases.

Editorial support was funded by Eye Pharma SpA Genova-Italy. The authors report no other conflicts of interest in this work.

1. López-Malo D, Villarón-Casares CA, Alarcón-Jiménez J, etc. Curcumin is used as a treatment option for retinal diseases. Antioxidants. 2020; 9(1):48. doi:10.3390/antiox9010048

2. Rodríguez Castaño P, Parween S, Pandey AV. The biological activity of curcumin on cytochrome P450 enzymes in the steroid production pathway. International J Molecular Science. 2019;20(18):4606. doi:10.3390/ijms20184606.

3. Mirzaee F, Hosseinzadeh L, Ashrafi-Kooshk MR, etc. The different effects of different "protein-based" carriers on the stability and bioavailability of curcumin: Spectral evaluation of in vitro antioxidant activity and cytotoxicity. Protein Pept Lett. 2019;26(2):132–147. doi: 10.2174/0929866525666181114152242.

4. Perrone D, Ardito F, Giannatempo G, etc. Curcumin's biological and therapeutic activities and anti-cancer properties. Exp Ther Med. 2015;10(5):1615–1623. doi:10.3892/etm.2015.2749

5. Pescosolido N, Giannotti R, Plateroti AM, Pascarella A, Nebbioso M. Curcumin: Ophthalmology therapeutic potential. Planta Med. 2014;80(4):249–254. doi:10.1055/s-0033-1351074

6. Deogade S, Ghate S. Curcumın: therapeutic applications in system and oral health. Int J Biol Pharm Res. 2015; 6(4): 281–290.

7. Gupta SC, Kismali G, Aggarwal BB. Curcumin, a component of turmeric: from farm to pharmacy. Biological factors. 2013;39(1):2-13. doi:10.1002/biof.1079

8. Ammon HP, Wahl MA. The pharmacological effects of turmeric. Planta Med. 1991;57(1):1-7. doi:10.1055/s-2006-960004

9. Takahashi M, Ishiko T, Kamohara H, etc. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) works by inhibiting signal transduction through IL-8 receptors Block the chemotaxis of neutrophils. Mediator inflammation. 2007; 2007: 10767. doi:10.1155/2007/10767

10. Lestari ML, Indrayanto G. Curcumin. Profiles Drug Subst Excip Relat Methodol. 2014; 39: 113-204. doi:10.1016/B978-0-12-800173-8.00003-9

11. Mahady GB, Pendland SL, Yun G, Lu ZZ. Turmeric (Curcuma longa) and curcumin can inhibit the growth of class 1 carcinogen Helicobacter pylori. Anticancer Research 2002;22(6C):4179-4181.

12. Reddy DNK, Huang FY, Wang SP, Kumar R. Curcumin-C3 encapsulated chitosan nanoparticles with synergistic antioxidant and antibacterial activities. Curr Pharm Des. 2020;26(39):5021-5029. doi:10.2174/1381612826666200609164830

13. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. The bioavailability of curcumin: problems and promises. Moore Pharmaceuticals. 2007; 4(6): 807-818. doi:10.1021/mp700113r

14. Payton F, Sandusky P, Alworth WL. NMR study on the structure of curcumin solution. J Nat Prod. 2007;70(2):143–146. doi:10.1021/np060263s

15. Radomska-Leśniewska DM, Osiecka-Iwan A, Hyc A, Góźdź A, Dąbrowska AM, Skopiński P. The therapeutic potential of curcumin in eye diseases. Cent Eur J Immunol. 2019;44(2):181–189. doi:10.5114/ceji.2019.87070

16. Srinivas C, Prabhakaran KV. Haridra (turmeric) and its effect on abhisayanda (conjunctivitis). Anc scientific life. 1989;8(3-4):279-282.

17. Awasthi S, Srivatava SK, Piper JT, Singhal SS, Chaubey M, Awasthi YC. Curcumin can prevent the formation of cataracts induced by 4-hydroxy-2-trans-nonenal in the lens of rats. This is J Clin Nutr. 1996;64(5):761–766. doi:10.1093/ajcn/64.5.761.

18. Lal B, Kapoor AK, Asthana OP, etc. Curcumin's efficacy in the treatment of chronic anterior uveitis. Phytother Res. 1999;13(4):318-322. doi:10.1002/(SICI)1099-1573(199906)13:4<318:AID-PTR445>3.0.CO;2-7

19. Wang LL, Sun Y, Huang K, Zheng L. Curcumin, a potential drug candidate for the treatment of retinal diseases. Mol Nutr Food Res. 2013;57(9):1557–1568. doi:10.1002/mnfr.201200718

20. Noorafshan A, Ashkani-Esfahani S. Summary of curcumin treatment effect. Curr Pharm Des. 2013;19(11):2032-2046.

21. Masuda T, Hidaka K, Shinohara A, Maekawa T, Takeda Y, Yamaguchi H. Chemical research on curcumin's antioxidant mechanism: analysis of curcumin free radical reaction products. J Agriculture Food Chemistry. 1999;47(1):71-77. doi:10.1021/jf9805348

22. Wang YJ, Pan MH, Cheng AL, et al. Stability of curcumin in buffer solution and characterization of its degradation products. J Pharm Biomedical Anal. 1997;15(12):1867-1876. doi:10.1016/s0731-7085(96)02024-9

23. Guo Li, Cai Xiaofeng, Li Jianjun, etc. Comparison of the inhibitory effects of demethoxycurcumin and bisdemethoxycurcumin on the expression of inflammatory mediators in vivo and in vitro. Arch Pharm Res. 2008;31(4):490–496. doi:10.1007/s12272-001-1183-8

24. Kocaadam B, Şanlier N. Curcumin, the active ingredient of turmeric (Curcuma longa) and its health effects. Crit Rev Food Sci Nutr. 2017;57(13):2889–2895. doi:10.1080/10408398.2015.1077195

25. Priyadarsini KI. The chemistry of curcumin: from extraction to therapeutic agent. molecular. 2014;19(12):20091–20112. doi:10.3390/molecules191220091

26. Peddada KV, Brown A, Verma V, Nebbioso M. The therapeutic potential of curcumin in major retinopathy. International Ophthalmology. 2019;39(3):725–734. doi:10.1007/s10792-018-0845-y

27. Gupta SK, Kumar B, Nag TC, etc. Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic, antioxidant and anti-inflammatory mechanisms. J Ocul Pharmacol Ther. 2011;27(2):123–130. doi:10.1089/jop.2010.0123

28. Singh S, Aggarwal BB. The activation of transcription factor NF-kappa B is inhibited by curcumin (diferuloylmethane) [corrected]. J Biochemistry. 1995;270(42):24995-25000. doi:10.1074/jbc.270.42.24995

29. Shishodia S, Sethi G, Aggarwal BB. Curcumin: Back to the root cause. Ann NY Acad Sci. 2005;1056:206-217. doi:10.1196/annals.1352.010

30. Devasagayam TP, Sainis KB. Immune system and antioxidants, especially those from Indian medicinal plants. J Exp Biol, India. 2002;40(6):639–655.

31. Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129(2):147–309. doi:10.1111/j.1365-2567.2009.03225.x

32. Aggarwal BB, Harikumar KB. Curcumin (an anti-inflammatory agent) has potential therapeutic effects on neurodegenerative diseases, cardiovascular, lung, metabolism, autoimmune and tumor diseases. Int J Biochem Cell Biol. 2009;41(1):40–59. doi:10.1016/j.biocel.2008.06.010

33. Priyadarsini KI. The free radical reaction of curcumin in a membrane model. Free radical biomedicine. 1997;23(6):838-843. doi:10.1016/s0891-5849(97)00026-9

34. Gorman AA, Hamblett I, Srinivasan VS, Wood PD. Curcumin-derived transients: pulsed laser and pulsed radiolysis studies. Photochemistry and photobiology. 1994;59(4):389-398. doi:10.1111/j.1751-1097.1994.tb05053.x

35. Sugiyama Y, Kawakishi S, Osawa T. The role of β-diketone moieties in the antioxidant mechanism of tetrahydrocurcumin. Biochemical Pharmacology. 1996;52(4):519-525. doi:10.1016/0006-2952(96)00302-4

36. Jovanovic SV, Boone CW, Steenken S, Trinoga M, Kaskey RB. How to use curcumin preferentially with water-soluble antioxidants. J Am Chem Soc. 2001;123(13):3064-3068. doi:10.1021/ja003823x

37. Litwinienko G, Ingold KU. The influence of abnormal solvents on the extraction of hydrogen atoms. 2. Settlement of the anti-oxidant dispute of curcumin. The effect of sequential proton loss and electron transfer. J Histochemistry. 2004;69(18):5888-5896. doi:10.1021/jo049254j

38. Ushio-Fukai M, Alexander RW. Reactive oxygen as a signal mediator of angiogenesis: the role of NAD(P)H oxidase. Moore Cell Biochemistry. 2004;264(1-2):85-97. doi:10.1023/B:MCBI.0000044378.09409.b5

39. Chen WH, Chen Y, Cui GH. Effects of TNF-α and curcumin on VEGF expression in Raji and U937 cells and angiogenesis in ECV304 cells. Chinese Medical Journal 2005;118(24):2052-2057.

40. Millanta F, Citi S, Della Santa D, Porciani M, Poli A. Expression of COX-2 in invasive breast cancer in dogs and cats: correlation with clinicopathological characteristics and prognostic molecular markers. Breast cancer Res treatment. 2006;98(1):115-120. doi:10.1007/s10549-005-9138-z.

41. Yoysungnoen P, Wirachwong P, Changtam C, Suksamrarn A, Patumraj S. The anticancer and antiangiogenic effects of curcumin and tetrahydrocurcumin on transplanted hepatocellular carcinoma in nude mice. World J Gastroenterology. 2008;14(13):2003-2009. doi:10.3748/wjg.14.2003

42. Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: effects on proliferation, apoptosis, signal transduction and angiogenesis in vitro and in vivo. cancer. 2005;104(6):1322–1331. doi:10.1002/cncr.21300

43. Ravindran J, Prasad S, Aggarwal BB. Curcumin and cancer cells: How many methods can curry selectively kill tumor cells? AAPS J. 2009;11(3):495-510. doi:10.1208/s12248-009-9128-x.

44. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. The multiple biological activities of curcumin: a brief review. life sciences. 2006;78(18):2081-2087. doi:10.1016/j.lfs.2005.12.007

45. Devassy JG, Nwachukwu ID, Jones PJ. Curcumin and cancer: barriers to health claims. Nutr Rev. 2015;73(3):155-165. doi:10.1093/nutrit/nuu064

46. ​​Sidhu GS, Singh AK, Thaloor D, etc. Curcumin promotes wound healing in animals. Wound repair and regeneration. 1998; 6(2): 167-177. doi:10.1046/j.1524-475x.1998.60211.x

47. Munia I, Gafray L, Bringer MA, etc. The cytoprotective effect of natural high bioavailability plant derivatives on human retinal cells. Nutrients. 2020;12(3):879. doi:10.3390/nu12030879

48. Lal B, Kapoor AK, Asthana OP, etc. Curcumin's efficacy in the treatment of chronic anterior uveitis. Phytother Res. 1999;13(4):318-322. doi:10.1002/(SICI)1099-1573(199906)13:

49. Allegri P, Mastromarino A, Neri P. Management of recurrence of chronic anterior uveitis: the efficacy of oral phospholipid curcumin therapy. Long-term follow-up clinical ophthalmology. 2010; 4: 1201-1206. doi:10.2147/OPTH.S13271.

50. Miserocchi E, Giuffrè C, Cicinelli MV, etc. Oral phospholipid curcumin in juvenile idiopathic arthritis-associated uveitis. Eur J Ophthalmol. 2019: 1120672119892804. doi:10.1177/1120672119892804

51. Mandal MN, Patlolla JM, Zheng L, etc. Curcumin protects retinal cells from cell death induced by light and oxidative stress. Free radical biomedicine. 2009;46(5):672-679. doi:10.1016/j.freeradbiomed.2008.12.006

52. Muangnoi C, Sharif U. The protective effect of curcumin ester prodrug curcumin diethyl disuccinate on H2O2-induced oxidative stress in human retinal pigment epithelial cells: a potential treatment approach for age-related macular degeneration. International J Molecular Science. 2019;20(13):3367. doi:10.3390/ijms20133367

53. Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and new therapies. Diabetes care. 2003;26(9):2653-2664. doi:10.2337/diacare.26.9.2653

54. Cheung N, Wong IY, Wong TY. Ocular anti-VEGF therapy for diabetic retinopathy: an overview of clinical efficacy and evolving applications. Diabetes care. 2014; 37(4): 900–905. doi:10.2337/dc13-1990

55. Kowluru RA, Kanwar M. The effect of curcumin on oxidative stress and inflammation of diabetic retina. Nutrients. 2007;4:8. doi:10.1186/1743-7075-4-8

56. Chiu J, Xu BY, Chen S, Feng B, Chakrabarti S. Oxidative stress-induced upregulation of poly(ADP-ribose) polymerase-dependent ET-1 expression in chronic diabetic complications. Can J Physiol Pharmacol. 2008;86(6):365–372. doi:10.1139/Y08-033

57. Premanand C, Rema M, Sameer MZ, Sujatha M, Balasubramanyam M. The effect of curcumin on the proliferation of human retinal endothelial cells in vitro. Invest in Ophthalmol Vis Sci. 2006;47(5):2179-2184. doi:10.1167/iovs.05-0580

58. Wang C, Nie Hua, Li Ke, et al. Curcumin inhibits the release of HMGB1 and reduces concanavalin A-induced hepatitis in mice. European Journal of Pharmacy. 2012;697(1–3):152–157. doi:10.1016/j.ejphar.2012.09.050

59. Kumar PA, Haseeb A, Suryanarayana P, Ehtesham NZ, Reddy GB. The expression of alphaA- and alphaB-crystallin increased in streptozotocin-induced diabetic rats. Arch Biochem Biophys. 2005;444(2):77–83. doi:10.1016/j.abb.2005.09.021

60. Mrudula T, Suryanarayana P, Srinivas PNBS, Reddy GB. The effect of curcumin on the expression of vascular endothelial growth factor induced by hyperglycemia in the retina of diabetic rats induced by streptozotocin. Biochem Biophys Res Commun. 2007;361(2):528-532. doi:10.1016/j.bbrc.2007.07.059

61. Khimmaktong W, Petpiboolthai H, Sriya P, Anupunpisit V. The effect of curcumin on the restoration and improvement of the characteristics of the choroidal microvascular system in diabetic rats. J Med Assoc Thai. 2014; 97 (Supplement 2): S39-46.

62. Ran Z, Zhang Y, Wen X, Ma J. Curcumin inhibits the inflammatory injury of human retinal pigment epithelial cells induced by high glucose through the ROS PI3K/AKT/mTOR signaling pathway. Mol Med Rep. 2019;19(2):1024–1031. doi:10.3892/mmr.2018.9749

63. Mazzolani F, Togni S. Oral curcumin-phospholipid delivery system for the treatment of central serous chorioretinopathy: a 12-month follow-up study. Clinical ophthalmology. 2013; 7: 939-945. doi:10.2147/OPTH.S45820

64. Ferrara M, Allegrini D, Sorrentino T, etc. Curcumin-based treatment of macular edema of rare etiology: evaluation of efficacy and safety. J Medical food. 2020;23(8):834–840. doi:10.1089/jmf.2019.0241

65. Wang L, Li C, Guo H, Kern TS, Huang K, Zheng L. Curcumin inhibits retinal neuron and vascular degeneration after ischemia-reperfusion injury. Public Science Library One. 2011;6(8):e23194. doi:10.1371/journal.pone.0023194

66. Wang S, Ye Q, Tu J, Zhang M, Ji B. Curcumin prevents hypertension from exacerbating retinal ischemia/reperfusion in a rat stroke model. Clinical trials of hypertension. 2017;39(8):711–717. doi:10.1080/10641963.2017.1313854

67. Ren Yongxin, Ma Jianxin, Zhao Fei, An Jianbo, Geng Yongxin, Liu Li. The effect of curcumin on epidermal growth factor in proliferative vitreoretinopathy. Cell Physiology and Biochemistry. 2018;47(5):2136–2146. doi:10.1159/000491525

68. Khan MI, Kersten FF, Azam M, etc. CLRN1 mutations cause non-syndromic retinitis pigmentosa. ophthalmology. 2011;118(7):1444–1448. doi:10.1016/j.ophtha.2010.10.047

69. Limoli PG, Vingolo EM, Limoli C, Nebbioso M. Antioxidant and biological properties of mesenchymal cells used to treat retinitis pigmentosa. Antioxidants. 2020; 9(10): E983. doi:10.3390/antiox9100983

70. Pagon RA. Retinitis pigmentosa. Survival ophthalmology. 1988;33(3):137-177. doi:10.1016/0039-6257(88)90085-9

71. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations that cause retinitis pigmentosa. Clinical genes. 2013; 84(2): 132–141. doi:10.1111/cge.12203

72. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795-1809. doi:10.1016/S0140-6736(06)69740-7

73. Hamel C. Retinitis Pigmentosa. Orphanet J Rare Dis. 2006;1(1):40. doi:10.1186/1750-1172-1-40

74. Grover S, Fishman GA, Alexander KR, Anderson RJ, Derlacki DJ. Visual impairment in patients with retinitis pigmentosa. ophthalmology. 1996;103(10):1593-1600. doi:10.1016/s0161-6420(96)30458-2

75. McCulloch DL, Marmor MF, Brigell MG, etc. ISCEV standard for full-field clinical electroretinogram (updated in 2015). ophthalmologist. 2015;130(1):1-12. doi:10.1007/s10633-014-9473-7

76. Liu G, Liu X, Li H, Du Q, Wang F. Optical coherence tomography analysis of retina in patients with retinitis pigmentosa. Eye Research 2016;56(3):111–122. doi:10.1159/000445063

77. Smith LE. Bone marrow-derived stem cells preserve cone vision in retinitis pigmentosa. J Clinical Investment. 2004;114(6):755-757. doi:10.1172/JCI22930

78. Dryja TP, Li T. Molecular genetics of retinitis pigmentosa. Hummer gene. 1995; 4: 1739-1743. doi:10.1093/hmg/4.suppl_1.1739

79. Illing ME, Rajan RS, Bence NF, Kopito RR. The rhodopsin mutants associated with autosomal dominant retinitis pigmentosa tend to aggregate and interact with the ubiquitin proteasome system. J Biochemistry. 2002;277:34150-34160. doi:10.1074/jbc.M204955200

80. Saliba RS, Munro PM, Luthert PJ, Cheetham ME. The cell fate of mutant rhodopsin: quality control, degradation and aggregate formation. J Cell Science. 2002;115(Pt 14):2907-2918. doi:10.1242/jcs.115.14.2907

81. Khajavi M, Shiga K, Wiszniewski W, etc. Oral curcumin alleviates the clinical and neuropathological phenotypes of trembler-J mice: a potential treatment for hereditary neuropathy. This is J Hum Genet. 2007;81(3):438-453. doi:10.1086/519926

82. Vasireddy V, Chavali VR, Joseph VT, etc. Curcumin rescues photoreceptor degeneration in P23H rhodopsin mutant transgenic rats. Public Science Library One. 2011;6(6):e21193. doi:10.1371/journal.pone.0021193

83. Jiangmoto Y, Yoshizawa K, Uehara N, etc. Curcumin inhibits N-methyl-N-nitrosourea-induced Sprague-Dawley rat photoreceptor cell apoptosis. in vivo. 2013;27(5):583–590.

84. Scott PA, Kaplan HJ, McCall MA. Prenatal exposure to curcumin protects the rod-shaped photoreceptors in the transgenic Pro23His pig model of retinitis pigmentosa. Transl Vis Sci Technol. 2015;4(5):5. doi:10.1167/tvst.4.5.5

85. Lin TC, Lin YY, Hsu CC, et al. The curcumin method based on nanomedicine improves the ros injury of optimal malnutrition-specific induced pluripotent stem cells. Cell transplantation. 2019;28(11):1345–1357. doi:10.1177/0963689719860130

86. Li Y, Sun W, Han N, Zou Y, Yin D. Curcumin inhibits the proliferation, migration, invasion and promotes apoptosis of retinoblastoma cell lines by regulating miR-99a and JAK/STAT pathways. BMC cancer. 2018;18(1):1230. doi:10.1186/s12885-018-5130-y

87. Bar-Sela G, Epelbaum R, Schaffer M. Curcumin as an anticancer agent: an overview of the gap between basic and clinical applications. Curr Med Chem. 2010;17(3):190-197. doi:10.2174/092986710790149738

88. Sharma RA, butler WP, Gescher AJ. The pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol. 2007;595:453-470. doi:10.1007/978-0-387-46401-5_20

89. Wahlström B, Blennow G. The fate of curcumin in rats. Acta Pharmacol Toxicol. 1978;43(2):86-92. doi:10.1111/j.1600-0773.1978.tb02240.x

90. Yang KY, Lin LC, Tseng TY, Wang SC, Tsai TH. Oral bioavailability of curcumin in rats and LC-MS/MS analysis of turmeric Chinese herbal medicine. J Chromatogr B Analytical technology biomedical life sciences. 2007;853(1–2):183–189. doi:10.1016/j.jchromb.2007.03.010

91. Noureddin SA, El-Shishtawy RM, Al-Footy KO. Curcumin analogs and their hybrid molecules act as multifunctional drugs. Eur J Med Chem. 2019;182:111631. doi:10.1016/j.ejmech.2019.111631

92. Wang Jie, Xiong Tao, Zhou Jie, etc. Enzymatic formation of curcumin in vitro and in vivo. Nano Resources 2018; 11: 3453–3461. doi:10.1007/s12274-018-1994-z

93. Chen Y, Lu Y, Lee RJ, Xiang G. Nano-encapsulated curcumin: its potential for biomedical applications. International J Nanomedicine. 2020; 15: 3099-3120. doi:10.2147/IJN.S210320

94. Wang Li, Wang C, Tao Zi, etc. Curcumin derivative WZ35 inhibits tumor cell growth in breast cancer through the ROS-YAP-JNK signaling pathway. J Exp Clinical Cancer Research. 2019;38(1):460. doi:10.1186/s13046-019-1424-4

95. Ohori H, Yamakoshi H, Tomizawa M, etc. Synthesis and biological analysis of novel curcumin analogs with enhanced cancer drug therapeutic potential. Moore cancer treatment. 2006;5(10):2563–2571. doi:10.1158/1535-7163.MCT-06-0174

96. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. The effect of piperine on the pharmacokinetics of curcumin in animal and human volunteers. Planta Med. 1998;64(4):353-356. doi:10.1055/s-2006-957450

97. Li M, Xin M, Guo C, Lin G, Wu X. New nanomicelle curcumin preparations for ocular administration: improved stability, solubility and ocular anti-inflammatory treatment. Drug Dev Ind Pharm. 2017;43(11):1846-1857. doi:10.1080/03639045.2017.1349787

98. Barenholz Y. Doxil®-the first FDA-approved nanomedicine: lessons learned. J Control release. 2012;160(2):117–134. doi:10.1016/j.jconrel.2012.03.020

99. Zhang W, Ma W, Zhang J, Song X, Sun W, Fan Y. The immunomodulatory activity of astragalus polysaccharide liposomes on macrophages and dendritic cells. Int J Biol Macromol. 2017; 105 (Part 1): 852–861. doi:10.1016/j.ijbiomac.2017.07.108

100. Sadeghi R, Razzaghdoust A, Bakhshandeh M, Nasirinezhad F, Mofid B. Nano-curcumin as a radioprotectant can prevent the death of mice caused by radiation. Nanomed J. 2019;6(1):43-49.

101. Shi HS, Gao Xiang, Li D, et al. Systemic administration of liposomal curcumin can inhibit radiation pneumonitis and make lung cancer sensitive to radiation. International J Nanomedicine. 2012; 7: 2601-2611. doi:10.2147/IJN.S31439

102. Cabral H, Kataoka K. Progress of drug-loaded polymer micelles into clinical research. J Control release. 2014; 190: 465-476. doi:10.1016/j.jconrel.2014.06.042

103. Kheiri Manjili H, Ghasemi P, Malvandi H, Mousavi MS, Attari E, Danafar H. Pharmacokinetics and in vivo delivery of curcumin by copolymerization of mPEG-PCL micelles. Eur J Pharm Biopharm. 2017; 116: 17-30. doi:10.1016/j.ejpb.2016.10.003

104. Phan QT, Le MH, Le TT, Tran TH, Xuan PN, Ha PT. Characteristics and cytotoxicity of folic acid modified curcumin loaded PLA-PEG micellar nanosystems with different PLA:PEG ratios. Int J Pharm. 2016;507(1–2):32–40. doi:10.1016/j.ijpharm.2016.05.003

105. Liu Li, Sun Li, Wu Qi, etc. Curcumin polymer micelles inhibit breast tumor growth and spontaneous lung metastasis. Int J Pharm. 2013;443(1–2):175–182. doi:10.1016/j.ijpharm.2012.12.032

106. Song Zu, Feng Rui, Sun Ming, etc. Curcumin-loaded PLGA-PEG-PLGA triblock copolymer micelles: preparation, pharmacokinetics and distribution in vivo. J Colloid Interface Science. 2011;354(1):116-123. doi:10.1016/j.jcis.2010.10.024

107. Alshamrani M, Sikder S, Coulibaly F, Mandal A, Pal D, Mitra AK. The self-assembled local nanomicelle formula can improve the absorption of curcumin in eye tissues. AAPS Pharmaceutical Technology. 2019;20(7):254. doi:10.1208/s12249-019-1404-1

108. Davis BM, Pahlitzsch M, Guo L, etc. The topical curcumin nanocarrier has a neuroprotective effect on eye diseases. Scientific Reports 2018;8(1):11066. doi:10.1038/s41598-018-29393-8

109. Duan Y, Cai X, Du H, Zhai G. A new in-situ gel system based on P123/TPGS mixed micelles and gellan gum for ocular delivery of curcumin. Colloidal surfing B Biological interface. 2015; 128: 322-330. doi:10.1016/j.colsurfb.2015.02.007

110. Zeighamian V, Darabi M, Akbarzadeh A, etc. PNIPAAm-MAA nanoparticles act as a delivery vehicle for curcumin against MCF-7 breast cancer cells. Artif Cell Nanomedicine Biotechnology. 2016;44(2):735–742. doi:10.3109/21691401.2014.982803

111. Lim KJ, Bisht S, Bar EE, Maitra A, Eberhart CG. The polymer nanoparticle preparation of curcumin can inhibit the growth, colony formation and stem-like parts of malignant brain tumors. Cancer biotherapy. 2011;11(5):464–473. doi:10.4161/cbt.11.5.14410

112. Xie Xia, Tao Q, Zou Ying, et al. PLGA nanoparticles increase the oral bioavailability of curcumin in rats: characteristics and mechanisms. J Agriculture Food Chemistry. 2011;59(17):9280–928​​9. doi:10.1021/jf202135j

113. Lou J, Hu W, Tian R, et al. Optimization and evaluation of thermosensitive ophthalmic in-situ gel containing curcumin albumin nanoparticles. International J Nanomedicine. 2014; 9: 2517-2525. doi:10.2147/IJN.S60270

114. Li Z, Barnes JC, Bosoy A, Stoddart JF, Zink JI. The application of mesoporous silica nanoparticles in biomedical applications. Chem Soc Rev. 2012;41(7):2590-2605. doi:10.1039/c1cs15246g

115. Trewyn BG, Giri S, Slowing II, Lin VS. Controlled release, drug delivery and biosensor system based on mesoporous silica nanoparticles. Chem Commun (Camb). 2007;1(31):3236-3245. doi:10.1039/b701744h

116. Wu SH, Mu Qing, Lin HP. Synthesis of mesoporous silica nanoparticles. Chem Soc Rev. 2013;42(9):3862-3875. doi:10.1039/c3cs35405a

117. Sun X, Wang N, Yang LY, Ouyang XK, Huang F. Folic acid and PEI modified mesoporous silica are used for targeted delivery of curcumin. pharmaceutics. 2019;11(9):430. doi:10.3390/pharmaceutics11090430

118. Ahmadi Nasab N, Hassani Kumleh H, Beygzadeh M, Teimourian S, Kazemzad M. Delivery of curcumin through pH-responsive chitosan mesoporous silica nanoparticles for cancer treatment. Artif Cell Nanomedicine Biotechnology. 2018;46(1):75–81. doi:10.1080/21691401.2017.1290648

119. Kotcherlakota R, Barui AK, Prashar S, etc. Curcumin loaded mesoporous silica: an effective drug delivery system for cancer treatment. Biomaterials Science. 2016; 4(3): 448–459. doi:10.1039/c5bm00552c

120. Park JH, Shin EY, Shin ME, etc. Enhancing retinal pigment epithelium (RPE) regeneration using curcumin/alginate hydrogel: an in vitro evaluation. Int J Biol Macromol. 2018; 117: 546-552. doi:10.1016/j.ijbiomac.2018.05.127

121. Huang Y, Hu L, Huang S, et al. Galactosylated BSA nanoparticles loaded with curcumin are used as targeted drug delivery vehicles to inhibit the proliferation and migration of hepatocellular carcinoma cells. International J Nanomedicine. 2018; 13: 8309–8323. doi:10.2147/IJN.S184379

122. Song Z, Lu Y, Zhang X, Wang H, Han J, Dong C. Novel curcumin human serum albumin nanoparticles functionalized with folic acid on the surface: characterization and in vitro/in vivo evaluation. The drug Devel Ther. 2016; 10: 2643-2649. doi:10.2147/DDDT.S112039

123. Li C, Luo T, Zheng Z, Murphy AR, Wang X, Kaplan DL. Curcumin functionalized silk material is used to enhance the adipogenic differentiation of bone marrow-derived human mesenchymal stem cells. Journal of Biomaterials. 2015; 11:222-232. doi:10.1016/j.actbio.2014.08.009

124. Wang P, Zhang L, Peng H, Li Y, Xiong J, Xu Z. The preparation and delivery of curcumin and solid lipid nanoparticles treat non-small cell lung cancer in vitro and in vivo. Mater Sci Eng C Mater Biol Appl. 2013;33(8):4802–4808. doi:10.1016/j.msec.2013.07.047

125. Yallapu MM, Jaggi M, Chauhan SC. β-cyclodextrin-curcumin self-assembly enhances the delivery of curcumin in prostate cancer cells. Colloidal surfing B Biological interface. 2010;79(1):113-125. doi:10.1016/j.colsurfb.2010.03.039

126. Chaniyilparampu RN, Nair AK, Parthasarathy K, etc. Application of curcumin and its metabolites in allergic eye/nasal diseases. International publication number. 2010; 25: WO2010109482A2.

127. Zhang J, Sun H, Zhou N, Zhang B, Ma J. Preparation and evaluation of biodegradable scleral plugs containing curcumin in rabbit eyes. Curr Eye Res. 2017;42(12):1597–1603. doi:10.1080/02713683.2016.1242753

128. Steigerwalt R, Nebbioso M, Appendino G, etc. Meriva®, a lecithin-based curcumin delivery system for the treatment of diabetic microangiopathy and retinopathy. Panminerva Med. 2012; 54 (1 Supplement 4): 11-16.

129. Madhusudana Rao K, Krishna Rao KS, Ramanjaneyulu G, Ha CS. Curcumin-encapsulated pH-sensitive gelatin-based interpenetrating polymer network nanogels are used for anticancer drug delivery. Int J Pharm. 2015;478(2):788-795. doi:10.1016/j.ijpharm.2014.12.001

130. Wei X, Senanayake TH, Bohling A, Vinogradov SV. Targeted nanogel conjugate for improving curcumin stability and cell permeability: synthesis, pharmacokinetics and tumor growth inhibition. Moore Pharmaceuticals. 2014; 11(9): 3112-3122. doi:10.1021/mp500290f

131. Mangalathillam S, Rejinold NS, Nair A, Lakshmanan VK, Nair SV, Jayakumar R. Curcumin is loaded with chitin nanogel to treat skin cancer through transdermal route. nanoscale. 2012; 4(1): 239-250. doi:10.1039/c1nr11271f

132. Ji P, Wang L, Chen Y, Wang S, Wu Z, Qi X. Hyaluronic acid hydrophilic surface repair curcumin nanocrystals are used for targeted breast cancer treatment with prolonged biodistribution. Biomaterials Science. 2020; 8(1): 462–472. doi:10.1039/c9bm01605h

133. Burgos-Morón E, Calderón-Montaño JM, Salvador J, Robles A, López-Lázaro M. The dark side of curcumin. International J Cancer. 2010;126(7):1771–1775. doi:10.1002/ijc.24967

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and include the Creative Commons Attribution-Non-commercial (unported, v3.0) license. By accessing the work, you hereby accept the terms. The use of the work for non-commercial purposes is permitted without any further permission from Dove Medical Press Limited, provided that the work has an appropriate attribution. For permission to use this work for commercial purposes, please refer to paragraphs 4.2 and 5 of our terms.

Contact Us• Privacy Policy• Associations and Partners• Testimonials• Terms and Conditions• Recommend this site• Top

Contact Us• Privacy Policy

© Copyright 2021 • Dove Press Ltd • Software development of maffey.com • Web design of Adhesion

The views expressed in all articles published here are those of specific authors and do not necessarily reflect the views of Dove Medical Press Ltd or any of its employees.

Dove Medical Press is part of Taylor & Francis Group, the academic publishing department of Informa PLC. Copyright 2017 Informa PLC. all rights reserved. This website is owned and operated by Informa PLC ("Informa"), and its registered office address is 5 Howick Place, London SW1P 1WG. Registered in England and Wales. Number 3099067. UK VAT group: GB 365 4626 36

In order to provide our website visitors and registered users with services that suit their personal preferences, we use cookies to analyze visitor traffic and personalize content. You can understand our use of cookies by reading our privacy policy. We also retain data about visitors and registered users for internal purposes and to share information with our business partners. By reading our privacy policy, you can understand what data we retain, how we process it, who we share it with, and your right to delete data.

If you agree to our use of cookies and the content of our privacy policy, please click "Accept".