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An Evaluation of Curcumin-Encapsulated Chitosan Nanoparticles for Transdermal Delivery

Nair RS, Morris A, Billa N, Leong CO

AAPS PharmSciTech, 2019 Jan 10;20(2):69.
PMID: 30631984 DOI: 10.1208/s12249-018-1279-6

Curcumin-loaded chitosan nanoparticles were synthesised and evaluated in vitro for enhanced transdermal delivery. Zetasizer® characterisation of three different formulations of curcumin nanoparticles (Cu-NPs) showed the size ranged from 167.3 ± 3.8 nm to 251.5 ± 5.8 nm, the polydispersity index (PDI) values were between 0.26 and 0.46 and the zeta potential values were positive (+ 18.1 to + 20.2 mV). Scanning electron microscopy (SEM) images supported this size data and confirmed the spherical shape of the nanoparticles. All the formulations showed excellent entrapment efficiency above 80%. FTIR results demonstrate the interaction between chitosan and sodium tripolyphosphate (TPP) and confirm the presence of curcumin in the nanoparticle. Differential scanning calorimetry (DSC) studies of Cu-NPs indicate the presence of curcumin in a disordered crystalline or amorphous state, suggesting the interaction between the drug and the polymer. Drug release studies showed an improved drug release at pH 5.0 than in pH 7.4 and followed a zero order kinetics. The in vitro permeation studies through Strat-M® membrane demonstrated an enhanced permeation of Cu-NPs compared to aqueous curcumin solution (p ˂ 0.05) having a flux of 0.54 ± 0.03 μg cm-2 h-1 and 0.44 ± 0.03 μg cm-2 h-1 corresponding to formulations 5:1 and 3:1, respectively. The cytotoxicity assay on human keratinocyte (HaCat) cells showed enhanced percentage cell viability of Cu-NPs compared to curcumin solution. Cu-NPs developed in this study exhibit superior drug release and enhanced transdermal permeation of curcumin and superior percentage cell viability. Further ex vivo and in vivo evaluations will be conducted to support these findings.

Matched MeSH terms: Curcumin/pharmacology
Chemopreventive activity of methanol extract of Melastoma malabathricum leaves in DMBA-induced mouse skin carcinogenesis

Kooi OK, Ling CY, Rodzi R, Othman F, Mohtarrudin N, Suhaili Z, et al.

Afr J Tradit Complement Altern Med, 2014;11(4):66-70.
PMID: 25392583

BACKGROUND: Melastoma malabathricum L. Smith (family Melastomaceae) is a shrub that has been used by the Malay practitioners of traditional medicine to treat various types of ailments. The present study aimed to determine the chemopreventive activity of methanol extract of M. malabathricum leaves (MEMM) using the standard 7,12-dimethylbenz(α)anthracene (DMBA)/croton oil-induced mouse skin carcinogenesis model.
MATERIALS AND METHODS: In the initiation phase, the mice received a single dose of 100µl/100 µg DMBA (group I-V) or 100µl acetone (group VI) topically on the dorsal shaved skin area followed by the promotion phase involving treatment with the respective test solutions (100 µl of acetone, 10 mg/kg curcumin or MEMM (30, 100 and 300mg/kg)) for 30 min followed by the topical application of tumour promoter (100µl croton oil). Tumors were examined weekly and the experiment lasted for 15 weeks.
RESULTS: MEMM and curcumin significantly (p<0.05) reduced the tumour burden, tumour incidence and tumour volume, which were further supported by the histopathological findings.
CONCLUSION: MEMM demonstrated chemoprevention possibly via its antioxidant and anti-inflammatory activities, and the action of flavonoids like quercitrin.

Matched MeSH terms: Curcumin/pharmacology
In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids

Mohd Faudzi SM, Leong SW, Auwal FA, Abas F, Wai LK, Ahmad S, et al.

Arch Pharm (Weinheim), 2021 Jan;354(1):e2000161.
PMID: 32886410 DOI: 10.1002/ardp.202000161

A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan-assay interference compounds-filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti-inflammatory ability via the suppression of nitric oxide (NO) on IFN-γ/LPS-activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single-crystal X-ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti-BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.

Matched MeSH terms: Curcumin/pharmacology*
Enhanced nanocurcumin toxicity against (PC3) tumor and microbial by using magnetic field in vitro

Aldahoun MA, Jaafar MS, Al-Akhras MH, Bououdina M

Artif Cells Nanomed Biotechnol, 2017 Jun;45(4):843-853.
PMID: 27137748 DOI: 10.1080/21691401.2016.1178137

Curcumin is more soluble in ethanol, dimethylsulfoxide, methanol and acetone than in water. In this study, nanocurcumin combined with 8 mT AC static magnetic field was used to enhance cellular uptake, bioavailability, and ultimate efficiency of curcumin against prostate cancer cell line (PC3), four bacteria strains (two Gram positive: Micrococcus luteus ATCC 9341, Staphylococcus aureus ATCC 29213 and two Gram negative: Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), mammalian cell line (HEK) and human erythrocytes (RBC). The efficiency (E%) between IC50 of nanocurcumin combined with magnetic field (NANOCUR-MF) and control against PC3 was 35.93%, which is three times higher compared to curcumin combined with magnetic field (CUR-MF); i.e., 10.77%. However, their E% against HEK was not significant; 1.4% for NANOCUR-MF and 1.95% for CUR-MF. Moreover, depending in minimum bacterial concentration (MBC), the use of MF leads to a reduction of MBCs for all tested bacteria compared with control. The obtained results established the applicability of (MF) in enhancing cellular uptake for PC3 and tested bacteria strains by increasing the penetration of drug (nanocurcumin and parent curcumin) into cell with fixing mild cytotoxic profile for HEK and RBC.

Matched MeSH terms: Curcumin/pharmacology*
Fulltext Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-κB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT)

Razali NA, Nazarudin NA, Lai KS, Abas F, Ahmad S

BMC Complement Altern Med, 2018 Jul 16;18(1):217.
PMID: 30012134 DOI: 10.1186/s12906-018-2223-8

BACKGROUND: Histamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells.
METHODS: Interleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways.
RESULTS: Histamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 ± 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC50) value of 4.91 ± 2.50 μM and median lethal concentration (LC50) value of 28.82 ± 7.56 μM. In gene expression level, we found that MS65 inhibits NF-κB and MAPK pathways through suppression of IKK/IκB/NFκB and c-Raf/MEK/ERK inflammatory cascades.
CONCLUSION: Taken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases.

Matched MeSH terms: Curcumin/pharmacology*
Fulltext Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice

Ming-Tatt L, Khalivulla SI, Akhtar MN, Mohamad AS, Perimal EK, Khalid MH, et al.

Basic Clin Pharmacol Toxicol, 2012 Mar;110(3):275-82.
PMID: 21967232 DOI: 10.1111/j.1742-7843.2011.00804.x

This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID(50) of 0.15 (0.13-0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID(50) of 0.35 (0.27-0.46) mg/kg and 0.07 (0.06-0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID(50) of 0.66 (0.41-1.07) mg/kg and 0.42 (0.38-0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators.

Matched MeSH terms: Curcumin/pharmacology
Fulltext A review on antibacterial, antiviral, and antifungal activity of curcumin

Moghadamtousi SZ, Kadir HA, Hassandarvish P, Tajik H, Abubakar S, Zandi K

Biomed Res Int, 2014;2014:186864.
PMID: 24877064 DOI: 10.1155/2014/186864

Curcuma longa L. (Zingiberaceae family) and its polyphenolic compound curcumin have been subjected to a variety of antimicrobial investigations due to extensive traditional uses and low side effects. Antimicrobial activities for curcumin and rhizome extract of C. longa against different bacteria, viruses, fungi, and parasites have been reported. The promising results for antimicrobial activity of curcumin made it a good candidate to enhance the inhibitory effect of existing antimicrobial agents through synergism. Indeed, different investigations have been done to increase the antimicrobial activity of curcumin, including synthesis of different chemical derivatives to increase its water solubility as well ass cell up take of curcumin. This review aims to summarize previous antimicrobial studies of curcumin towards its application in the future studies as a natural antimicrobial agent.

Matched MeSH terms: Curcumin/pharmacology*
Fulltext Identification of curcumin analogues with anti-seizure potential in vivo using chemical and genetic zebrafish larva seizure models

Choo BKM, Kundap UP, Faudzi SMM, Abas F, Shaikh MF, Samarut É

Biomed Pharmacother, 2021 Oct;142:112035.
PMID: 34411917 DOI: 10.1016/j.biopha.2021.112035

Seizures are the outward manifestation of abnormally excessive or synchronous brain activity. While seizures can be somewhat symptomatically managed with anti-epileptic drugs (AEDs), many patients are still refractory to the currently available AEDs. As a result, there is a need to identify new molecules with anti-seizure properties. Curcumin is the principle curcuminoid of Curcuma longa, or colloquially turmeric, and has been experimentally proven to have anti-convulsive properties, but its poor bioavailability has dampened further therapeutic interest. Hence, this study aimed to ask if structural analogues of curcumin with an adequate bioavailability could have an anti-seizure effect in vivo. To do so, we tested these analogues following a multipronged approach combining the use of several zebrafish seizure models (chemically-induced and genetic) and complementary assays (behavioural and brain activity). Overall, from the 68 analogues tested, we found 15 different derivatives that were able to significantly decrease the behavioural hyperactivity induced by pentylenetetrazol. Of those, only a few showed an effect on the hyperactivity phenotype of two genetic models of brain seizures that are the gabra1 and gabrg2 knockouts. Two analogues, CA 80(1) and CA 74(1), were able to significantly alleviate brain seizures of gabrg2-mutant larvae. As a result, these analogues are good candidates as novel anti-seizure agents.

Matched MeSH terms: Curcumin/pharmacology*
Fulltext Curcumin Attenuates Lead-Induced Cerebellar Toxicity in Rats via Chelating Activity and Inhibition of Oxidative Stress

Abubakar K, Muhammad Mailafiya M, Danmaigoro A, Musa Chiroma S, Abdul Rahim EB, Abu Bakar Zakaria MZ

Biomolecules, 2019 09 06;9(9).
PMID: 31489882 DOI: 10.3390/biom9090453

Lead (Pb) is a toxic, environmental heavy metal that induces serious clinical defects in all organs, with the nervous system being its primary target. Curcumin is the main active constituent of turmeric rhizome (Curcuma longa) with strong antioxidant and anti-inflammatory properties. This study is aimed at evaluating the therapeutic potentials of curcumin on Pb-induced neurotoxicity. Thirty-six male Sprague Dawley rats were randomly assigned into five groups with 12 rats in the control (normal saline) and 6 rats in each of groups, i.e., the lead-treated group (LTG) (50 mg/kg lead acetate for four weeks), recovery group (RC) (50 mg/kg lead acetate for four weeks), treatment group 1 (Cur100) (50 mg/kg lead acetate for four weeks, followed by 100 mg/kg curcumin for four weeks) and treatment group 2 (Cur200) (50 mg/kg lead acetate for four weeks, followed by 200 mg/kg curcumin for four weeks). All experimental groups received oral treatment via orogastric tube on alternate days. Motor function was assessed using a horizontal bar method. The cerebellar concentration of Pb was evaluated using ICP-MS technique. Pb-administered rats showed a significant decrease in motor scores and Superoxide Dismutase (SOD) activity with increased Malondialdehyde (MDA) levels. In addition, a marked increase in cerebellar Pb concentration and alterations in the histological architecture of the cerebellar cortex layers were recorded. However, treatment with curcumin improved the motor score, reduced Pb concentration in the cerebellum, and ameliorated the markers of oxidative stress, as well as restored the histological architecture of the cerebellum. The results of this study suggest that curcumin attenuates Pb-induced neurotoxicity via inhibition of oxidative stress and chelating activity.

Matched MeSH terms: Curcumin/pharmacology*
Pharmacological evaluation and docking studies of α,β-unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A₂, cyclooxygenases, lipoxygenase and proinflammatory cytokines

Bukhari SN, Lauro G, Jantan I, Bifulco G, Amjad MW

Bioorg Med Chem, 2014 Aug 1;22(15):4151-61.
PMID: 24938495 DOI: 10.1016/j.bmc.2014.05.052

Arachidonic acid and its metabolites have generated high level of interest among researchers due to their vital role in inflammation. The inhibition of enzymes involved in arachidonic acid metabolism has been considered as synergistic anti-inflammatory effect. A series of novel α,β-unsaturated carbonyl based compounds were synthesized and evaluated for their inhibitory activity on secretory phospholipase A₂ (sPLA₂), cyclooxygenases (COX), soybean lipoxygenase (LOX) in addition to proinflammatory cytokines comprising IL-6 and TNF-α. Six α,β-unsaturated carbonyl based compounds (2, 3, 4, 12, 13 and 14) exhibited strong inhibition of sPLA₂ activity, with IC₅₀ values in the range of 2.19-8.76 μM. Nine compounds 1-4 and 10-14 displayed inhibition of COX-1 with IC₅₀ values ranging from 0.37 to 1.77 μM (lower than that of reference compound), whereas compounds 2, 10, 13 and 14 strongly inhibited the COX-2. The compounds 10-14 exhibited strong inhibitory activity against LOX enzyme. All compounds were evaluated for the inhibitory activities against LPS-induced TNF-α and IL-6 release in the macrophages. On the basis of screening results, five active compounds 3, 4, 12, 13 and 14 were found strong inhibitors of TNF-α and IL-6 release in a dose-dependent manner. Molecular docking experiments were performed to clarify the molecular aspects of the observed COX and LOX inhibitory activities of the investigated compounds. Present findings increases the possibility that these α,β-unsaturated carbonyl based compounds might serve as beneficial starting point for the design and development of improved anti-inflammatory agents.

Matched MeSH terms: Curcumin/pharmacology
Effects of novel diarylpentanoid analogues of curcumin on secretory phospholipase A2 , cyclooxygenases, lipo-oxygenase, and microsomal prostaglandin E synthase-1

Ahmad W, Kumolosasi E, Jantan I, Bukhari SN, Jasamai M

Chem Biol Drug Des, 2014 Jun;83(6):670-81.
PMID: 24406103 DOI: 10.1111/cbdd.12280

Arachidonic acid and its metabolites have generated a heightened interest due to their significant role in inflammation. Inhibiting the enzymes involved in arachidonic acid metabolism has been considered as the synergistic anti-inflammatory effect. A series of novel curcumin diarylpentanoid analogues were synthesized and evaluated for their inhibitory effects on activity of secretory phospholipase A2 , cyclooxygenases, soybean lipo-oxygenase as well as microsomal prostaglandin E synthase-1. Among the curcumin analogues, compounds 3, 6, 9, 12, and 17 exhibited strong inhibition of secretory phospholipase A2 activity, with IC50 values ranging from 5.89 to 11.02 μm. Seven curcumin analogues 1, 3, 6, 7, 9, 11, and 12 showed inhibition of cyclooxygenases-2 with IC50 values in the range of 46.11 to 94.86 μm, which were lower than that of curcumin. Compounds 3, 6, 7, 12, and 17 showed strong inhibition of lipo-oxygenase enzyme activity. Preliminary screening of diarylpentanoid curcumin analogues for microsomal prostaglandin E synthase-1 activity revealed that four diarylpentanoid curcumin analogues 5, 6, 7, and 13 demonstrated higher inhibition of microsomal prostaglandin E synthase-1 activity with IC50 ranging from 2.41 to 4.48 μm, which was less than that of curcumin. The present results suggest that some of these diarylpentanoid analogues were able to inhibit the activity of these enzymes. This raises the possibility that diarylpentanoid analogues of curcumin might serve as useful starting point for the design of improved anti-inflammatory agents.

Matched MeSH terms: Curcumin/pharmacology*
Natural-derived compounds and their mechanisms in potential autosomal dominant polycystic kidney disease (ADPKD) treatment

Mahendran R, Lim SK, Ong KC, Chua KH, Chai HC

Clin Exp Nephrol, 2021 Nov;25(11):1163-1172.
PMID: 34254206 DOI: 10.1007/s10157-021-02111-x

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic kidney disorder that impairs renal functions progressively leading to kidney failure. The disease affects between 1:400 and 1:1000 ratio of the people worldwide. It is caused by the mutated PKD1 and PKD2 genes which encode for the defective polycystins. Polycystins mimic the receptor protein or protein channel and mediate aberrant cell signaling that causes cystic development in the renal parenchyma. The cystic development is driven by the increased cyclic AMP stimulating fluid secretion and infinite cell growth. In recent years, natural product-derived small molecules or drugs targeting specific signaling pathways have caught attention in the drug discovery discipline. The advantages of natural products over synthetic drugs enthusiast researchers to utilize the medicinal benefits in various diseases including ADPKD.
CONCLUSION: Overall, this review discusses some of the previously studied and reported natural products and their mechanisms of action which may potentially be redirected into ADPKD.

Matched MeSH terms: Curcumin/pharmacology
Cellular uptake and anticancer effects of mucoadhesive curcumin-containing chitosan nanoparticles

Chuah LH, Roberts CJ, Billa N, Abdullah S, Rosli R

Colloids Surf B Biointerfaces, 2014 Apr 1;116:228-36.
PMID: 24486834 DOI: 10.1016/j.colsurfb.2014.01.007

Curcumin, which is derived from turmeric has gained much attention in recent years for its anticancer activities against various cancers. However, due to its poor absorption, rapid metabolism and elimination, curcumin has a very low oral bioavailability. Therefore, we have formulated mucoadhesive nanoparticles to deliver curcumin to the colon, such that prolonged contact between the nanoparticles and the colon leads to a sustained level of curcumin in the colon, improving the anticancer effect of curcumin on colorectal cancer. The current work entails the ex vivo mucoadhesion study of the formulated nanoparticles and the in vitro effect of mucoadhesive interaction between the nanoparticles and colorectal cancer cells. The ex vivo study showed that curcumin-containing chitosan nanoparticles (CUR-CS-NP) have improved mucoadhesion compared to unloaded chitosan nanoparticles (CS-NP), suggesting that curcumin partly contributes to the mucoadhesion process. This may lead to an enhanced anticancer effect of curcumin when formulated in CUR-CS-NP. Our results show that CUR-CS-NP are taken up to a greater extent by colorectal cancer cells, compared to free curcumin. The prolonged contact offered by the mucoadhesion of CUR-CS-NP onto the cells resulted in a greater reduction in percentage cell viability as well as a lower IC50, indicating a potential improved treatment outcome. The formulation and free curcumin appeared to induce cell apoptosis in colorectal cancer cells, by arresting the cell cycle at G2/M phase. The superior anticancer effects exerted by CUR-CS-NP indicated that this could be a potential treatment for colorectal cancer.

Matched MeSH terms: Curcumin/pharmacology*
Quercetin-Decorated Curcumin Liposome Design for Cancer Therapy: In-Vitro and In-Vivo Studies

Ravichandiran V, Masilamani K, Senthilnathan B, Maheshwaran A, Wong TW, Roy P

Curr Drug Deliv, 2017;14(8):1053-1059.
PMID: 27572089 DOI: 10.2174/1567201813666160829100453

BACKGROUND: Curcumin is a yellow polyphenolic chemopreventive agent isolated from the rhizomes of Curcuma longa. It is approved as Generally Regarded as Safe by US FDA. Nonetheless, its clinical success is limited due to its poor aqueous solubility, fast metabolism and short biological half-life attributes.
OBJECTIVE: Quercetin-decorated liposomes of curcumin (QCunp) are perceived to be able to overcome these biopharmaceutical drawbacks.
METHODS: Curcumin liposomes with/without quercetin were prepared by lipid hydration technique. The liposomes were characterized for their particle size, zeta potential, surface morphology, drug loading and release characteristics. The toxicity of the liposomes were evaluated in-vitro and their invivo efficacy were tested against Dalton's ascites lymphoma in mice.
RESULTS: Liposomes designed showed particle size of 261.8 ± 2.1 nm with a negative zeta potential of -22.6±1.6 mV. Quercetin decorated liposomes were more effective in increasing the life span and body weight of lymphoma inflicted mice compared to those without quercetin. Similarly, the presence of quercetin also contributed to enhanced cytotoxicity of the liposomal formulation towards HT-29 cells and HCT-15 cells.
CONCLUSION: Newer liposomal design exhibited promising potential to emerge as alternative anticancer therapeutics.

Matched MeSH terms: Curcumin/pharmacology
Docking Studies of Curcumin and Analogues with Various Phosphodiesterase 4 Subtypes

Yi YX, Gaurav A, Akowuah GA

Curr Drug Discov Technol, 2020;17(2):248-260.
PMID: 30332967 DOI: 10.2174/1570163815666181017091655

INTRODUCTION: The primary aim of this study is to understand the binding of curcumin and its analogues to different PDE4 subtypes and identify the role of PDE4 subtype inhibition in the anti-inflammatory property of curcumin. Docking analysis has been used to acquire the above mentioned structural information and this has been further used for designing of curcumin derivatives with better anti-inflammatory activity.
MATERIALS AND METHODS: Curcumin and its analogues were subjected to docking using PDE4A, PDE4B, PDE4C and PDE4D as the targets. A data set comprising 18 analogues of curcumin, was used as ligands for docking of PDE4 subtypes. Curcumin was used as the standard for comparison. Docking was performed using AutoDock Vina 1.1.2 software integrated in LigandScout 4.1. During this process water molecules were removed from proteins, charges were added and receptor structures were minimised by applying suitable force fields. The docking scores were compared, and the selectivity of compounds for PDE4B over PDE4D was calculated as well.
RESULTS: All curcumin analogues used in the study showed good binding affinity with all PDE4 subtypes, with evident selectivity towards PDE4B subtype. Analogue A11 provides the highest binding affinity among all ligands.
CONCLUSION: Curcumin and analogues have moderate to strong affinity towards all PDE4 subtypes and have evident selectivity towards PDE4B. The Oxygen atom of the methoxy group plays a key role in PDE4B binding and any alterations could interfere with the binding. Tetrahydropyran side chain and heterocyclic rings are also suggested to be helpful in PDE4B binding.

Matched MeSH terms: Curcumin/pharmacology*
Curcumin Sensitizes Cancers Towards TRAIL-induced Apoptosis via Extrinsic and Intrinsic Apoptotic Pathways

Ngai SC

Curr Drug Targets, 2020;21(9):849-854.
PMID: 32116190 DOI: 10.2174/1389450121666200302124426

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a natural protein expressed in a wide range of tissues in our body. It is a promising anti-cancer agent due to its selective killing of cancer cells, rendering normal cells unharmed. However, resistance occurs either intrinsically or develops over the course of TRAIL treatment. In view of its specificity to cancer cells, there is a pushing need to overcome TRAIL resistance. Curcumin (Cur), a natural active constituent of turmeric, has been evidenced to have anti-cancer properties. However, it is limited by its sparing solubility and low bioavailability. Combinational therapy is one of the most frequently used strategies to overcome these limitations, which has been proved to be more effective than monotherapy by achieving synergistic effects and reducing toxicity. This review aims to discuss TRAIL and its underlying apoptotic mechanisms, the combinational treatment of Cur and TRAIL in view of their respective limitations, and the underlying apoptotic mechanisms activated by the sensitization of cancers by Cur towards TRAIL-induced apoptosis. Finally, this review discusses the research gap and the author's insight into this research area in bridging the research gap from bench to bedside.

Matched MeSH terms: Curcumin/pharmacology*
Natural Polyphenols in the Treatment of Alzheimer's Disease

Syarifah-Noratiqah SB, Naina-Mohamed I, Zulfarina MS, Qodriyah HMS

Curr Drug Targets, 2018;19(8):927-937.
PMID: 28356027 DOI: 10.2174/1389450118666170328122527

Neurodegenerative disease is an incurable disease which involves the degeneration or death of the nerve cells. Alzheimer's Disease (AD) is a neurodegenerative disease discovered in 1906 by Alois Alzheimer, a German clinical psychiatrist and neuroanatomist. The main pathological hallmarks of this disease are the formation of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangle (NFT). The accumulation of the amyloid protein aggregates in the brain of AD patients leads to oxidative stress and inflammation. Other postulated reasons for the development of this disease are cholinergic depletion and excessive glutamatergic neurotransmission. The current drugs approved and marketed for the treatment of AD are cholinesterase inhibitors (ChEIs) and N-methyl-Daspartate (NMDA) receptor antagonists. The function of ChEIs is to avoid cholinergic depletion; whereas the function of NMDA receptor antagonist is to block excessive glutamatergic neurotransmission. Unfortunately, the current drugs prescribed for AD show only modest improvement in terms of symptomatic relief and delay the progression of the disease. This review will discuss about several polyphenolic compounds as potential natural treatment options for AD. Three compounds are highlighted in this review - Curcumin (Cur), Resveratrol (Rsv) and Epigallocatechin-3- gallate (EGCG). These compounds have huge potential for AD treatment, especially due to their low frequency of adverse events. However, the current conventional pharmaceutical drugs remain as the mainstay of treatment for AD.

Matched MeSH terms: Curcumin/pharmacology
3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one, a Novel Curcumin Analogue, Inhibits Cellular and Humoral Immune Responses in Male Balb/c Mice

Arshad L, Jantan I, Bukhari SNA, Fauzi MB

Curr Pharm Biotechnol, 2018;19(6):468-482.
PMID: 29968535 DOI: 10.2174/1389201019666180703092723

BACKGROUND: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has previously been shown to manifest potent immunosuppressive effects on the in vitro phagocytosis process of human neutrophils.
OBJECTIVE: In the present study, BBP was investigated for it's in vivo innate and adaptive immune responses mediated by different humoral and cellular immune factors.
METHODS: Male Balb/c mice were orally fed with BBP (5, 10 and 20 mg/kg) for a period of 14 days and immunized with sheep red blood cells (sRBC) on day 0 for the determination of adaptive responses. The effects of BBP on phagocytosis process of neutrophils isolated from blood of treated/untreated animals were determined. The ceruloplasmin and lysozyme serum levels and myeloperoxidase (MPO) plasma level were also monitored. The mechanism was further explored by assessing its effects on the proliferation of T and B lymphocytes, T-lymphocytes subsets CD4+ and CD8+ and on the secretion of Th1/Th2 cytokines as well as serum immunoglobulins (IgG, IgM) and delayed type hypersensitivity (DTH) reaction.
RESULTS: BBP showed a significant dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity and reactive oxygen species (ROS) production. In comparison to the sensitized control group, a dose-dependent inhibition was observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines. Moreover, a statistically significant decrease was perceived in serum levels of ceruloplasmin, lysozyme and immunoglobulins and MPO plasma level of BBP-treated mice. BBP also dose-dependently inhibited sheep red blood cells (sRBC)-induced swelling rate of mice paw in DTH.
CONCLUSION: These findings suggest the potential of BBP as a potent immunosuppressive agent.

Matched MeSH terms: Curcumin/pharmacology
The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis

Chin KY

Drug Des Devel Ther, 2016;10:3029-3042.
PMID: 27703331

Osteoarthritis is a degenerative disease of the joint affecting aging populations worldwide. It has an underlying inflammatory cause, which contributes to the loss of chondrocytes, leading to diminished cartilage layer at the affected joints. Compounds with anti-inflammatory properties are potential treatment agents for osteoarthritis. Curcumin derived from Curcuma species is an anti-inflammatory compound as such. This review aims to summarize the antiosteoarthritic effects of curcumin derived from clinical and preclinical studies. Many clinical trials have been conducted to determine the effectiveness of curcumin in osteoarthritic patients. Extracts of Curcuma species, curcuminoids and enhanced curcumin, were used in these studies. Patients with osteoarthritis showed improvement in pain, physical function, and quality of life after taking curcumin. They also reported reduced concomitant usage of analgesics and side effects during treatment. In vitro studies demonstrated that curcumin could prevent the apoptosis of chondrocytes, suppress the release of proteoglycans and metal metalloproteases and expression of cyclooxygenase, prostaglandin E-2, and inflammatory cytokines in chondrocytes. These were achieved by blocking the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) system in the chondrocytes, by preventing the activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, phosphorylation, and translocation of the p65 subunit of NF-κB complexes into the nucleus. In conclusion, curcumin is a potential candidate for the treatment of osteoarthritis. More well-planned randomized control trials and enhanced curcumin formulation are required to justify the use of curcumin in treating osteoarthritis.

Matched MeSH terms: Curcumin/pharmacology*
Fulltext Enhanced immunosuppressive effects of 3,5-bis[4(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one, an α, β-unsaturated carbonyl-based compound as PLGA-b-PEG nanoparticles

Arshad L, Jantan I, Bukhari SNA

Drug Des Devel Ther, 2019;13:1421-1436.
PMID: 31118577 DOI: 10.2147/DDDT.S185191

Background: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has been revealed to possess strong in vitro and in vivo immunosuppressive effects. Purpose: The aim of present study was to prepare and characterize BBP-encapsulated polylactic-co-glycolic acid-block-polyethylene glycol (PLGA-b-PEG) nanoparticles and to evaluate its in vivo efficacy against innate and adaptive immune responses. Methods: Male BALB/c mice were orally administered with BBP alone and BBP- encapsulated nanoparticles equivalent to 5, 10 and 20 mg/kg of BBP in distilled water for a period of 14 days. The immunomodulatory potential was appraised by determining its effects on non-specific and specific immune parameters. Results: The results showed that BBP was successfully encapsulated in PLGA-b-PEG polymer with 154.3 nm size and high encapsulation efficiency (79%) while providing a sustained release for 48 hours. BBP nanoparticles showed significant enhanced dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity, reactive oxygen species (ROS) production, serum levels of ceruloplasmin and lysozyme, immunoglobulins and myloperoxidase (MPO) plasma levels when compared to unencapsulated BBP. Enhanced dose-dependent inhibition was also observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines, and reduction in rat paw oedema in BBP nanoparticles treated mice. At higher doses the suppressive effects of the BBP nanoparticles on various cellular and humoral parameters of immune responses were comparable to that of cyclosporine-A at 20 mg/kg. Conclusion: These findings suggest that the immunosuppressive effects of BBP were enhanced as PLGA-b-PEG nanoparticles.

Matched MeSH terms: Curcumin/pharmacology

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