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Parida S, Jena M, Behera AK, Mandal AK, Nayak R, Patra S. A Novel Phytocolorant, Neoxanthin, as a Potent Chemopreventive: Current Progress and Future Prospects. Curr Med Chem 2024; 31:5149-5164. [PMID: 38173069 DOI: 10.2174/0109298673273106231208102105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/18/2023] [Accepted: 11/10/2023] [Indexed: 01/05/2024]
Abstract
Cancer is a general term for a group of similar diseases. It is a combined process that results from an accumulation of abnormalities at different biological levels, which involves changes at both genetic and biochemical levels in the cells. Several modifiable risk factors for each type of cancer include heredity, age, and institutional screening guidelines, including colonoscopy, mammograms, prostate-specific antigen testing, etc., which an individual cannot modify. Although a wide range of resources is available for cancer drugs and developmental studies, the cases are supposed to increase by about 70% in the next two decades due to environmental factors commonly driven by the way of living. The drugs used in cancer prevention are not entirely safe, have potential side effects and are generally unsuitable owing to substantial monetary costs. Interventions during the initiation and progression of cancer can prevent, diminish, or stop the transformation of healthy cells on the way to malignancy. Diet modifications are one of the most promising lifestyle changes that can decrease the threat of cancer development by nearly 40%. Neoxanthin is a xanthophyll pigment found in many microalgae and macroalgae, having significant anti-cancer, antioxidant and chemo-preventive activity. In this review, we have focused on the anti-cancer activity of neoxanthin on different cell lines and its cancer-preventive activity concerning obesity and oxidative stress. In addition to this, the preclinical studies and future perspectives are also discussed in this review.
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Affiliation(s)
- Sudhamayee Parida
- Algal Biotechnology and Molecular Systematics Laboratory, Post Graduate Department of Botany, Berhampur University, Berhampur, 760007, India
| | - Mrutyunjay Jena
- Algal Biotechnology and Molecular Systematics Laboratory, Post Graduate Department of Botany, Berhampur University, Berhampur, 760007, India
| | - Akshaya Kumar Behera
- Algal Biotechnology and Molecular Systematics Laboratory, Post Graduate Department of Botany, Berhampur University, Berhampur, 760007, India
| | - Amiya Kumar Mandal
- Algal Biotechnology and Molecular Systematics Laboratory, Post Graduate Department of Botany, Berhampur University, Berhampur, 760007, India
| | - Rabindra Nayak
- Algal Biotechnology and Molecular Systematics Laboratory, Post Graduate Department of Botany, Berhampur University, Berhampur, 760007, India
| | - Srimanta Patra
- Department of Life Science, NIT Rourkela, Rourkela, India
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Gopinatha Pillai MS, Aiswarya SU, Keerthana CK, Rayginia TP, Anto RJ. Targeting receptor tyrosine kinase signaling: Avenues in the management of cutaneous squamous cell carcinoma. iScience 2023; 26:106816. [PMID: 37235052 PMCID: PMC10206193 DOI: 10.1016/j.isci.2023.106816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023] Open
Abstract
Non-melanoma skin cancer (NMSC) is the most frequently diagnosed cancer worldwide. Among the various types of NMSCs, cutaneous squamous cell carcinoma (cSCC) exhibits more aggressive phenotype and is also the second-most prevalent type. Receptor tyrosine kinases (RTK) triggers key signaling events that play critical roles in the development of various cancers including cSCC. Unsurprisingly, for this reason, this family of proteins has become the cynosure of anti-cancer drug discovery pipelines and is also being considered as attractive targets against cSCC. Though inhibition of RTKs in cSCC has yielded favourable results, there is still scope for bettering the therapeutic outcome. In this review, we discuss the relevance of RTK signaling in the progression of cutaneous squamous cell carcinoma, and observations from clinical trials that used RTK inhibitors against cSCC. Backed by results from preclinical studies, including those from our lab, we also give insights into the scope of using some natural products as effective suppressors of RTK signaling and skin carcinogenesis.
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Affiliation(s)
| | - Sreekumar U. Aiswarya
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Chenicheri K. Keerthana
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Tennyson P. Rayginia
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
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Elmowafy M, Shalaby K, Elkomy MH, Awad Alsaidan O, Gomaa HAM, Abdelgawad MA, Massoud D, Salama A, El-Say KM. Development and assessment of phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery. Int J Pharm 2022; 629:122375. [PMID: 36351506 DOI: 10.1016/j.ijpharm.2022.122375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/08/2022]
Abstract
Luteolin is an excellent flavone possessing several beneficial properties such as antioxidant and anti-inflammatory effects which are interesting for skin delivery. Development of an appropriate skin delivery system could be a promising strategy to improve luteolin cutaneous performance.So, the main aim of this work was to fabricate, characterize and evaluate phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery. The influence of phospholipid/oil ratio, surfactant type and chitosan coating were investigated. The prepared formulations underwent in vitro assessment and the selected formulations were evaluated ex vivo and in vivo. The mean diameters of investigated formulations varied between 174 nm and 628 nm while zeta potential varied between -25.7 ± 4.8 mV and 6.8 ± 1.7 mV. Increasing in phospholipid/oil ratios resulted in decrease in particles size with little effect on zeta potential and drug encapsulation. Cremophor EL showed the lowest particle sizes and the highest drug encapsulation. Chitosan coating shifted zeta potential towards positive values. Structural analyses showed that luteolin is incorporated into lipid core of nanocapsules. Selected formulations (LNC4 and LNC13) exhibited sustained in vitro release and antioxidant activity. LNC13 (chitosan coated) showed higher flux (0.457 ± 0.113 µg/cm2/h), permeability (45.70 ± 11.66 *10-5 cm2/h) and skin retention (121.66 ± 7.6 µg/cm2 after 24 h) when compared to LNC4 and suspension. It also showed disordered the integrity of the stratum corneum, increased epidermal thickness and relieving most of inflammatory features in animal model. In conclusion, this study proves that lipid nanocapsules could effectively deliver luteolin into skin and then can be established as a potential system in the pharmaceutical and cosmeceutical horizons.
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Affiliation(s)
- Mohammed Elmowafy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia.
| | - Khaled Shalaby
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Mohammed H Elkomy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Omar Awad Alsaidan
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Hesham A M Gomaa
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Mohamed A Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Diaa Massoud
- Department of Biology, College of Science, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Ayman Salama
- Department of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Khalid M El-Say
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Corrêa JGDS, Bianchin M, Lopes AP, Silva E, Ames FQ, Pomini AM, Carpes ST, de Carvalho Rinaldi J, Cabral Melo R, Kioshima ES, Bersani-Amado CA, Pilau EJ, de Carvalho JE, Ruiz ALTG, Visentainer JV, Santin SMDO. Chemical profile, antioxidant and anti-inflammatory properties of Miconia albicans (Sw.) Triana (Melastomataceae) fruits extract. JOURNAL OF ETHNOPHARMACOLOGY 2021; 273:113979. [PMID: 33647428 DOI: 10.1016/j.jep.2021.113979] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/10/2021] [Accepted: 02/22/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Miconia albicans (Sw.) Triana has been widely used in Brazilian popular medicine for the treatment of several diseases. Aerial parts are used as an infusion to treat arthrosis and arthritis, to relieve rheumatic and stomach pains, and intestinal disorders due to its anti-inflammatory, anti-mutagenic anti-nociceptive, digestive and hepatoprotective properties. AIM OF THE STUDY This study aimed to characterize the of M. albicans (Sw.) Triana fruits extract (MAFRE) chemical profile and to evaluate its antioxidant, anti-inflammatory and antitumor activities, as well as its toxicity. MATERIALS AND METHODS Maceration with methanol as liquid extractor was used to prepare MAFRE. M. albicans (Sw.) Triana fruits chemical composition was characterized by UHPLC-QTOF-MS/MS and GC-FID (fatty acid methyl esters composition from lyophilized fruits). MAFRE antioxidant potential was evaluated in vitro using a combination of assays: Folin-Ciocalteu reducing capacity, DPPH• and ABTS radical scavenging ability and ferric reducing antioxidant power (FRAP). In vitro antiproliferative activity was investigated in four human tumor cell lines (U251, 786-0, HT29 and MDA-MB-231) while the effect on the non-tumor cell viability was assessed in the VERO cell line using the on-step MTT assay. In addition, in vivo anti-inflammatory effect was assessed by Croton oil-induced ear edema in mice followed by myeloperoxidase (MPO) activity evaluation. RESULTS Thirty-five compounds were identified by UHPLC-QTOF-MS/MS. Among it flavonoids derived from quercetin (8), myricetin (1), kaempferol (2), terpenoids (6) and other compounds (18). GC-FID analysis identified and quantified nine fatty acids: palmitic, stearic, arachidic, behenic, elaidic, oleic, eicosenoic, and linoleic acids. The most abundant fatty acids were polyunsaturated fatty acids (5.33 ± 0.17 mg g-1), followed by saturated fatty acids (2.38 ± 0.07 mg g-1) and monounsaturated fatty acids (1.74 ± 0.09 mg g-1). The extract revealed high content of phenolic compounds (43.68 ± 0.50 mg GAE/g of extract), potent antioxidant, and ferrous chelating capacities. Morever, it proved to be non-toxic to the VERO cells, not affecting cells viability (95% of viable cells). No antiproliferative effect against human tumor cell lines were found. Furthermore, MAFRE significantly (p<0.05) reduced ear edema (≈35%) and MPO activity (84.5%) having a statistical effect similar to traditional steroidal and non-steroidal anti-inflammatory drugs. CONCLUSIONS Taken together, the results evidenced that M. albicans fruit extract has antioxidant properties, a higher concentration of phenolic compounds, flavonoids, fatty acids, and also topical anti-inflammatory activity with low toxicity of extract on VERO cells. Through the ethnomedicinal study, these findings supporting the popular use of M. albicans, but also highlight that not only aerial parts and leaves deserve attention, but the fruits also have anti-inflammatory proprieties and can be a source of phenolic compounds and other substances with potential health benefices.
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Affiliation(s)
| | - Mirelli Bianchin
- Department of Chemistry, State University of Maringá, Paraná, Brazil
| | - Ana Paula Lopes
- Department of Chemistry, State University of Maringá, Paraná, Brazil
| | - Evandro Silva
- Department of Chemistry, State University of Maringá, Paraná, Brazil
| | - Franciele Q Ames
- Department of Pharmacology Applied to Therapeutics, State University of Maringá, Paraná, Brazil
| | - Armando M Pomini
- Department of Chemistry, State University of Maringá, Paraná, Brazil
| | - Solange T Carpes
- Department of Chemistry, Federal Technological University of Paraná, Pato Branco, PR, Brazil
| | | | - Raquel Cabral Melo
- Postgraduate Program in Biosciences and Pathophysiology, State University of Maringá, Paraná, Brazil
| | - Erika S Kioshima
- Postgraduate Program in Biosciences and Pathophysiology, State University of Maringá, Paraná, Brazil
| | - Ciomar A Bersani-Amado
- Department of Pharmacology Applied to Therapeutics, State University of Maringá, Paraná, Brazil
| | - Eduardo J Pilau
- Department of Chemistry, State University of Maringá, Paraná, Brazil
| | | | - Ana Lúcia T G Ruiz
- Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, São Paulo, Brazil
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Lima EP, Gonçalves OH, Ames FQ, Castro-Hoshino LV, Leimann FV, Cuman RKN, Comar JF, Bersani-Amado CA. Anti-inflammatory and Antioxidant Activity of Nanoencapsulated Curcuminoids Extracted from Curcuma longa L. in a Model of Cutaneous Inflammation. Inflammation 2020; 44:604-616. [PMID: 33164160 DOI: 10.1007/s10753-020-01360-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 08/14/2020] [Accepted: 10/05/2020] [Indexed: 12/01/2022]
Abstract
The present study evaluated the anti-inflammatory effect of nanoencapsulated curcuminoid preparations of poly(vinyl pyrrolidone) (Nano-cur) and free curcuminoids (Cur) in an experimental model of croton oil-induced cutaneous inflammation. Male Swiss mice, weighing 25-30 g, received oral treatment by gavage 1 h before CO application or topical treatment immediately after CO application (200 μg diluted in 70% acetone) with a single dose of Cur and Nano-cur. After 6 h, the animals were anesthetized and euthanized. The ears were sectioned into disks (6.0 mm diameter) and used to determine edema, myeloperoxidase (MPO) activity, and oxidative stress. Photoacoustic spectroscopy (PAS) was used to evaluate the percutaneous penetration of Cur and Nano-cur. Topical treatment with both preparations had a similar inhibitory effect on the development of edema, MPO activity, and the oxidative response. The PAS technique showed that the percutaneous permeation of both topically applied preparations was similar. Oral Nano-cur administration exerted a higher anti-inflammatory effect than Cur. Topical Cur and Nano-cur application at the same dose similarly inhibited the inflammatory and oxidative responses. Oral Nano-cur administration inhibited such responses at doses that were eight times lower than Cur, suggesting the better bioavailability of Nano-cur compared with Cur.Graphical abstract.
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Affiliation(s)
- Emanuele P Lima
- Department of Pharmacology and Therapeutic, State University of Maringá (UEM), Avenue Colombo, 5790, Maringa, PR, 87020-900, Brazil
| | - Odinei H Gonçalves
- Post-Graduation Program of Food Technology (PPGTA), Federal University of Technology - Paraná (UTFPR), P O Box 271, BR 369, km 0.5, Campo Mourão, PR, 87301-006, Brazil
| | - Franciele Q Ames
- Department of Pharmacology and Therapeutic, State University of Maringá (UEM), Avenue Colombo, 5790, Maringa, PR, 87020-900, Brazil
| | - Lidiane V Castro-Hoshino
- Department of Physics, State University of Maringá (UEM), Avenue Colombo, 5790, Maringa, PR, 87020-900, Brazil
| | - Fernanda V Leimann
- Post-Graduation Program of Food Technology (PPGTA), Federal University of Technology - Paraná (UTFPR), P O Box 271, BR 369, km 0.5, Campo Mourão, PR, 87301-006, Brazil
| | - Roberto K N Cuman
- Department of Pharmacology and Therapeutic, State University of Maringá (UEM), Avenue Colombo, 5790, Maringa, PR, 87020-900, Brazil
| | - Jurandir F Comar
- Department of Biochemistry, State University of Maringá (UEM), Avenue Colombo, 5790, Maringa, PR, 87020-900, Brazil
| | - Ciomar A Bersani-Amado
- Department of Pharmacology and Therapeutic, State University of Maringá (UEM), Avenue Colombo, 5790, Maringa, PR, 87020-900, Brazil.
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Mora-Ramiro B, Jiménez-Estrada M, Zentella-Dehesa A, Ventura-Gallegos JL, Gomez-Quiroz LE, Rosiles-Alanis W, Alarcón-Aguilar FJ, Almanza-Pérez JC. Cacalol Acetate, a Sesquiterpene from Psacalium decompositum, Exerts an Anti-inflammatory Effect through LPS/NF-KB Signaling in Raw 264.7 Macrophages. JOURNAL OF NATURAL PRODUCTS 2020; 83:2447-2455. [PMID: 32672964 DOI: 10.1021/acs.jnatprod.0c00300] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Inflammatory diseases remain critical health problems worldwide. The search for anti-inflammatory drugs is a primary activity in the pharmaceutical industry. Cacalol is a sesquiterpene with anti-inflammatory potential that is isolated from Psacalium decompositum, a medicinal plant with several scientific reports supporting its anti-inflammatory activity. Cacalol acetate (CA) is the most stable form. Nevertheless, the participation of CA in the main signaling pathway associated with inflammation is unknown. Our aim was to study the anti-inflammatory effect of CA and to determine its participation in NF-κB signaling. In TPA-induced edema in mice, CA produced 70.3% inhibition. To elucidate the influence of CA on the NF-κB pathway, RAW 264.7 macrophages were pretreated with CA and then stimulated with LPS, evaluating NF-ΚB activation, IKK phosphorylation, IΚB-α, p65, cytokine expression, and COX-2 release and activity. CA inhibited NF-κB activation and its upstream signaling, decreasing phosphorylation IKB-α and p65 levels. CA also reduced expression and secretion of TNF-α, IL-1β, and IL-6. Additionally, it decreased the activity and expression of COX-2 mRNA. These data support that CA regulates the NF-κB signaling pathway, which might explain, at least in part, its anti-inflammatory effect. CA is a bioactive molecule useful for the development of anti-inflammatory agents with innovative mechanisms of action.
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Affiliation(s)
- B Mora-Ramiro
- Posgrado en Biología Experimental, Division de CBS, UAM-Iztapalapa., San Rafael Atlixco 186, Vicentina, Delegación Iztapalapa, C.P. 09340, Ciudad de México, México
| | - M Jiménez-Estrada
- Departamento de Productos Naturales, Instituto de Química, UNAM, Circuito, Mario de La Cueva s/n, C.U., 04510 Ciudad de México, México
| | - A Zentella-Dehesa
- Programa Institucional de Cáncer de Mama, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, UNAM, Circuito, Mario de La Cueva s/n, C.U., 04510 Ciudad de México, México
- Unidad de Bioquímica, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, México
| | - J L Ventura-Gallegos
- Programa Institucional de Cáncer de Mama, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, UNAM, Circuito, Mario de La Cueva s/n, C.U., 04510 Ciudad de México, México
- Unidad de Bioquímica, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, México
| | - L E Gomez-Quiroz
- Departamento de Ciencias de la Salud, CBS, UAM-Iztapalapa, San Rafael Atlixco 186, Vicentina, Delegación Iztapalapa, C.P. 09340, Ciudad de México, México
| | - W Rosiles-Alanis
- Posgrado en Biología Experimental, Division de CBS, UAM-Iztapalapa., San Rafael Atlixco 186, Vicentina, Delegación Iztapalapa, C.P. 09340, Ciudad de México, México
| | - F J Alarcón-Aguilar
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de CBS, UAM-Iztapalapa, San Rafael Atlixco 186, Vicentina, Delegación Iztapalapa, C.P. 09340, Ciudad de México, México
| | - J C Almanza-Pérez
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de CBS, UAM-Iztapalapa, San Rafael Atlixco 186, Vicentina, Delegación Iztapalapa, C.P. 09340, Ciudad de México, México
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Pinto NDCC, Maciel MDSF, Rezende NDS, Duque APDN, Mendes RDF, da Silva JB, Evangelista MDR, Monteiro LC, da Silva JM, da Costa JDC, Scio E. Preclinical studies indicate that INFLATIV, an herbal medicine cream containing Pereskia aculeata, presents potential to be marketed as a topical anti-inflammatory agent and as adjuvant in psoriasis therapy. J Pharm Pharmacol 2020; 72:1933-1945. [PMID: 32846458 DOI: 10.1111/jphp.13357] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/03/2020] [Accepted: 07/25/2020] [Indexed: 11/27/2022]
Abstract
OBJECTIVES A previous study reported that the hexane fraction (HF) obtained from Pereskia aculeata leaves showed promising topical anti-inflammatory activity. Intending its future use in clinical practice, a herbal medicine cream named INFLATIV was developed. Its anti-inflammatory and antipsoriatic potential were investigated. INFLATIV was subjected to preliminary accelerated stability tests and to a degradation profile assessment. METHODS INFLATIV was prepared at 6% and 12%. The anti-inflammatory activity was assessed by croton oil single and multiple application challenge in mice. Mouse tail test was used for antipsoriatic potential investigation. Cutaneous atrophy test was performed. Preliminary accelerated stability tests were performed together with a degradation profile by GC-MS analysis. KEY FINDINGS The anti-inflammatory activity shown by INFLATIV was comparable to dexamethasone. However, the skin atrophy caused by that drug was not observed. INFLATIV modified skin parakeratotic differentiation into orthokeratosis, which revealed its antipsoriatic potential. The ingredients used were suitable to carry the bioactives as they were well permeated by the skin. The preliminary accelerated stability tests indicated that INFLATIV 6% is more stable than 12%. CONCLUSIONS The results demonstrated the relevant therapeutic and marketing potentials of INFLATIV, which is likely to be further evaluated in clinical trials for drug registration process with regulatory agencies.
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Affiliation(s)
- Nícolas de Castro Campos Pinto
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Mariana de Souza Ferreira Maciel
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Nathalia Dos Santos Rezende
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Ana Paula do Nascimento Duque
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Renata de Freitas Mendes
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Jucélia Barbosa da Silva
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Monique de Rezende Evangelista
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Luana Cahon Monteiro
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Josiane Mello da Silva
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Juliana de Carvalho da Costa
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Elita Scio
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
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8
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Gonçalves DS, de S Melo SM, Jacomini AP, J V da Silva M, Pianoski KE, Ames FQ, Aguiar RP, Oliveira AF, Volpato H, Bidóia DL, Nakamura CV, Bersani-Amado CA, Back DF, Moura S, Paula FR, Rosa FA. Synthesis of novel 3,5,6-trisubstituted 2-pyridone derivatives and evaluation for their anti-inflammatory activity. Bioorg Med Chem 2020; 28:115549. [PMID: 32503692 DOI: 10.1016/j.bmc.2020.115549] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/26/2020] [Accepted: 05/05/2020] [Indexed: 11/19/2022]
Abstract
The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo anti-inflammatory activity, reducing ear edema and myeloperoxidase (MPO) activity. The most active compounds (2a and 7a) were inhibitors of COX enzymes. Compound 2a selectively inhibited the COX-2, while 7a was nonselective. Further, the compound 2a showed effective binding at the active site of COX-2 co-crystal by docking molecular study.
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Affiliation(s)
- Davana S Gonçalves
- Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Samara M de S Melo
- Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Andrey P Jacomini
- Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Michael J V da Silva
- Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Karlos E Pianoski
- Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Franciele Q Ames
- Departamento de Farmacologia e Terapêutica, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Rafael P Aguiar
- Departamento de Farmacologia e Terapêutica, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Alisson Felipe Oliveira
- Departamento de Farmácia, Universidade Federal do Pampa (UNIPAMPA), 97500-970 Uruguaiana, RS, Brazil
| | - Hélito Volpato
- Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá (UEM), 87020-900 Maringá, PR, Brazil
| | - Danielle L Bidóia
- Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá (UEM), 87020-900 Maringá, PR, Brazil
| | - Celso V Nakamura
- Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá (UEM), 87020-900 Maringá, PR, Brazil
| | - Ciomar A Bersani-Amado
- Departamento de Farmacologia e Terapêutica, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil
| | - Davi F Back
- Departamento de Química, Universidade Federal de Santa Maria (UFSM), 97110-970 Santa Maria, RS, Brazil
| | - Sidnei Moura
- Instituto de Biotecnologia, Universidade de Caxias do Sul (UCS), 295070-560 Caxias do Sul, RS, Brazil
| | - Fávero R Paula
- Departamento de Farmácia, Universidade Federal do Pampa (UNIPAMPA), 97500-970 Uruguaiana, RS, Brazil
| | - Fernanda A Rosa
- Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil.
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9
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Mishra S, Srivastava S, Divakar A, Mandal P, Dewangan J, Chaturvedi S, Wahajuddin M, Kumar S, Tripathi A, Rath SK. Celecoxib reduces Deoxynivalenol induced proliferation, inflammation and protein kinase C translocation via modulating downstream targets in mouse skin. Chem Biol Interact 2020; 326:109128. [PMID: 32416088 DOI: 10.1016/j.cbi.2020.109128] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 04/13/2020] [Accepted: 05/05/2020] [Indexed: 12/26/2022]
Abstract
Exposure to mycotoxins is mostly by ingestion but also occurs by the dermal and inhalation routes. The present study for the first time demonstrated that mycotoxin Deoxynivalenol (DON), permeates through Swiss albino mice skin, which demands awareness of health risks in people who are dermally exposed to mycotoxins especially agricultural farmers. Despite the widespread contamination of DON in food commodities studies to alleviate DON's toxicity are sparsely reported. Thus effective measures to combat mycotoxins associated toxicity remains an imperative aspect to be considered from the angle of dermal exposure. Topical application of Celecoxib (1-2 mg), followed by DON (100 μg) application on the dorsal side of mice, resulted in substantial decrease in DON-induced (i) edema, hyperplasia, cell proliferation (ii) inhibition of cytokine and prostaglandin-E2 levels (iii) phosphorylation of ERK1/2, JNK, p38, MAPKKs, CREB, P90-RSK (iv) downregulation of c-Jun, c- Fos, phospho-NF-kB and their downstream target proteins cyclin D1 and COX-2. Using Ro-31-8220 (Protein-Kinase-C inhibitor), it was observed PKC was responsible for DON induced upregulation of COX-2 and iNOS proteins. Treatment of Celecoxib decreased DON-induced translocation of Protein Kinase C isozymes (α,ε,γ), demonstrating the role of PKC in DON-mediated biochemical and molecular alterations responsible for its dermal toxicity. The present findings indicate that topical application of celecoxib is effective in the management of inflammatory skin disorders induced by foodborne fungal toxin DON. The skin permeation potential of Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor NSAID, was also assessed, and the results indicated that the permeation was relatively lower as compared to the oral mode of administration. Hence topical use of celecoxib may be preferred over oral dosing because of lower systemic absorption and to avoid the unwanted side effects. This study provides a prospect for exploring the clinical efficacy of topically applied COX-2 inhibitors for the management of inflammatory skin disorders induced by foodborne fungal toxins.
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Affiliation(s)
- Sakshi Mishra
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Sonal Srivastava
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Aman Divakar
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Payal Mandal
- Food Drug and Chemical Toxicology Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226 001, Uttar Pradesh, India
| | - Jayant Dewangan
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Swati Chaturvedi
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Muhammad Wahajuddin
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Sadan Kumar
- Immunotoxicology Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Anurag Tripathi
- Food Drug and Chemical Toxicology Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226 001, Uttar Pradesh, India
| | - Srikanta Kumar Rath
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
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10
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Elmowafy M, Shalaby K, Ali HM, Alruwaili NK, Salama A, Ibrahim MF, Akl MA, Ahmed TA. Impact of nanostructured lipid carriers on dapsone delivery to the skin: in vitro and in vivo studies. Int J Pharm 2019; 572:118781. [DOI: 10.1016/j.ijpharm.2019.118781] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 10/09/2019] [Accepted: 10/09/2019] [Indexed: 01/03/2023]
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11
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Rakariyatham K, Du Z, Yuan B, Gao Z, Song M, Pan C, Han Y, Wu X, Tang Z, Zhang G, Xiao H. Inhibitory effects of 7,7′-bromo-curcumin on 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation. Eur J Pharmacol 2019; 858:172479. [DOI: 10.1016/j.ejphar.2019.172479] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 12/30/2022]
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12
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Tremmel L, Rho O, Slaga TJ, DiGiovanni J. Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin. Mol Carcinog 2019; 58:185-195. [PMID: 30346064 DOI: 10.1002/mc.22918] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/19/2018] [Accepted: 09/23/2018] [Indexed: 12/23/2022]
Abstract
Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventative agents. The purpose of this study was to examine the effects of the combination of ursolic acid (UA) and curcumin (Curc) for potential combinatorial inhibition of skin tumor promotion using the mouse two-stage skin carcinogenesis model. In short-term experiments, the combination of UA + Curc given topically prior to 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly inhibited activation of epidermal EGFR, p70S6K, NF-κB p50, Src, c-Jun, Rb, and IκBα. Levels of c-Fos, c-Jun, and Cox-2 were also significantly reduced by the combination compared to the TPA treated group. The alterations in these signaling pathways by the combination of UA + Curc were associated with decreased epidermal proliferation as assessed by measuring BrdU incorporation. Significant effects were also seen with the combination on epidermal inflammatory gene expression and dermal inflammation, with the greatest effects on expression of IL-1β, IL-6, IL-22, and CXCL2. Furthermore, results from skin tumor experiments demonstrated that the combination of UA + Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on tumor free survival, tumor size, and tumor weight, although tumor incidence and multiplicity were also further reduced by the combination. These results demonstrate the potential cancer chemopreventive activity and mechanism(s) for the combination of UA + Curc.
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Affiliation(s)
- Lisa Tremmel
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - Okkyung Rho
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - Thomas J Slaga
- Department of Pharmacology, UT Health Science Center San Antonio, San Antonio, Texas
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, Texas
- Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, Texas
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13
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Wares MA, Tobita N, Kawauchi S, Sato S, Nishidate I. Noninvasive evaluation of hemodynamics and light scattering property during two-stage mouse cutaneous carcinogenesis based on multispectral diffuse reflectance images at isosbestic wavelengths of hemoglobin. JOURNAL OF BIOMEDICAL OPTICS 2019; 24:1-11. [PMID: 30635994 PMCID: PMC6975185 DOI: 10.1117/1.jbo.24.3.031020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 12/11/2018] [Indexed: 05/06/2023]
Abstract
We investigate a multispectral imaging method to evaluate spatiotemporal changes in both cutaneous hemoglobin concentration and light scattering parameter in mouse skin through diffuse reflectance spectroscopy using the reflectance images acquired at isosbestic wavelengths of hemoglobin (420, 450, 500, and 585 nm). In the proposed approach, Monte Carlo simulation-based empirical formulas are introduced to extract the scattering power b representing the wavelength dependence of light scattering spectrum of skin tissue, as well as the total hemoglobin concentration Cth in dermal vasculatures. The use of isosbestic wavelengths of hemoglobin enables the values of Cth and b to be estimated independently of the oxygenation of hemoglobin. Experiments using in vivo mice two-stage chemical carcinogenesis model are performed to confirm the feasibility of the proposed method for evaluating the changes in cutaneous vasculatures and tissue morphology during tumor initiation, promotion, and progression processes. The experimental results reveal that the changes in scattering power b of back skin are significantly reduced and followed by the increase in total hemoglobin concentration Cth in the carcinogenesis mice group, which indicates morphological changes in skin tissue such as edema and cell swelling caused by tumor promotion and successive angiogenesis along with tumor progression. The results suggest that the potential of the present method to detect cutaneous carcinogenesis in an early stage and monitor physiological changes during promotion and progression process of nonmelanoma tumors.
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Affiliation(s)
- Md. Abdul Wares
- Tokyo University of Agriculture and Technology, Graduate School of Bio-Applications and Systems Engineering, Tokyo, Japan
- Ministry of Fisheries and Livestock, Government of Bangladesh, Department of Livestock Services, Dhaka, Bangladesh
| | - Naoki Tobita
- Tokyo University of Agriculture and Technology, Graduate School of Bio-Applications and Systems Engineering, Tokyo, Japan
| | - Satoko Kawauchi
- National Defense Medical College Research Institute, Division of Bio-Information and Therapeutic Systems, Tokorozawa, Saitama
| | - Shunichi Sato
- National Defense Medical College Research Institute, Division of Bio-Information and Therapeutic Systems, Tokorozawa, Saitama
| | - Izumi Nishidate
- Tokyo University of Agriculture and Technology, Graduate School of Bio-Applications and Systems Engineering, Tokyo, Japan
- Address all correspondence to Izumi Nishidate, E-mail:
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14
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Avtanski D, Poretsky L. Phyto-polyphenols as potential inhibitors of breast cancer metastasis. Mol Med 2018; 24:29. [PMID: 30134816 PMCID: PMC6016885 DOI: 10.1186/s10020-018-0032-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 05/27/2018] [Indexed: 12/31/2022] Open
Abstract
Breast cancer is the most common cancer among women as metastasis is currently the main cause of mortality. Breast cancer cells undergoing metastasis acquire resistance to death signals and increase of cellular motility and invasiveness.Plants are rich in polyphenolic compounds, many of them with known medicinal effects. Various phyto-polyphenols have also been demonstrated to suppress cancer growth. Their mechanism of action is usually pleiotropic as they target multiple signaling pathways regulating key cellular processes such as proliferation, apoptosis and differentiation. Importantly, some phyto- polyphenols show low level of toxicity to untransformed cells, but selective suppressing effects on cancer cells proliferation and differentiation.In this review, we summarize the current information about the mechanism of action of some phyto-polyphenols that have demonstrated anti-carcinogenic activities in vitro and in vivo. Gained knowledge of how these natural polyphenolic compounds work can give us a clue for the development of novel anti-metastatic agents.
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Affiliation(s)
- Dimiter Avtanski
- Gerald J. Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, New York, NY, 10022, USA.
- Division of Endocrinology and Metabolism, Department of Medicine, Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, 110 E 59th Street, Suite 8B, Room 837, New York, NY, 10022, USA.
| | - Leonid Poretsky
- Gerald J. Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, New York, NY, 10022, USA
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15
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Auger F, Martin F, Pétrault O, Samaillie J, Hennebelle T, Trabelsi MS, Bailleul F, Staels B, Bordet R, Duriez P. Risperidone-induced metabolic dysfunction is attenuated by Curcuma longa extract administration in mice. Metab Brain Dis 2018; 33:63-77. [PMID: 29034440 DOI: 10.1007/s11011-017-0133-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 10/09/2017] [Indexed: 12/12/2022]
Abstract
Antipsychotics, such as risperidone, increase food intake and induce alteration in glucose and lipid metabolism concomitantly with overweight and body fat increase, these biological abnormalities belong to the metabolic syndrome definition (high visceral adiposity, hypertriglyceridemia, hyperglycemia, low HDL-cholesterol and high blood pressure). Curcumin is a major component of traditional turmeric (Curcuma longa) which has been reported to improve lipid and glucose metabolism and to decrease weight in obese mice. We questioned the potential capacity of curcumin, contained in Curcuma longa extract (Biocurcuma™), to attenuate the risperidone-induced metabolic dysfunction. Two groups of mice were treated once a week, for 22 weeks, with intraperitoneal injection of risperidone (Risperdal) at a dose 12.5 mpk. Two other groups received intraperitoneal injection of the vehicle of Risperdal following the same schedule. Mice of one risperidone-treated groups and of one of vehicle-treated groups were fed a diet with 0.05% Biocurcuma™ (curcumin), while mice of the two other groups received the standard diet. Curcumin limited the capacity of risperidone to reduce spontaneous motricity, but failed to impede risperidone-induced increase in food intake. Curcumin did not reduce the capacity of risperidone to induce weight gain, but decreased visceral adiposity and decreased the risperidone-induced hepatomegaly, but not steatosis. Furthermore, curcumin repressed the capacity of risperidone to induce the hepatic over expression of enzymes involved in lipid metabolism (LXRα, FAS, ACC1, LPL, PPARγ, ACO, SREBP2) and decreased risperidone-induced glucose intolerance and hypertriglyceridemia. Curcumin decreased risperidone-induced increases in serum markers of hepatotoxicity (ALAT, ASAT), as well as of one major hepatic pro-inflammatory transcription factor (NFκB: p105 mRNA and p65 protein). These findings support that nutritional doses of curcumin contained in Curcuma longa extract are able to partially counteract the risperidone-induced metabolic dysfunction in mice, suggesting that curcumin ought to be tested to reduce the capacity of risperidone to induce the metabolic syndrome in human.
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Affiliation(s)
- Florent Auger
- Joint Service of Life's Imaging Platform, University of Lille, UDSL, Lille, France
- Inserm, CHU Lille, U1171 - Degenerative & Vascular Cognitive Disorders, University of Lille, F-59000, Lille, France
| | - Françoise Martin
- Faculty of Pharmacy, University of Lille, UDSL, Lille, France
- INSERM U 1011, University of Lille, UDSL, Lille, France
- Pasteur Institute, Lille, France
- European Genomic Institute for Diabetes (E.G.I.D.), 3508, Lille, FR, France
| | - Olivier Pétrault
- Inserm, CHU Lille, U1171 - Degenerative & Vascular Cognitive Disorders, University of Lille, F-59000, Lille, France
- Laboratory of Blood Brain Barrier Physiopathology, University of Artois, Lens, France
| | - Jennifer Samaillie
- Faculty of Pharmacy, University of Lille, UDSL, Lille, France
- Interdisciplinary Group of Research in Therapeutic Innovation and Optimization, 4481, Lille, EA, France
| | - Thierry Hennebelle
- Faculty of Pharmacy, University of Lille, UDSL, Lille, France
- Interdisciplinary Group of Research in Therapeutic Innovation and Optimization, 4481, Lille, EA, France
| | - Mohamed-Sami Trabelsi
- INSERM U 1011, University of Lille, UDSL, Lille, France
- Pasteur Institute, Lille, France
- European Genomic Institute for Diabetes (E.G.I.D.), 3508, Lille, FR, France
| | - François Bailleul
- Faculty of Pharmacy, University of Lille, UDSL, Lille, France
- Interdisciplinary Group of Research in Therapeutic Innovation and Optimization, 4481, Lille, EA, France
| | - Bart Staels
- Faculty of Pharmacy, University of Lille, UDSL, Lille, France
- INSERM U 1011, University of Lille, UDSL, Lille, France
- Pasteur Institute, Lille, France
- European Genomic Institute for Diabetes (E.G.I.D.), 3508, Lille, FR, France
| | - Régis Bordet
- Inserm, CHU Lille, U1171 - Degenerative & Vascular Cognitive Disorders, University of Lille, F-59000, Lille, France
| | - Patrick Duriez
- Inserm, CHU Lille, U1171 - Degenerative & Vascular Cognitive Disorders, University of Lille, F-59000, Lille, France.
- Faculty of Pharmacy, University of Lille, UDSL, Lille, France.
- Faculté de Pharmacie, Université de Lille, 3 rue du Pr. Laguesse, 59000, Lille, France.
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16
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Regulation of Polyamine Metabolism by Curcumin for Cancer Prevention and Therapy. Med Sci (Basel) 2017; 5:medsci5040038. [PMID: 29258259 PMCID: PMC5753667 DOI: 10.3390/medsci5040038] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 12/12/2017] [Accepted: 12/14/2017] [Indexed: 12/31/2022] Open
Abstract
Curcumin (diferuloylmethane), the natural polyphenol responsible for the characteristic yellow pigment of the spice turmeric (Curcuma longa), is traditionally known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. In human cancer cell lines, curcumin has been shown to decrease ornithine decarboxylase (ODC) activity, a rate-limiting enzyme in polyamine biosynthesis that is frequently upregulated in cancer and other rapidly proliferating tissues. Numerous studies have demonstrated that pretreatment with curcumin can abrogate carcinogen-induced ODC activity and tumor development in rodent tumorigenesis models targeting various organs. This review summarizes the results of curcumin exposure with regard to the modulation of polyamine metabolism and discusses the potential utility of this natural compound in conjunction with the exploitation of dysregulated polyamine metabolism in chemopreventive and chemotherapeutic settings.
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17
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Pinheiro RP, Moraes MA, Santos BCS, Fabri RL, Del-Vechio-Vieira G, Yamamoto CH, Araújo ALSM, Araújo ALA, Sousa OV. Identification of compounds from Palicourea rigida leaves with topical anti-inflammatory potential using experimental models. Inflammopharmacology 2017; 26:1005-1016. [PMID: 29138954 DOI: 10.1007/s10787-017-0415-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 10/28/2017] [Indexed: 01/12/2023]
Abstract
Palicourea rigida Kunth is traditionally used for the treatment of skin diseases, kidney pains and ovarian inflammation. Based on these traditional uses, this study evaluated the topical anti-inflammatory activity of the ethanol extract from P. rigida leaves (EEPR) and identified bioactive compounds. Ear edema was induced in Swiss mice by the topical application of Croton oil, arachidonic acid, phenol and capsaicin. Histopathological analysis and myeloperoxidase and N-acetyl-β-D-glucosaminidase activities were determined. EEPR was characterized by UHPLC-UV-MS HPLC and the isolated compound was identified through 1H and 13C nuclear magnetic resonance and mass fragmentation. Interaction profiles between quercetin 3-O-β-D-glucoside and cyclooxygenase-1 and -2 were established by molecular docking. EEPR significantly inhibited ear edema induced by Croton oil (p < 0.001), arachidonic acid (p < 0.01), phenol (p < 0.001) and capsaicin (p < 0.01 or p < 0.001). Histopathological analysis showed a reduction of edema, inflammatory cell infiltration and vasodilation. Additionally, the myeloperoxidase and N-acetyl-β-D-glucosaminidase activities were decreased (p < 0.001). From spectroscopic data, quercetin 3-O-β-D-glucoside was the identified compound. This compound can to interact with cyclooxygenase-1 and -2 through van der Waals interactions and dipole-dipole and hydrogen bonding's, demonstrating inhibition of these enzymes. The results indicate that EEPR is a source of active compounds with topical anti-inflammatory activity, justifying the traditional use of P. rigida and showing that this species has a therapeutic potential to treat skin inflammatory processes.
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Affiliation(s)
- Rafael P Pinheiro
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil
| | - Muiara A Moraes
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil
| | - Bruna C S Santos
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil
| | - Rodrigo L Fabri
- Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Campus Universitário, Juiz de Fora, Minas Gerais, 36036-330, Brazil
| | - Glauciemar Del-Vechio-Vieira
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil
| | - Célia H Yamamoto
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil
| | - Ana Lúcia S M Araújo
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil
| | - Aílson L A Araújo
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil
| | - Orlando V Sousa
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Campus Universitário, São Pedro, Minas Gerais, 36036-900, Brazil.
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18
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Ames FQ, Sato F, de Castro LV, de Arruda LLM, da Rocha BA, Cuman RKN, Baesso ML, Bersani-Amado CA. Evidence of anti-inflammatory effect and percutaneous penetration of a topically applied fish oil preparation: a photoacoustic spectroscopy study. JOURNAL OF BIOMEDICAL OPTICS 2017; 22:55003. [PMID: 28492854 DOI: 10.1117/1.jbo.22.5.055003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 04/19/2017] [Indexed: 05/20/2023]
Abstract
This paper investigates the topical anti-inflammatory effect of a fish oil preparation (FOP) in a croton oil (CO) model of skin inflammation. The photoacoustic spectroscopy (PAS) was applied to estimate the percutaneous penetration of the FOP and as a model to evaluate the topical inflammatory response. After applying CO, the groups of mice received a topical application of a FOP on the left ear. The right ear received the vehicle that was used to dilute the CO. After 6 h, ear tissue was collected to determine the percent inhibition of edema, myeloperoxidase (MPO) activity, and cytokine levels and to perform PAS measurements. Treatment with FOP reduced edema and MPO activity, which was at least partially attributed to a decrease in the levels of tumor necrosis factor, interleukin- 1 ? , interleukin-6, keratinocyte-derived chemokine, and monocyte chemoattractant protein-1. The topically applied FOP penetrated into the tissue and decreased the area of the bands that characterize inflamed tissue. The present results demonstrated the topical anti-inflammatory effect of the FOP. PAS suggests that FOP anti-inflammatory activity is linked with its ability to penetrate through the skin.
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Affiliation(s)
- Franciele Q Ames
- State University of Maringá, Department of Pharmacology and Therapeutics, Maringá, Paraná, Brazil
| | - Francielle Sato
- State University of Maringá, Department of Physics, Maringá, Paraná, Brazil
| | | | - Laura L M de Arruda
- State University of Maringá, Department of Pharmacology and Therapeutics, Maringá, Paraná, Brazil
| | - Bruno A da Rocha
- State University of Maringá, Department of Pharmacology and Therapeutics, Maringá, Paraná, Brazil
| | - Roberto K N Cuman
- State University of Maringá, Department of Pharmacology and Therapeutics, Maringá, Paraná, Brazil
| | - Mauro L Baesso
- State University of Maringá, Department of Physics, Maringá, Paraná, Brazil
| | - Ciomar A Bersani-Amado
- State University of Maringá, Department of Pharmacology and Therapeutics, Maringá, Paraná, Brazil
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19
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Rodrigues KCM, Chibli LA, Santos BCS, Temponi VS, Pinto NCC, Scio E, Del-Vechio-Vieira G, Alves MS, Sousa OV. Evidence of Bioactive Compounds from Vernonia polyanthes Leaves with Topical Anti-Inflammatory Potential. Int J Mol Sci 2016; 17:ijms17121929. [PMID: 27916942 PMCID: PMC5187762 DOI: 10.3390/ijms17121929] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/22/2016] [Accepted: 11/08/2016] [Indexed: 01/30/2023] Open
Abstract
Vernonia polyanthes Less. (Asteraceae), popularly known as "assa-peixe", is a plant species used in Brazilian traditional medicine for the treatment of cutaneous damage, cicatrization, inflammation, and rheumatism. Based on these ethnopharmacological findings, the current study evaluated the topical anti-inflammatory effects of the hexane (HEVP) and ethyl acetate (EAEVP) extracts from V. polyanthes leaves in experimental models of skin inflammation. Chemical characterization was carried out by HPLC-UV/DAD analysis. Anti-inflammatory activity was evaluated using Croton oil-, arachidonic acid (AA)-, phenol-, ethyl phenylpropiolate (EPP)-, and capsaicin-induced ear edema models in mice. Histopathological evaluation and measurements of myeloperoxidase (MPO) and N-acetyl-β-d-glucosaminidase (NAG) enzymes were also performed. Rutin, luteolin, and apigenin were identified in EAEVP. Topically applied HEVP and EAEVP significantly (p < 0.05, p < 0.01 or p < 0.001) reduced edema induced by five different irritants at the doses tested (0.1, 0.5 and 1.0 mg/ear). Histopathological analysis revealed a reduction of edema, inflammatory cell infiltration, and vasodilation. In addition, the enzymes activity (MPO and NAG) in the ear tissues was reduced by the topical treatment of HEVP and EAEVP (p < 0.05, p < 0.01 or p < 0.001). The results suggest that V. polyanthes leaves are effective against cutaneous damage, which support its traditional use and open up new possibilities for the treatment of skin disorders.
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Affiliation(s)
- Kamilla C M Rodrigues
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Lucas A Chibli
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Bruna C S Santos
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Vanessa S Temponi
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Nícolas C C Pinto
- Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Elita Scio
- Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Glauciemar Del-Vechio-Vieira
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Maria S Alves
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
| | - Orlando V Sousa
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil.
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Pany S, You Y, Das J. Curcumin Inhibits Protein Kinase Cα Activity by Binding to Its C1 Domain. Biochemistry 2016; 55:6327-6336. [PMID: 27776404 DOI: 10.1021/acs.biochem.6b00932] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Curcumin is a polyphenolic nutraceutical that acts on multiple biological targets, including protein kinase C (PKC). PKC is a family of serine/threonine kinases central to intracellular signal transduction. We have recently shown that curcumin selectively inhibits PKCα, but not PKCε, in CHO-K1 cells [Pany, S. (2016) Biochemistry 55, 2135-2143]. To understand which domain(s) of PKCα is responsible for curcumin binding and inhibitory activity, we made several domain-swapped mutants in which the C1 (combination of C1A and C1B) and C2 domains are swapped between PKCα and PKCε. Phorbol ester-induced membrane translocation studies using confocal microscopy and immunoblotting revealed that curcumin inhibited phorbol ester-induced membrane translocation of PKCε mutants, in which the εC1 domain was replaced with αC1, but not the PKCα mutant in which αC1 was replaced with the εC1 domain, suggesting that αC1 is a determinant for curcumin's inhibitory effect. In addition, curcumin inhibited membrane translocation of PKCε mutants, in which the εC1A and εC1B domains were replaced with the αC1A and αC1B domains, respectively, indicating the role of both αC1A and αC1B domains in curcumin's inhibitory effects. Phorbol 13-acetate inhibited the binding of curcumin to αC1A and αC1B with IC50 values of 6.27 and 4.47 μM, respectively. Molecular docking and molecular dynamics studies also supported the higher affinity of curcumin for αC1B than for αC1A. The C2 domain-swapped mutants were inactive in phorbol ester-induced membrane translocation. These results indicate that curcumin binds to the C1 domain of PKCα and highlight the importance of this domain in achieving PKC isoform selectivity.
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Affiliation(s)
- Satyabrata Pany
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States
| | - Youngki You
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States
| | - Joydip Das
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States
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21
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Capuani B, Pacifici F, Pastore D, Palmirotta R, Donadel G, Arriga R, Bellia A, Di Daniele N, Rogliani P, Abete P, Sbraccia P, Guadagni F, Lauro D, Della-Morte D. The role of epsilon PKC in acute and chronic diseases: Possible pharmacological implications of its modulators. Pharmacol Res 2016; 111:659-667. [PMID: 27461137 DOI: 10.1016/j.phrs.2016.07.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 07/22/2016] [Indexed: 02/06/2023]
Abstract
Epsilon Protein kinase C (εPCK) is a particular kinase that, when activated, is able to protect against different stress injuries and therefore has been proposed to be a potential molecular target against acute and chronic diseases. Particular attention has been focused on εPCK for its involvement in the protective mechanism of Ischemic Preconditioning (IPC), a powerful endogenous mechanism characterized by subthreshold ischemic insults able to protect organs against ischemic injury. Therefore, in the past decades several εPCK modulators have been tested with the object to emulate εPCK mediate protection. Among these the most promising, so far, has been the ΨεRACK peptide, a homologous of RACK receptor for εPKC, that when administrated can mimic its effect in the cells. However, results from studies on εPCK indicate controversial role of this kinase in different organs and diseases, such as myocardial infarct, stroke, diabetes and cancer. Therefore, in this review we provide a discussion on the function of εPCK in acute and chronic diseases and how the different activators and inhibitors have been used to modulate its activity. A better understanding of its function is still needed to definitively target εPCK as novel therapeutic strategy.
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Affiliation(s)
- Barbara Capuani
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Pacifici
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Donatella Pastore
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Raffaele Palmirotta
- Department of Biomedical Sciences and Human Oncology, University of Bari ⿿Aldo Moro⿿, Bari, Italy
| | - Giulia Donadel
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Roberto Arriga
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Alfonso Bellia
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Nicola Di Daniele
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Paola Rogliani
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Pasquale Abete
- Department of Translational Medical Sciences, University of Naples ⿿Federico II⿿, Naples, Italy
| | - Paolo Sbraccia
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Fiorella Guadagni
- IRCCS San Raffaele Pisana, Rome, Italy; San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Davide Lauro
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - David Della-Morte
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS San Raffaele Pisana, Rome, Italy.
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22
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Abstract
Polyphenols are a widely used class of compounds in dermatology. While phenol itself, the most basic member of the phenol family, is chemically synthesized, most polyphenolic compounds are found in plants and form part of their defense mechanism against decomposition. Polyphenolic compounds, which include phenolic acids, flavonoids, stilbenes, and lignans, play an integral role in preventing the attack on plants by bacteria and fungi, as well as serving as cross-links in plant polymers. There is also mounting evidence that polyphenolic compounds play an important role in human health as well. One of the most important benefits, which puts them in the spotlight of current studies, is their antitumor profile. Some of these polyphenolic compounds have already presented promising results in either in vitro or in vivo studies for non-melanoma skin cancer and melanoma. These compounds act on several biomolecular pathways including cell division cycle arrest, autophagy, and apoptosis. Indeed, such natural compounds may be of potential for both preventive and therapeutic fields of cancer. This review evaluates the existing scientific literature in order to provide support for new research opportunities using polyphenolic compounds in oncodermatology.
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Affiliation(s)
- Adilson Costa
- Department of Dermatology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Winship Cancer Institute, 101 Woodruff Circle, Atlanta, GA, 30322, USA
| | - Michael Yi Bonner
- Department of Dermatology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Winship Cancer Institute, 101 Woodruff Circle, Atlanta, GA, 30322, USA
| | - Jack L Arbiser
- Department of Dermatology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Winship Cancer Institute, 101 Woodruff Circle, Atlanta, GA, 30322, USA.
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Das J, Ramani R, Suraju MO. Polyphenol compounds and PKC signaling. Biochim Biophys Acta Gen Subj 2016; 1860:2107-21. [PMID: 27369735 DOI: 10.1016/j.bbagen.2016.06.022] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/01/2016] [Accepted: 06/26/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Naturally occurring polyphenols found in food sources provide huge health benefits. Several polyphenolic compounds are implicated in the prevention of disease states, such as cancer. One of the mechanisms by which polyphenols exert their biological actions is by interfering in the protein kinase C (PKC) signaling pathways. PKC belongs to a superfamily of serine-threonine kinase and are primarily involved in phosphorylation of target proteins controlling activation and inhibition of many cellular processes directly or indirectly. SCOPE OF REVIEW Despite the availability of substantial literature data on polyphenols' regulation of PKC, no comprehensive review article is currently available on this subject. This article reviews PKC-polyphenol interactions and its relevance to various disease states. In particular, salient features of polyphenols, PKC, interactions of naturally occurring polyphenols with PKC, and future perspective of research on this subject are discussed. MAJOR CONCLUSIONS Some polyphenols exert their antioxidant properties by regulating the transcription of the antioxidant enzyme genes through PKC signaling. Regulation of PKC by polyphenols is isoform dependent. The activation or inhibition of PKC by polyphenols has been found to be dependent on the presence of membrane, Ca(2+) ion, cofactors, cell and tissue types etc. Two polyphenols, curcumin and resveratrol are in clinical trials for the treatment of colon cancer. GENERAL SIGNIFICANCE The fact that 74% of the cancer drugs are derived from natural sources, naturally occurring polyphenols or its simple analogs with improved bioavailability may have the potential to be cancer drugs in the future.
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Affiliation(s)
- Joydip Das
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, United States.
| | - Rashmi Ramani
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, United States
| | - M Olufemi Suraju
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, United States
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24
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Pany S, Majhi A, Das J. Selective Modulation of Protein Kinase C α over Protein Kinase C ε by Curcumin and Its Derivatives in CHO-K1 Cells. Biochemistry 2016; 55:2135-43. [PMID: 26983836 DOI: 10.1021/acs.biochem.6b00057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Members of the protein kinase C (PKC) family of serine/threonine kinases regulate various cellular functions, including cell growth, differentiation, metabolism, and apoptosis. Modulation of isoform-selective activity of PKC by curcumin (1), the active constituent of Curcuma L., is poorly understood, and the literature data are inconsistent and obscure. The effect of curcumin (1) and its analogues, 4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl oleate (2), (9Z,12Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12-dienoate (3), (9Z,12Z,15Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12,15-trienoate (4), and (1E,6E)-1-[4-(hexadecyloxy)-3-methoxyphenyl]-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (5), and didemethylcurcumin (6) on the membrane translocation of PKCα, a conventional PKC, and PKCε, a novel PKC, has been studied in CHO-K1 cells, in which these PKC isoforms are endogenously expressed. Translocation of PKC from the cytosol to the membrane was measured using immunoblotting and confocal microscopy. 1 and 6 inhibited the TPA-induced membrane translocation of PKCα but not of PKCε. Modification of the hydroxyl group of curcumin with a long aliphatic chain containing unsaturated double bonds in 2-4 completely abolished this inhibition property. Instead, 2-4 showed significant translocation of PKCα but not of PKCε to the membrane. No membrane translocation was observed with 1, 6, or the analogue 5 having a saturated long chain for either PKCα or PKCε. 1 and 6 inhibited TPA-induced activation of ERK1/2, and 2-4 activated it. ERK1/2 is the downstream readout of PKC. These results show that the hydroxyl group of curcumin is important for PKC activity and the curcumin template can be useful in developing isoform specific PKC modulators for regulating a particular disease state.
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Affiliation(s)
- Satyabrata Pany
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States
| | - Anjoy Majhi
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States
| | - Joydip Das
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States
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Maru GB, Hudlikar RR, Kumar G, Gandhi K, Mahimkar MB. Understanding the molecular mechanisms of cancer prevention by dietary phytochemicals: From experimental models to clinical trials. World J Biol Chem 2016; 7:88-99. [PMID: 26981198 PMCID: PMC4768127 DOI: 10.4331/wjbc.v7.i1.88] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/04/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
Chemoprevention is one of the cancer prevention approaches wherein natural/synthetic agent(s) are prescribed with the aim to delay or disrupt multiple pathways and processes involved at multiple steps, i.e., initiation, promotion, and progression of cancer. Amongst environmental chemopreventive compounds, diet/beverage-derived components are under evaluation, because of their long history of exposure to humans, high tolerability, low toxicity, and reported biological activities. This compilation briefly covers and compares the available evidence on chemopreventive efficacy and probable mechanism of chemoprevention by selected dietary phytochemicals (capsaicin, curcumin, diallyl sulphide, genistein, green/black tea polyphenols, indoles, lycopene, phenethyl isocyanate, resveratrol, retinoids and tocopherols) in experimental systems and clinical trials. All the dietary phytochemicals covered in this review have demonstrated chemopreventive efficacy against spontaneous or carcinogen-induced experimental tumors and/or associated biomarkers and processes in rodents at several organ sites. The observed anti-initiating, anti-promoting and anti-progression activity of dietary phytochemicals in carcinogen-induced experimental models involve phytochemical-mediated redox changes, modulation of enzymes and signaling kinases resulting to effects on multiple genes and cell signaling pathways. Results from clinical trials using these compounds have not shown them to be chemopreventive. This may be due to our: (1) inability to reproduce the exposure conditions, i.e., levels, complexity, other host and lifestyle factors; and (2) lack of understanding about the mechanisms of action and agent-mediated toxicity in several organs and physiological processes in the host. Current research efforts in addressing the issues of exposure conditions, bioavailability, toxicity and the mode of action of dietary phytochemicals may help address the reason for observed mismatch that may ultimately lead to identification of new chemopreventive agents for protection against broad spectrum of exposures.
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Barbosa AGR, Oliveira CDM, Lacerda-Neto LJ, Vidal CS, Saraiva RDA, da Costa JGM, Coutinho HDM, Galvao HBF, de Menezes IRA. Evaluation of chemical composition and antiedematogenic activity of the essential oil of Hyptis martiusii Benth. Saudi J Biol Sci 2015; 24:355-361. [PMID: 28149173 PMCID: PMC5272940 DOI: 10.1016/j.sjbs.2015.10.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 09/29/2015] [Accepted: 10/07/2015] [Indexed: 10/31/2022] Open
Abstract
Evaluations of the therapeutic potential of medicinal plants and their components have been the subject of many studies. Furthermore, the biological activities of various plant species have been reported in various pieces of literature. Hyptis martiusii Benth (Lamiaceae), popularly known as "mad balm" is commonly found in the North, Southeast, and Northeast of Brazil. Its leaves are used ethnobiologically as antiulcerogenic, antimicrobial, antitumor and as insecticide. This study aimed to analyze the chemical composition of the essential oil of H. martiusii Benth (OEHM) by GC/MS as well as its possible topical activity as an antiedematogenic. This is verified by the models of ear edema induced by single (acute edema) and multiple (chronic edema) applications of croton oil topically, and systemically verified through the model of paw edema induced by carrageenan 1%. Doses of 50, 75 and 100 mg/kg OEHM were used in all tests. Chemical analysis of the oil revealed the 1,8-cineole (34.58%) and δ-carene (21:58%) as major components present in the essential oil. On the model of ear edema, acute and chronic OEHM in all the tested doses showed no significant antiedematogenic activity (p < 0.05). The systemic model of paw edema induced by carrageenin showed that a dose of 100 mg/kg effectively reduced swelling by 55.37% in the second hour evaluation when compared to the saline group. The anti-inflammatory systemic effect can give greater bioavailability of the components present in the essential oil and your interference in cytokines and leukotriene, thromboxane and prostaglandin biosynthesis. It is therefore concluded that OEHM presents systemic antiedematogenic activity but not topical activity at these doses.
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Affiliation(s)
- Andreza G R Barbosa
- Department of Biological Chemistry, Laboratory of Pharmacology and Molecular Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil
| | - Cicera D M Oliveira
- Department of Biological Chemistry, Laboratory of Pharmacology and Molecular Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil
| | - Luiz J Lacerda-Neto
- Department of Biological Chemistry, Laboratory of Pharmacology and Molecular Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil
| | - Cinara S Vidal
- Department of Biological Chemistry, Laboratory of Pharmacology and Molecular Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil
| | - Rogério de A Saraiva
- Department of Biological Chemistry, Laboratory of Pharmacology and Molecular Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil
| | - José G M da Costa
- Department of Biological Chemistry, Laboratory of Research in Natural Product, Regional University of Cariri - URCA, Crato, CE, Brazil
| | - Henrique D M Coutinho
- Department of Biological Chemistry, Laboratory of Microbiology and Molecular Biology, Regional University of Cariri - URCA, Crato, CE, Brazil
| | - Hericka B F Galvao
- St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
| | - Irwin R A de Menezes
- Department of Biological Chemistry, Laboratory of Pharmacology and Molecular Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil
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Pinto NDCC, Machado DC, da Silva JM, Conegundes JLM, Gualberto ACM, Gameiro J, Moreira Chedier L, Castañon MCMN, Scio E. Pereskia aculeata Miller leaves present in vivo topical anti-inflammatory activity in models of acute and chronic dermatitis. JOURNAL OF ETHNOPHARMACOLOGY 2015; 173:330-337. [PMID: 26226436 DOI: 10.1016/j.jep.2015.07.032] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 07/21/2015] [Accepted: 07/23/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The leaves of Pereskia aculeata Miller (Cactaceae), known as Barbados gooseberry, are used in Brazilian traditional medicine as emollients and to treat skin wounds and inflammation. This study investigated the topical anti-inflammatory activity of the hexane fraction (HF) obtained from the methanol extract of the leaves of this species in models of acute and chronic ear dermatitis in mice. MATERIAL AND METHODS Mice ear edema was induced by topical application of croton oil, arachidonic acid, capsaicin, ethyl-phenylpropiolate and phenol; and by subcutaneous injection of histamine. Ear biopsies were obtained to determine the levels of IL-1β, IL-6 and TNF-α cytokines by ELISA assay. Histopathological analysis was also performed to evaluate the HF activity in croton oil multiple application test. In addition, acute dermal irritation/corrosion test in rats was accomplished. HF chemical characterization was performed by GC-MS analysis. RESULTS HF intensively reduced the inflammatory process induced by all irritant agents used, except for arachidonic acid. This activity is related, at least in part, to the reduction of IL-6 and TNF-α cytokines levels. Moreover, when the glucocorticoid receptor antagonist mifepristone was used, HF failed to respond to the croton oil application.The results strongly suggested a glucocorticoid-like effect, which was reinforced by the presence of considerable amounts of sterol compounds identified in HF. The acute dermal irritaton/corrosion test showed no signs of toxicity. CONCLUSIONS This study showed that the acute and chronic anti-inflammatory activity of P. aculeata leaves is very promising, and corroborates to better understand their ethnopharmacological applications.
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Affiliation(s)
- Nícolas de Castro Campos Pinto
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Biological Science Institute, Federal University of Juiz de Fora, 36036-900, Juiz de Fora, MG Brazil
| | - Danielle Cunha Machado
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Biological Science Institute, Federal University of Juiz de Fora, 36036-900, Juiz de Fora, MG Brazil
| | - Josiane Mello da Silva
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Biological Science Institute, Federal University of Juiz de Fora, 36036-900, Juiz de Fora, MG Brazil
| | - Jéssica Leiras Mota Conegundes
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Biological Science Institute, Federal University of Juiz de Fora, 36036-900, Juiz de Fora, MG Brazil
| | - Ana Cristina Moura Gualberto
- Department of Parasitology, Microbiology and Immunology, Biological Sciences Institute, Federal University of Juiz de Fora, 36036 900, Juiz de Fora, MG, Brazil
| | - Jacy Gameiro
- Department of Parasitology, Microbiology and Immunology, Biological Sciences Institute, Federal University of Juiz de Fora, 36036 900, Juiz de Fora, MG, Brazil
| | - Luciana Moreira Chedier
- Department of Botany, Biological Science Institute, Federal University of Juiz de Fora, 36036-900, Juiz de Fora, MG Brazil
| | | | - Elita Scio
- Laboratory of Bioactive Natural Products, Department of Biochemistry, Biological Science Institute, Federal University of Juiz de Fora, 36036-900, Juiz de Fora, MG Brazil.
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28
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Kumar G, Tajpara P, Bukhari AB, Ramchandani AG, De A, Maru GB. Dietary curcumin post-treatment enhances the disappearance of B(a)P-derived DNA adducts in mouse liver and lungs. Toxicol Rep 2014; 1:1181-1194. [PMID: 28962328 PMCID: PMC5598465 DOI: 10.1016/j.toxrep.2014.11.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 11/07/2014] [Accepted: 11/07/2014] [Indexed: 01/04/2023] Open
Abstract
Effects of dietary curcumin on disappearance of DNA adducts were studied. Curcumin post-treatment enhanced the disappearance of BPDE-DNA adducts in liver/lungs. Curcumin post-treatment augmented B(a)P-induced apoptosis during 24–120 h. Curcumin post-treatment increased PCNA in B(a)P-treated tissues during 7–28 days. Curcumin-mediated increase in apoptosis and cell proliferation decreased DNA adducts. To study the post-treatment effects of dietary curcumin on the levels of benzo(a)pyrene [B(a)P]-induced DNA adducts, mice were administered oil or B(a)P and randomized into 7 subgroups after 24 h. One of the subgroups from both the oil and B(a)P groups was killed at 24 h while the remaining 6 subgroups were shifted to powdered control or 0.05% curcumin diet and killed after 24, 72 and 120 h (experiment 1), and 7, 14, and 28 days (experiment 2). Quantitative comparisons of BPDE-DNA nuclear adducts (area and intensity) in immunohistochemically stained lungs and liver sections was carried out by IHC profiler. A time-dependent decrease in the levels of adducts in B(a)P-treated animals was further enhanced by curcumin exposure compared to the levels in time-matched controls. To assess the contribution of apoptosis and cell proliferation in observed curcumin-mediated enhanced decrease of BPDE-DNA adducts, comparative evaluation of apoptosis and cell proliferation markers was undertaken. Results suggested enhancement of B(a)P-induced apoptosis in liver and lungs by curcumin during 24–120 h while no such enhancement was observed at 7–28 days. Results suggest curcumin-mediated enhancement in apoptosis (experiment 1) and adduct dilution (experiment 2) to be the reason for the observed higher decrease of BPDE-DNA adducts.
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Affiliation(s)
- Gaurav Kumar
- Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210, India
| | - Pooja Tajpara
- Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210, India
| | - Amirali B Bukhari
- Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210, India
| | - Asha G Ramchandani
- Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210, India
| | - Abhijit De
- Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210, India
| | - Girish B Maru
- Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210, India
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29
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Affiliation(s)
- Joydip Das
- Department of Pharmacological
and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 521 Science and Research Building 2, Houston, Texas 77204, United States
| | - Ghazi M. Rahman
- Department of Pharmacological
and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 521 Science and Research Building 2, Houston, Texas 77204, United States
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30
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Chibli LA, Rodrigues KCM, Gasparetto CM, Pinto NCC, Fabri RL, Scio E, Alves MS, Del-Vechio-Vieira G, Sousa OV. Anti-inflammatory effects of Bryophyllum pinnatum (Lam.) Oken ethanol extract in acute and chronic cutaneous inflammation. JOURNAL OF ETHNOPHARMACOLOGY 2014; 154:330-338. [PMID: 24727190 DOI: 10.1016/j.jep.2014.03.035] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 02/26/2014] [Accepted: 03/14/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bryophyllum pinnatum (Lam.) Oken (Crassulaceae), popularly known in Brazil as "folha-da-fortuna", is a plant species used in folk medicine for the external and internal treatment of inflammation, infection, wound, burn, boil, ulcers and gastritis, and several other diseases. The present study aimed to perform the chemical characterization and the evaluation of the topical anti-inflammatory effect of the ethanol extract of Bryophyllum pinnatum leaves (EEBP) in acute and chronic mice ear edema models induced by different irritant agents. MATERIALS AND METHODS The EEBP chemical characterization was performed by HPLC-UV DAD. Ear edema on Swiss mice was induced by the topical application of Croton oil (single and multiple applications), arachidonic acid, phenol, capsaicin and ethyl phenylpropiolate (EPP). The topical anti-inflammatory effect of EEBP was evaluated by measuring the ear weight (acute inflammation models) and thickness (chronic inflammation model). Histopathological analyses of ear tissue samples sensitized with Croton oil (single and multiple applications) were also performed. RESULTS The flavonoids rutin, quercetin, luteolin and luteolin7-O-β-d-glucoside were detected in EEBP. Topical application of EEBP significantly (P<0.001) inhibited the ear edema induced by Croton oil single application (inhibition of 57%), arachidonic acid (inhibition of 67%), phenol (inhibition of 80%), capsaicin (inhibition of 72%), EPP (inhibition of 75%) and Croton oil multiple application (55% after 9 days). Histopathological analyses confirmed the topical anti-inflammatory effect of EEBP since it was observed reduction of edema, epidermal hyperplasia, inflammatory cells infiltration and vasodilation. CONCLUSIONS The results suggest that EEBP is effective as a topical anti-inflammatory agent in acute and chronic inflammatory processes possibly due to inhibition of arachidonic acid pathway, which justify the traditional use of Bryophyllum pinnatum as a remedy for skin disorders.
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Affiliation(s)
- Lucas A Chibli
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Kamilla C M Rodrigues
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Carolina M Gasparetto
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Nícolas C C Pinto
- Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Rodrigo L Fabri
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Elita Scio
- Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Maria S Alves
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Glauciemar Del-Vechio-Vieira
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
| | - Orlando V Sousa
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, Campus Universitário, São Pedro, CEP 36036-330, Juiz de Fora, MG, Brazil.
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Garg R, Caino MC, Kazanietz MG. Regulation of Transcriptional Networks by PKC Isozymes: Identification of c-Rel as a Key Transcription Factor for PKC-Regulated Genes. PLoS One 2013; 8:e67319. [PMID: 23826267 PMCID: PMC3694964 DOI: 10.1371/journal.pone.0067319] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 05/16/2013] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Activation of protein kinase C (PKC), a family of serine-threonine kinases widely implicated in cancer progression, has major impact on gene expression. In a recent genome-wide analysis of prostate cancer cells we identified distinctive gene expression profiles controlled by individual PKC isozymes and highlighted a prominent role for PKCδ in transcriptional activation. PRINCIPAL FINDINGS Here we carried out a thorough bioinformatics analysis to dissect transcriptional networks controlled by PKCα, PKCδ, and PKCε, the main diacylglycerol/phorbol ester PKCs expressed in prostate cancer cells. Despite the remarkable differences in the patterns of transcriptional responsive elements (REs) regulated by each PKC, we found that c-Rel represents the most frequent RE in promoters regulated by all three PKCs. In addition, promoters of PKCδ-regulated genes were particularly enriched with REs for CREB, NF-E2, RREB, SRF, Oct-1, Evi-1, and NF-κB. Most notably, by using transcription factor-specific RNAi we were able to identify subsets of PKCδ-regulated genes modulated by c-Rel and CREB. Furthermore, PKCδ-regulated genes condensed under the c-Rel transcriptional regulation display significant functional interconnections with biological processes such as angiogenesis, inflammatory response, and cell motility. CONCLUSION/SIGNIFICANCE Our study identified candidate transcription factors in the promoters of PKC regulated genes, in particular c-Rel was found as a key transcription factor in the control of PKCδ-regulated genes. The deconvolution of PKC-regulated transcriptional networks and their nodes may greatly help in the identification of PKC effectors and have significant therapeutics implications.
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Affiliation(s)
- Rachana Garg
- Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - M. Cecilia Caino
- Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Marcelo G. Kazanietz
- Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- * E-mail:
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Thangapazham RL, Sharad S, Maheshwari RK. Skin regenerative potentials of curcumin. Biofactors 2013; 39:141-9. [PMID: 23315856 DOI: 10.1002/biof.1078] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 11/29/2012] [Indexed: 01/11/2023]
Abstract
Curcumin, an active constituent of the spice turmeric, is well known for its chemopreventive properties and is found to be beneficial in treating various disorders including skin diseases. Curcumin protects skin by quenching free radicals and reducing inflammation through the inhibition of nuclear factor-kappa B. Curcumin also affects other signaling pathways including transforming growth factor-β and mitogen-activated protein kinase pathway. Curcumin also modulates the phase II detoxification enzymes which are crucial in detoxification reactions and for protection against oxidative stress. In the present review, the biological mechanisms of the chemopreventive potential of curcumin in various skin diseases like psoriasis, vitiligo, and melanoma is discussed. The application of curcumin in skin regeneration and wound healing is also elucidated. We also explored the recent innovations and advances involved in the development of transdermal delivery systems to enhance the bioavailability of curcumin, particularly in the skin. Recent clinical trials pertaining to the use of curcumin in skin diseases establishes its benefits and also the need for additional clinical trials in other diseases are discussed.
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Affiliation(s)
- Rajesh L Thangapazham
- Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
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Garg R, Blando J, Perez CJ, Wang H, Benavides FJ, Kazanietz MG. Activation of nuclear factor κB (NF-κB) in prostate cancer is mediated by protein kinase C epsilon (PKCepsilon). J Biol Chem 2012; 287:37570-37582. [PMID: 22955280 PMCID: PMC3481351 DOI: 10.1074/jbc.m112.398925] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Revised: 08/20/2012] [Indexed: 02/05/2023] Open
Abstract
Protein kinase C ε (PKCε) has emerged as an oncogenic kinase and plays important roles in cell survival, mitogenesis and invasion. PKCε is up-regulated in most epithelial cancers, including prostate, breast, and lung cancer. Here we report that PKCε is an essential mediator of NF-κB activation in prostate cancer cells. A strong correlation exists between PKCε overexpression and NF-κB activation status in prostate cancer cells. Moreover, transgenic overexpression of PKCε in the mouse prostate causes preneoplastic lesions that display significant NF-κB hyperactivation. PKCε RNAi depletion or inhibition in prostate cancer cells diminishes NF-κB translocation to the nucleus with subsequent impairment of both activation of NF-κB transcription and induction of NF-κB responsive genes in response to the proinflammatory cytokine tumor necrosis factor α (TNFα). On the other hand, PKCε overexpression in normal prostate cells enhances activation of the NF-κB pathway. A mechanistic analysis revealed that TNFα activates PKCε via a C1 domain/diacylglycerol-dependent mechanism that involves phosphatidylcholine-phospholipase C. Moreover, PKCε facilitates the assembly of the TNF receptor-I signaling complex to trigger NF-κB activation. Our studies identified a molecular link between PKCε and NF-κB that controls key responses implicated in prostate cancer progression.
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Affiliation(s)
- Rachana Garg
- From the Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Jorge Blando
- the Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, and
| | - Carlos J. Perez
- the Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957
| | - HongBin Wang
- From the Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Fernando J. Benavides
- the Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957
| | - Marcelo G. Kazanietz
- From the Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Killian PH, Kronski E, Michalik KM, Barbieri O, Astigiano S, Sommerhoff CP, Pfeffer U, Nerlich AG, Bachmeier BE. Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2. Carcinogenesis 2012; 33:2507-19. [DOI: 10.1093/carcin/bgs312] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Soetikno V, Sari FR, Sukumaran V, Lakshmanan AP, Mito S, Harima M, Thandavarayan RA, Suzuki K, Nagata M, Takagi R, Watanabe K. Curcumin prevents diabetic cardiomyopathy in streptozotocin-induced diabetic rats: Possible involvement of PKC–MAPK signaling pathway. Eur J Pharm Sci 2012; 47:604-14. [DOI: 10.1016/j.ejps.2012.04.018] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 03/23/2012] [Accepted: 04/21/2012] [Indexed: 10/28/2022]
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Kumar G, Dange P, Kailaje V, Vaidya MM, Ramchandani AG, Maru GB. Polymeric black tea polyphenols modulate the localization and activity of 12-O-tetradecanoylphorbol-13-acetate-mediated kinases in mouse skin: mechanisms of their anti-tumor-promoting action. Free Radic Biol Med 2012; 53:1358-70. [PMID: 22841871 DOI: 10.1016/j.freeradbiomed.2012.07.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 07/05/2012] [Accepted: 07/17/2012] [Indexed: 02/06/2023]
Abstract
Polymeric black tea polyphenols (PBPs) have been shown to possess anti-tumor-promoting effects in two-stage skin carcinogenesis. However, their mechanisms of action are not fully elucidated. In this study, mechanisms of PBP-mediated antipromoting effects were investigated in a mouse model employing the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Compared to controls, a single topical application of TPA to mouse skin increased the translocation of protein kinase C (PKC) from cytosol to membrane. Pretreatment with PBPs 1-3 decreased TPA-induced translocation of PKC isozymes (α, β, η, γ, ε) from cytosol to membrane, whereas PBPs 4 and 5 were less effective. The levels of PKCs δ and ζ in cytosol/membrane were similar in all the treatment groups. Complementary confocal microscopic evaluation showed a decrease in TPA-induced PKCα fluorescence in PBP-3-pretreated membranes, whereas pretreatment with PBP-5 did not show a similar decrease. Based on the experiments with specific enzyme inhibitors and phosphospecific antibodies, both PBP-3 and PBP-5 were observed to decrease TPA-induced level and/or activity of phosphatidylinositol 3-kinase (PI3K) and AKT1 (pS473). An additional ability of PBP-3 to inhibit site-specific phosphorylation of PKCα at all three positions responsible for its activation [PKCα (pT497), PKC PAN (βII pS660), PKCα/βII (pT638/641)] and AKT1 at the Thr308 position, along with a decrease in TPA-induced PDK1 protein level, correlated with the inhibition of translocation of PKC, which may impart relatively stronger chemoprotective activity to PBP-3 than to PBP-5. Altogether, PBP-mediated decrease in TPA-induced PKC phosphorylation correlated well with decreased TPA-induced NF-κB phosphorylation and downstream target proteins associated with proliferation, apoptosis, and inflammation in mouse skin. Results suggest that the antipromoting effects of PBPs are due to modulation of TPA-induced PI3K-mediated signal transduction.
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Affiliation(s)
- Gaurav Kumar
- Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India
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Li Y, Zhang D, Chen C, Ruan Z, Li Y, Huang Y. MicroRNA-212 displays tumor-promoting properties in non-small cell lung cancer cells and targets the hedgehog pathway receptor PTCH1. Mol Biol Cell 2012; 23:1423-34. [PMID: 22357618 PMCID: PMC3327317 DOI: 10.1091/mbc.e11-09-0777] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Overexpression of microRNA-212 promoted cell cycle progression and cell proliferation, migration, and invasion in non–small cell lung cancer cells. PTCH1, a receptor of hedgehog pathway, is a functional target of miR-212. The role of miR-212 in cell proliferation may be mediated by PTCH1. Dysexpression of microRNAs has been found in many tumors, including lung cancer. The hedgehog (Hh) signaling pathway plays an important role during normal development, and the abnormal regulation of its members has also been related to many tumors. However, little is known about the relationship between microRNA and the Hh pathway. In this paper, we report microRNA-212 (miR-212) playing a role in non-small cell lung cancer (NSCLC) and targeting PTCH1, a receptor of the Hh pathway. We found that miR-212 was up-regulated when cells were treated with 4ß-12-O-tetradecanoylphorbol-13-acetate (TPA). We ectopically expressed miR-212 in NSCLC cell lines to examine the influence of miR-212 overexpression. The results showed that overexpression of miR-212 in NSCLC cells promoted cell cycle progression and cell proliferation, migration, and invasion. The promoting effects of miR-212 on cell proliferation, migration, and invasion were partially reversed by the miR-212 inhibitor anti-miR-212. These results suggested that miR-212 might have tumor-promoting properties. Potential targets of miR-212 were predicted, and we showed tumor suppressor PTCH1 was a functional target of miR-212. PTCH1 may be responsible for the effect of miR-212 on cell proliferation. Altogether, our results indicated that miR-212 was involved in tumorigenesis, and the oncogenic activity of miR-212 in NSCLC cells was due, in part, to suppression of PTCH1.
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Affiliation(s)
- Yuan Li
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China
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Pinheiro BG, Silva ASB, Souza GEP, Figueiredo JG, Cunha FQ, Lahlou S, da Silva JKR, Maia JGS, Sousa PJC. Chemical composition, antinociceptive and anti-inflammatory effects in rodents of the essential oil of Peperomia serpens (Sw.) Loud. JOURNAL OF ETHNOPHARMACOLOGY 2011; 138:479-486. [PMID: 21971207 DOI: 10.1016/j.jep.2011.09.037] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 07/29/2011] [Accepted: 09/20/2011] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Peperomia serpens (Piperaceae), popularly known as "carrapatinho", is an epiphyte herbaceous liana grown wild on different host trees in the Amazon rainforest. Its leaves are largely used in Brazilian folk medicine to treat inflammation, pain and asthma. AIM OF THE STUDY This study investigated the effects of essential oil of Peperomia serpens (EOPs) in standard rodent models of pain and inflammation. MATERIALS AND METHODS The antinociceptive activity was evaluated using chemical (acetic acid and formalin) and thermal (hot plate) models of nociception in mice whereas the anti-inflammatory activity was evaluated by carrageenan- and dextran-induced paw edema tests in rats croton oil-induced ear edema, as well as cell migration, rolling and adhesion induced by carrageenan in mice. Additionally, phytochemical analysis of the EOPs has been also performed. RESULTS Chemical composition of the EOPs was analyzed by gas chromatography and mass spectrometry (GC/MS). Twenty-four compounds, representing 89.6% of total oil, were identified. (E)-Nerolidol (38.0%), ledol (27.1%), α-humulene (11.5%), (E)-caryophyllene (4.0%) and α-eudesmol (2.7%) were found to be the major constituents of the oil. Oral pretreatment with EOPs (62.5-500 mg/kg) significantly reduced the writhing number evoked by acetic acid injection, with an ED(50) value of 188.8 mg/kg that was used thereafter in all tests. EOPs had no significant effect on hot plate test but reduced the licking time in both phases of the formalin test, an effect that was not significantly altered by naloxone (0.4 mg/kg, s.c.). EOPs inhibited the edema formation induced by carrageenan and dextran in rats. In mice, EOPs inhibited the edema formation by croton oil as well as the leukocyte and neutrophil migration, the rolling and the adhesion of leukocytes. CONCLUSIONS These data show for the first time that EOPs has a significant and peripheral antinociceptive effect that seems unrelated to interaction with the opioid system. EOPs also displays a significant anti-inflammatory effect in acute inflammation models. This effect seems to be related to components which inhibit the production of several inflammatory mediators. These results support the widespread use of Peperomia serpens in popular medicine to treat inflammation and pain.
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Affiliation(s)
- B G Pinheiro
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pará, 66075-900 Belém, Pará, Brazil
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Zeng DX, Xu YJ, Liu XS, Wang R, Xiang M. Cigarette smoke extract induced rat pulmonary artery smooth muscle cells proliferation via PKCα-mediated cyclin D1 expression. J Cell Biochem 2011; 112:2082-8. [PMID: 21465534 DOI: 10.1002/jcb.23131] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Cigarette smoke could induce pulmonary smooth muscle cells (PASMCs) proliferation. Although our previous study had implied the involvement of protein kinase Cα (PKCα), the molecular mechanism underlying PKCα pathway in this process is still unknown. In this study, rat PASMCs were stimulated by cigarette smoke extract (CSE) or PMA (a special activator to PKCα). Two percent CSE and PMA significantly enhanced cyclin D1 expression and cells proliferation. But cyclin D1-specific siRNA successfully inhibited DNA synthesis in CSE-treated or PMA-treated cells. On the other hand, PKCα-specific siRNA significantly suppressed cyclin D1 expression in CSE-treated cells. Moreover, PKCα-specific siRNA resulted in a cell-cycle arrest in G0/G1 and decreased cells number significantly. We conclude that CSE induced rat PASMCs proliferation at least partly via PKCα-mediated cyclin D1 expression.
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Affiliation(s)
- Da-Xiong Zeng
- Key Laboratory of Pulmonary Diseases of Ministry of Health, Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China
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Curcumin modulates PKCα activity by a membrane-dependent effect. Arch Biochem Biophys 2011; 513:36-41. [PMID: 21741352 DOI: 10.1016/j.abb.2011.06.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 06/18/2011] [Accepted: 06/22/2011] [Indexed: 11/22/2022]
Abstract
Curcumin modulates the activity of protein kinase Cα (PKCα) when assayed in the presence of vesicles including phosphatidylcholine, phosphatidylserine and diacylglycerol. Increasing concentrations of curcumin progressively increased PKCα activity at concentrations lower than 20μM, but at higher concentrations of curcumin the activity decreased although, at concentrations of curcumin of up to 100μM the activity was always higher than the basal one (in the absence of curcumin). The maximum activity was reached at 3μM curcumin, at 20 and 30mol% of phosphatidylserine, 10μM Ca(2+) and 2mol% diacylglycerol. The same type of modulation was observed when changing the concentration of phosphatidylserine, diacylglycerol and Ca(2+). No effect of curcumin was found when the activity was assayed in the presence of Triton X-100 mixed micelles which included phosphatidylserine and diacylglycerol, indicating that the effect of curcumin was membrane-dependent. The pattern of binding of PKCα to membrane vesicles as a function of curcumin concentration closely correlated with the pattern of activating effect. It was concluded that the effect of curcumin on PKCα activity was related to its effect on the membrane, which may modulate the binding of the enzyme to the membrane.
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Schemies J, Uciechowska U, Sippl W, Jung M. NAD(+) -dependent histone deacetylases (sirtuins) as novel therapeutic targets. Med Res Rev 2011; 30:861-89. [PMID: 19824050 DOI: 10.1002/med.20178] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Histone deacetylases (HDACs) are enzymes that cleave off acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Four different classes of HDACs have been identified in humans so far. Although classes I, II, and IV are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD(+)) for their catalytic activity. According to their homology to Sir2p, a yeast histone deacetylase, the class III is also termed sirtuins. Seven members have been described in humans so far. As sirtuins are involved in many physiological and pathological processes, their activity has been associated with the pathogenesis of cancer, HIV, metabolic, or neurological diseases. Herein, we present an overview over sirtuins including their biology, targets, inhibitors, and activators and their potential as new therapeutic agents.
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Affiliation(s)
- Jörg Schemies
- Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany
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Leonarduzzi G, Sottero B, Poli G. Targeting tissue oxidative damage by means of cell signaling modulators: The antioxidant concept revisited. Pharmacol Ther 2010; 128:336-74. [DOI: 10.1016/j.pharmthera.2010.08.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Accepted: 08/02/2010] [Indexed: 12/25/2022]
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Andújar I, Recio MC, Bacelli T, Giner RM, Ríos JL. Shikonin reduces oedema induced by phorbol ester by interfering with IkappaBalpha degradation thus inhibiting translocation of NF-kappaB to the nucleus. Br J Pharmacol 2010; 160:376-88. [PMID: 20423347 DOI: 10.1111/j.1476-5381.2010.00696.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND AND PURPOSE In the present paper we studied the effect of shikonin on ear oedema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), and determined the mechanisms through which shikonin might exert its topical anti-inflammatory action. EXPERIMENTAL APPROACH Acute ear oedema was induced in mice by topical application of TPA. The in vitro assays used macrophages RAW 264.7 cells stimulated with lipopolysaccharide. Cyclooxygenase-2, inducible nitric oxide synthase, protein kinase Calpha, extracellular signal-regulated protein kinase (ERK), phosphorylated ERK (pERK), c-Jun N-terminal kinase (JNK), pJNK, p38, p-p38, p65, p-p65, inhibitor protein of nuclear factor-kappaB (NF-kappaB) (IkappaBalpha) and pIkappaBalpha were measured by Western blotting, activation and binding of NF-kappaB to DNA was detected by reporter gene and electrophoretic mobility shift assay, respectively, and NF-kappaB p65 localization was detected by immunocytochemistry. KEY RESULTS Shikonin reduced the oedema (inhibitory dose 50 = 1.0 mg per ear), the expression of cyclooxygenase-2 (70%) and of inducible nitric oxide synthase (100%) in vivo. It significantly decreased TPA-induced translocation of protein kinase Calpha, the phosphorylation and activation of ERK, the nuclear translocation of NF-kappaB and the TPA-induced NF-kappaB-DNA-binding activity in mouse skin. Moreover, in RAW 264.7 cells, shikonin significantly inhibited the binding of NF-kappaB to DNA in a dose-dependent manner and the nuclear translocation of p65. CONCLUSIONS AND IMPLICATIONS Shikonin exerted its topical anti-inflammatory action by interfering with the degradation of IkappaBalpha, thus inhibiting the activation of NF-kappaB.
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Affiliation(s)
- I Andújar
- Departament de Farmacologia, Universitat de València, Burjassot, Spain
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Kremer R, Best LA, Savulescu D, Gavish M, Nagler RM. Pleural fluid analysis of lung cancer vs benign inflammatory disease patients. Br J Cancer 2010; 102:1180-4. [PMID: 20216542 PMCID: PMC2853096 DOI: 10.1038/sj.bjc.6605607] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Correct diagnosis of pleural effusion (PE) as either benign or malignant is crucial, although conventional cytological evaluation is of limited diagnostic accuracy, with relatively low sensitivity rates. METHODS We identified biological markers accurately detected in a simple PE examination. We analysed data from 19 patients diagnosed with lung cancer (nine adeno-Ca, five non-small-cell Ca (not specified), four squamous-cell Ca, one large-cell Ca) and 22 patients with benign inflammatory pathologies: secondary to trauma, pneumonia or TB. RESULTS Pleural effusion concentrations of seven analysed biological markers were significantly lower in lung cancer patients than in benign inflammatory patients, especially in matrix metalloproteinase (MMP)-9, MMP-3 and CycD1 (lower by 65% (P<0.000003), 40% (P<0.0007) and 34% (P<0.0001), respectively), and in Ki67, ImAnOx, carbonyls and p27. High rates of sensitivity and specificity values were found for MMP-9, MMP-3 and CycD1: 80 and 100%; 87 and 73%; and 87 and 82%, respectively. CONCLUSION Although our results are of significant merit in both the clinical and pathogenetic aspects of lung cancer, further research aimed at defining the best combination for marker analysis is warranted. The relative simplicity in analysing these markers in any routine hospital laboratory may result in its acceptance as a new diagnostic tool.
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Affiliation(s)
- R Kremer
- Department of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel
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Majhi A, Rahman GM, Panchal S, Das J. Binding of curcumin and its long chain derivatives to the activator binding domain of novel protein kinase C. Bioorg Med Chem 2010; 18:1591-8. [PMID: 20100661 PMCID: PMC2843403 DOI: 10.1016/j.bmc.2009.12.075] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Revised: 12/24/2009] [Accepted: 12/31/2009] [Indexed: 01/08/2023]
Abstract
Protein kinase C (PKC) is a family of serine/threonine kinases that play a central role in cellular signal transduction. The second messenger diacylglycerol having two long carbon chains acts as the endogenous ligand for the PKCs. Polyphenol curcumin, the active constituent of Curcuma longa is an anti-cancer agent and modulates PKC activity. To develop curcumin derivatives as effective PKC activators, we synthesized several long chain derivatives of curcumin, characterized their absorption and fluorescence properties and studied their interaction with the activator binding second cysteine-rich C1B subdomain of PKCdelta, PKCepsilon and PKCtheta. Curcumin (1) and its C16 long chain analog (4) quenched the intrinsic fluorescence of PKCdeltaC1B, PKCepsilonC1B and PKCthetaC1B in a manner similar to that of PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA). The EC(50)s of the curcumin derivatives for fluorescence quenching varied in the range of 4-11 microM, whereas, EC(50)s for TPA varied in the range of 3-6 microM. Fluorescence emission maxima of 1 and 4 were blue shifted and the fluorescence anisotropy values were increased in the presence of the C1B domains in a manner similar to that shown by the fluorescent analog of TPA, sapintoxin-D, confirming that they were bound to the proteins. Molecular docking of 1 and 4 with novel PKC C1B revealed that both the molecules form hydrogen bonds with the protein residues. The present result shows that curcumin and its long chain derivatives bind to the C1B subdomain of novel PKCs and can be further modified structurally to improve its binding and activity.
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Affiliation(s)
- Anjoy Majhi
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204
| | - Ghazi M. Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204
| | - Shyam Panchal
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204
| | - Joydip Das
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204
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Wang X, Ramirez A, Budunova I. Overexpression of connexin26 in the basal keratinocytes reduces sensitivity to tumor promoter TPA. Exp Dermatol 2009; 19:633-40. [DOI: 10.1111/j.1600-0625.2009.01013.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Kashfi K. Anti-inflammatory agents as cancer therapeutics. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2009; 57:31-89. [PMID: 20230759 DOI: 10.1016/s1054-3589(08)57002-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer prevention sometimes referred to as tertiary prevention or chemoprevention makes use of specific xenobiotics or drugs to prevent, delay, or retard the development of cancer. Over the last two decades or so cancer prevention has made significant strides. For example, prevention of lung cancer through smoking cessation; cervical cancer prevention through regular Pap smear tests; colon cancer prevention through screening colonoscopy; and prostate cancer reductions by prostate-specific antigen measurements in conjunction with regular prostate examinations. The seminal epidemiological observation that nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon and other cancers has provided the impetus to develop novel chemoprevention approaches against cancer. To that end, a number of "designer drugs" have been synthesized that are in different stages of development, evaluation, and deployment. Some include the cyclooxygenase-2-specific inhibitors (coxibs), nitric oxide-releasing NSAIDs (NO-NSAIDs and NONO-NSAIDs), hydrogen sulfide-releasing NSAIDs, modulators of the lipoxygenase pathway, prostanoid receptor blockers, and chemokine receptor antagonists. In addition to these novel agents, there are also a host of naturally occurring compounds/micronutrients that have chemopreventive properties. This chapter reviews these classes of compounds, their utility and mechanism(s) of action against the background of mediators that link inflammation and cancer.
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Affiliation(s)
- Khosrow Kashfi
- Department of Physiology and Pharmacology, Sophie Davis School of Biomedical Education, The City College of The City University of New York, New York 10031, USA
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Pan MH, Lai CS, Dushenkov S, Ho CT. Modulation of inflammatory genes by natural dietary bioactive compounds. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2009; 57:4467-77. [PMID: 19489612 DOI: 10.1021/jf900612n] [Citation(s) in RCA: 181] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Several epidemiologic studies have shown that chronic inflammation predisposes individuals to various types of cancer. Many cancers arise from sites of infection, chronic irritation, and inflammation. Conversely, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumors. Natural bioactive compounds in dietary plant products including fruits, vegetables, grains, legumes, tea, and wine are claimed to help prevent cancer, degenerative diseases, and chronic and acute inflammation. Modern methods in cell and molecular biology allow us to understand the interactions of different natural bioactive compounds with basic mechanisms of inflammatory response. The molecular pathways of this cancer-related inflammation are now unraveled. Natural bioactive compounds exert anti-inflammatory activity by modulating pro-inflammatory gene expressions have shown promising chemopreventive activity. This review summarizes current knowledge on natural bioactive compounds that act through the signaling pathways and modulate inflammatory gene expressions, thus providing evidence for these substances in cancer chemopreventive action.
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Affiliation(s)
- Min-Hsiung Pan
- Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung 811, Taiwan.
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Pan MH, Chiou YS, Chen WJ, Wang JM, Badmaev V, Ho CT. Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Carcinogenesis 2009; 30:1234-42. [PMID: 19447859 DOI: 10.1093/carcin/bgp121] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, anti-proliferation and analgesic potential. However, the effects of pterostilbene in preventing invasion of cancer cells have not been studied. Here, we report our finding that pterostilbene significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma cells (HepG(2) cells). Increase in the enzyme activity, protein and messenger RNA levels of matrix metalloproteinase (MMP)-9 were observed in TPA-treated HepG(2) cells, and these were blocked by pterostilbene. In addition, pterostilbene can inhibit TPA-induced expression of vascular endothelial growth factor, epidermal growth factor and epidermal growth factor receptor. Transient transfection experiments also showed that pterostilbene strongly inhibited TPA-stimulated nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1)-dependent transcriptional activity in HepG(2) cells. Moreover, pterostilbene can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases 1/2 and phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 and 250 mg/kg intraperitoneally) after inoculation with HepG(2) cells into the tail vein. Presented data reveal that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.
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Affiliation(s)
- Min-Hsiung Pan
- Department of Seafood Science, National Kaohsiung Marine University, No. 142 Hai-Chuan Road, Nan-Tzu, Kaohsiung 811, Taiwan.
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Fraser CC. G protein-coupled receptor connectivity to NF-kappaB in inflammation and cancer. Int Rev Immunol 2009; 27:320-50. [PMID: 18853342 DOI: 10.1080/08830180802262765] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Complex intracellular network interactions regulate gene expression and cellular behavior. Whether at the site of inflammation or within a tumor, individual cells are exposed to a plethora of signals. The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes that control key cellular activities involved in inflammatory diseases and cancer. NF-kappaB is regulated by several distinct signaling pathways that may be activated individually or simultaneously. Multiple ligands and heterologous cell-cell interactions have an impact on NF-kappaB activity. The G protein-coupled receptor (GPCR) superfamily makes up the largest class of transmembrane receptors in the human genome and has multiple molecularly distinct natural ligands. GPCRs regulate proliferation, differentiation, and chemotaxis and play a major role in inflammatory diseases and cancer. Both GPCRs and NF-kappaB have been, and continue to be, major targets for drug discovery. A clear understanding of network interactions between GPCR signaling pathways and those that control NF-kB may be valuable for the development of better drugs and drug combinations.
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