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García-Dolores F, Hernández-Torres MA, Fuentes-Medel E, Díaz A, Guevara J, Baltazar-Gaytan E, Aguilar-Hernández L, Nicolini H, Morales-Medina JC, González-Cano SI, de la Cruz F, Gil-Velazco A, Tendilla-Beltrán H, Flores G. Atrophy and Higher Levels of Inflammatory-Related Markers in the Posterior Cerebellar Lobe Cortex in Chronic Alcohol Use Disorder: A Cross-Sectional Study. Neuropathol Appl Neurobiol 2025; 51:e70011. [PMID: 40141018 DOI: 10.1111/nan.70011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 02/27/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025]
Abstract
AIMS Alcohol use disorder (AUD) involves excessive and chronic ethanol consumption, leading to various health issues, including cerebellar atrophy. The cerebellum is particularly susceptible to ethanol-induced damage through neuroinflammation, oxidative stress and excitotoxicity. This damage has been documented predominantly in the anterior lobe, primarily due to its role in motor function, which is often impaired in patients with AUD. However, less is known about the impact of AUD on the posterior cerebellar lobes. In contrast, alterations in the posterior lobe have been associated with cerebellar cognitive affective syndrome (CCAS). Moreover, the cerebellum is an asymmetric structure with spatial functions being left-lateralised. We hypothesised that the posterior cerebellar lobe in AUD cases would show increased inflammation compared with healthy controls. METHODS This cross-sectional study examined the structural integrity and neuroinflammatory state of the left posterior cerebellar lobe cortex in post-mortem samples from nine males with chronic AUD and 9 control cases. RESULTS Chronic AUD cases showed significant cerebellar damage. Immunohistochemistry revealed higher levels of reactive astrogliosis (GFAP), increased Treg cell markers (CD45 and FOXP3), increased mitochondria marker (MitoTrackerTM), elevated COX2 (indicating inflammation and Treg cell activity), increased cFos protein (cell activity marker), and higher caspase 3 (Casp3) levels, suggesting excessive cell death. These findings indicate that chronic AUD leads to atrophy in the left posterior cerebellar lobe cortex due to neuroinflammation driven by reactive astrogliosis, Treg cell infiltration, and COX2 activity. CONCLUSIONS The study highlights the inflammatory consequences of chronic AUD, potentially linked to cerebellar atrophy and subsequent motor and cognitive impairments. Targeting neuroinflammation could help mitigate the neurodegenerative effects of chronic AUD.
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Affiliation(s)
- Fernando García-Dolores
- Instituto de Ciencias Forenses (INCIFO), Tribunal Superior de Justicia de la Ciudad de México (TSJCDMX), Mexico City, Mexico
| | | | - Estefania Fuentes-Medel
- Departamento de Farmacia, Facultad de Ciencias Químicas (FCQ), Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Alfonso Díaz
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Jorge Guevara
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Eduardo Baltazar-Gaytan
- Facultad de Medicina, Universidad Veracruzana (UV) Región Córdoba, Orizaba, Mexico
- Facultad de Enfermería, Universidad Veracruzana (UV) Región Córdoba, Orizaba, Mexico
| | | | - Humberto Nicolini
- Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Julio César Morales-Medina
- Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
| | | | - Fidel de la Cruz
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City, Mexico
| | - Alicia Gil-Velazco
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Hiram Tendilla-Beltrán
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Gonzalo Flores
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
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Abdulrazaq JA, Zakari MA, Ibrahim Y, Ahmad H. Expression of cyclooxygenase-2 (COX-2) in colorectal carcinoma in an indigenous African population of Kano, Nigeria. Ecancermedicalscience 2024; 18:1816. [PMID: 40171463 PMCID: PMC11959126 DOI: 10.3332/ecancer.2024.1816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Indexed: 01/05/2025] Open
Abstract
Background cyclooxygenases-2 (COX-2) over-expression has been noticed in colorectal cancers (CRCs) with adverse outcomes, serving as a potential marker for prognosis, targeted therapy and as a window in CRC prevention. Unfortunately, there are scarce data regarding COX-2 expression in CRC in Africa where CRC incidence is on the increase with younger age affectation and unfavourable outcomes. Aims This retrospective study aims to determine the proportion of CRCs that over-express COX-2 and document any relationship between COX-2 over-expression with clinicopathological features such as histologic subtype, tumour grade, age and sex. Methods All the 139 CRCs that were histologically diagnosed at Aminu Kano Teaching Hospital over a 5-year period were included, but only 124 Formalin-fixed paraffin-embedded tissue blocks were sectioned and stained with COX-2 antibody. COX-2 expression was scored for distribution (no cells = 0, 1%-10% = 1, 11%-50% = 2, 51%-80% = 3, 81%-100% = 4) and intensity (no stain = 0; weak = 1; moderate = 2, strong = 3). The immunoreactive score (IRS) is a product of intensity (I) and distribution (D) as: 9-12 strongly +, 5-8 moderately +, 1-4 weakly + and 0 negative. Over-expression of COX-2 is an IRS of 5-12. Outcomes were statistically evaluated with clinicopathological data. Results The CRCs occurred more commonly in males (M: F, 2:1), in the middle age group (mostly between 30 and 59 years), and 51.1% of cases occurred before 50 years and peaked in the 6th decade. Over-expression of COX-2 was observed in 46.8% (58/124) and was strongly associated with adenocarcinoma (ADC) not otherwise specified (NOS) (moderately and poorly differentiated tumours) but not with age or sex. Conclusion The over-expression of COX-2 was significantly associated with ADC NOS (moderately and poorly differentiated tumours), indicating that it may influence the outcome of CRCs with possible variation in tumour subtype.
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Affiliation(s)
- Jimoh Ajanaku Abdulrazaq
- Department of Pathology, Federal University of Health Sciences Azare, Azare 751101, Bauchi, Nigeria
| | | | - Yusuf Ibrahim
- Department of Pathology, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
| | - Hamza Ahmad
- Department of Pathology, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
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Repici A, Capra AP, Hasan A, Basilotta R, Scuderi SA, Campolo M, Paterniti I, Esposito E, Ardizzone A. Ulva pertusa Modulated Colonic Oxidative Stress Markers and Clinical Parameters: A Potential Adjuvant Therapy to Manage Side Effects During 5-FU Regimen. Int J Mol Sci 2024; 25:12988. [PMID: 39684698 DOI: 10.3390/ijms252312988] [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: 11/05/2024] [Revised: 11/24/2024] [Accepted: 11/30/2024] [Indexed: 12/18/2024] Open
Abstract
One of the most used chemotherapy agents in clinical practice is 5-Fluorouracil (5-FU), a fluorinated pyrimidine in the category of antimetabolite agents. 5-FU is used to treat a variety of cancers, including colon, breast, pancreatic, and stomach cancers, and its efficacy lies in its direct impact on the patient's DNA and RNA. Specifically, its mechanism blocks the enzymes thymidylate synthetase and uracil phosphatase, inhibiting the synthesis of uracil, which cannot be incorporated into nuclear and cytoplasmic RNA. Despite being one of the most used drugs in oncology, it is associated with several significant side effects, including inflammation of the mouth, loss of appetite, and reduction in blood cells. In our study, we examined the reduction of side effects in a 5-FU regimen administered at doses of 15 mg/kg and 6 mg/kg for 14 days in 6-week-old male Sprague-Dawley rats. On the 14th day, the rats were treated orally for 2 weeks with 100 mg/kg of Ulva pertusa, a well-known seaweed from the Ulvaceae family, which has demonstrated powerful biological properties. The administration of this green alga alleviated the side effects of 5-FU, improving several parameters including body weight, food intake, and diarrhea index. It also helped reduce side effects in the blood, kidneys, and liver. Histological and molecular analyses were conducted on serum and colon tissues from the rats, examining changes in colon structure and the release of oxidative stress markers such as iNOS, COX-2, and nitrotyrosine. Several biochemical indicators, including SOD, CAT, GSH, MDA, and ascorbic acid, were also evaluated. Overall, our data indicated Ulva pertusa to be a promising therapeutic against 5-FU's adverse effects, therefore, it could be worthwhile to investigate the possibility of using this alga in safer cancer treatment formulations. Certainly, future preclinical and clinical studies could assess the alga's efficacy in diverse cancer treatment regimens, exploring its role as an adjuvant therapy that may reduce chemotherapy-related toxicity without compromising therapeutic outcomes.
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Affiliation(s)
- Alberto Repici
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Anna Paola Capra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Ahmed Hasan
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
- Center of Neuroscience, School of Advanced Studies, University of Camerino, 62032 Camerino, Italy
| | - Rossella Basilotta
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Sarah Adriana Scuderi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Michela Campolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Alessio Ardizzone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
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Singh MT, Thaggikuppe Krishnamurthy P, Magham SV. Harnessing the synergistic potential of NK1R antagonists and selective COX-2 inhibitors for simultaneous targeting of TNBC cells and cancer stem cells. J Drug Target 2024; 32:258-269. [PMID: 38252517 DOI: 10.1080/1061186x.2024.2309568] [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: 09/26/2023] [Accepted: 01/11/2024] [Indexed: 01/24/2024]
Abstract
Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.
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Affiliation(s)
- Madhu Tanya Singh
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Praveen Thaggikuppe Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Sai Varshini Magham
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
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Pereira F, Fernández-Barral A, Larriba MJ, Barbáchano A, González-Sancho JM. From molecular basis to clinical insights: a challenging future for the vitamin D endocrine system in colorectal cancer. FEBS J 2024; 291:2485-2518. [PMID: 37699548 DOI: 10.1111/febs.16955] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/03/2023] [Accepted: 09/11/2023] [Indexed: 09/14/2023]
Abstract
Colorectal cancer (CRC) is one of the most life-threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH)2D3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH)2D3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D3 supplementation conducted in both healthy individuals and CRC patients.
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Affiliation(s)
- Fábio Pereira
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Ourense, Spain
| | - Asunción Fernández-Barral
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - María Jesús Larriba
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - Antonio Barbáchano
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - José Manuel González-Sancho
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
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Preethy H A, Venkatakrishnan YB, Ramakrishnan V, Krishnan UM. A network pharmacological approach for the identification of potential therapeutic targets of Brahmi Nei - a complex traditional Siddha formulation. J Biomol Struct Dyn 2024:1-24. [PMID: 38459935 DOI: 10.1080/07391102.2024.2322612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 02/19/2024] [Indexed: 03/11/2024]
Abstract
Brahmi Nei (BN), a traditional Indian polyherbal formulation has been described in classical texts for the treatment of anxiety and depression, as well as to fortify the immune system. The individual herbs of BN have been used for treatment of wide range of disorders including cognition, inflammation, skin ailments and cancer etc., This diverse basket of therapeutic activity suggests that BN may possess therapeutic benefits to other disorders. So, the present study aims to identify the potential therapeutic targets of BN using a network pharmacological approach to comprehend the multi target action of its multiple phytoconstituents. We have employed Randić Index for the first time to calculate the contribution score of module segregated targets towards diseases. Our results suggests that BN targets could also be effective in other diseases such as lysosomal storage disorders, respiratory disorders etc., apart from neurological disorders. The key targets with highest topological measures of Targets-(Pathway)-Targets network were identified as potential therapeutic targets of BN. And the top hit target PTGS2, a gene encoding for cyclooxygenase-2 was further evaluated using molecular docking, molecular dynamic simulation and in vitro studies. Our findings open up new therapeutic facets for BN that can be explored systematically in future.
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Affiliation(s)
- Agnes Preethy H
- Centre for Nanotechnology & Advanced Biomaterials (CeNTAB), SASTRA Deemed University, Thanjavur, India
- School of Chemical & Biotechnology (SCBT), SASTRA Deemed University, Thanjavur, India
| | | | | | - Uma Maheswari Krishnan
- Centre for Nanotechnology & Advanced Biomaterials (CeNTAB), SASTRA Deemed University, Thanjavur, India
- School of Chemical & Biotechnology (SCBT), SASTRA Deemed University, Thanjavur, India
- School of Arts, Sciences, Humanities & Education (SASHE), SASTRA Deemed University, Thanjavur, India
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Park Y, Cao L, Baek S, Jeong S, Yun HJ, Kim MB, Lee SG. The Role of Sargahydroquinoic Acid and Sargachromenol in the Anti-Inflammatory Effect of Sargassum yezoense. Mar Drugs 2024; 22:107. [PMID: 38535449 PMCID: PMC10971697 DOI: 10.3390/md22030107] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/21/2024] [Accepted: 02/24/2024] [Indexed: 01/03/2025] Open
Abstract
The anti-inflammatory effect of the ethanol extract of Sargassum yezoense and its fractions were investigated in this study. The ethanol extract exhibited a strong anti-inflammatory effect on lipopolysaccharide-stimulated RAW 264.7 macrophages and effectively suppressed the M1 polarization of murine bone-marrow-derived macrophages stimulated by lipopolysaccharides and IFN-γ (interferon-gamma). Through a liquid-liquid extraction process, five fractions (n-hexane, chloroform, ethyl acetate, butanol, and aqueous) were acquired. Among these fractions, the chloroform fraction (SYCF) was found to contain the highest concentration of phenolic compounds, along with two primary meroterpenoids, sargahydroquinoic acid (SHQA) and sargachromenol (SCM), and exhibit significant antioxidant capacity. It also demonstrated a robust anti-inflammatory effect. A direct comparison was conducted to assess the relative contribution of SHQA and SCM to the anti-inflammatory properties of SYCF. The concentrations of SHQA and SCM tested were determined based on their relative abundance in SYCF. SHQA contributed to a significant portion of the anti-inflammatory property of SYCF, while SCM played a limited role. These findings not only highlight the potential of the chloroform-ethanol fractionation approach for concentrating meroterpenoids in S. yezoense but also demonstrate that SHQA and other bioactive compounds work additively or synergistically to produce the potent anti-inflammatory effect of SYCF.
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Affiliation(s)
- Yena Park
- Department of Smart Green Technology Engineering, Pukyong National University, Busan 48513, Republic of Korea; (Y.P.); (S.B.); (S.J.)
| | - Lei Cao
- Department of Food Science and Biotechnology, Gachon University, Seongnam 13120, Republic of Korea;
| | - Suhyeon Baek
- Department of Smart Green Technology Engineering, Pukyong National University, Busan 48513, Republic of Korea; (Y.P.); (S.B.); (S.J.)
| | - Seungjin Jeong
- Department of Smart Green Technology Engineering, Pukyong National University, Busan 48513, Republic of Korea; (Y.P.); (S.B.); (S.J.)
| | - Hyun Jung Yun
- Food Safety and Processing Research Division, National Institute of Fisheries Science, Busan 46083, Republic of Korea;
| | - Mi-Bo Kim
- Department of Food Science and Nutrition, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Sang Gil Lee
- Department of Smart Green Technology Engineering, Pukyong National University, Busan 48513, Republic of Korea; (Y.P.); (S.B.); (S.J.)
- Department of Food Science and Nutrition, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
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Khan MZI, Khan D, Akbar MY, Wang H, Haq IU, Chen JZ. 3D-QSAR pharmacophore modeling, virtual screening, molecular docking, MD simulations, in vitro and in vivo studies to identify potential anti-hyperplasia drugs. Biotechnol J 2024; 19:e2300437. [PMID: 38403464 DOI: 10.1002/biot.202300437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/13/2023] [Accepted: 01/02/2024] [Indexed: 02/27/2024]
Abstract
Psoriasis is a common immune-mediated skin condition characterized by aberrant keratinocytes and cell proliferation. The purpose of this study was to explore the FDA-approved drugs by 3D-QSAR pharmacophore model and evaluate their efficiency by in-silico, in vitro, and in vivo psoriasis animal model. A 3D-QSAR pharmacophore model was developed by utilizing HypoGen algorithm using the structural features of 48 diaryl derivatives with diverse molecular patterns. The model was validated by a test set of 27 compounds, by cost analysis method, and Fischer's randomization test. The correlation coefficient of the best model (Hypo2) was 0.9601 for the training set while it was 0.805 for the test set. The selected model was taken as a 3D query for the virtual screening of over 3000 FDA-approved drugs. Compounds mapped with the pharmacophore model were further screened through molecular docking. The hits that showed the best docking results were screened through in silico skin toxicity approach. Top five hits were selected for the MD simulation studies. Based on MD simulations results, the best two hit molecules, that is, ebastine (Ebs) and mebeverine (Mbv) were selected for in vitro and in vivo antioxidant studies performed in mice. TNF-α and COX pro-inflammatory mediators, biochemical assays, histopathological analyses, and immunohistochemistry observations confirmed the anti-inflammatory response of the selected drugs. Based on these findings, it appeared that Ebs can effectively treat psoriasis-like skin lesions and down-regulate inflammatory responses which was consistent with docking predictions and could potentially be employed for further research on inflammation-related skin illnesses such as psoriasis.
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Affiliation(s)
| | - Dildar Khan
- Faculty of Biological Sciences, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Yasir Akbar
- Computational Biology Lab, National Centre for Bioinformatics Quaid-i-Azam University, Islamabad, Pakistan
| | - Hao Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ihsan-Ul Haq
- Faculty of Biological Sciences, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Jian-Zhong Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
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Muhammad N, Khan R, Seraj F, Khan A, Ullah U, Wadood A, Ajmal A, Uzma, Ali B, Khan KM, Ain Nawaz NU, AlMasoud N, Alomar TS, Rauf A. In vivo analgesic, anti-inflammatory and molecular docking studies of S-naproxen derivatives. Heliyon 2024; 10:e24267. [PMID: 38304837 PMCID: PMC10831619 DOI: 10.1016/j.heliyon.2024.e24267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/27/2023] [Accepted: 01/05/2024] [Indexed: 02/03/2024] Open
Abstract
In the current studies two naproxen derivatives (NPD) were evaluated for analgesic and anti-inflammatory properties. The acetic acid and hot plate animal models were used to screen the compounds for analgesic potential. While the anti-inflammatory potential was evaluated through animal paw edema, induced by several inflammatory mediators (carrageenan, bradykinin, and prostaglandin E2), the xylene-induced ear edema was also used as an inflammatory model. Both NPDs showed significant (p < 0.001) antinociceptive effects in the acetic acid-induced writhing paradigm. In the case of the hot plate, the NPD 1 at the tested dose of 5 mg/kg enhanced the latency time after 60 min of injection, which remained significant (p < 0.001) up to the end of the experiment duration. The maximum percent inhibition of NPD 1 was 87.53. The naloxone injection significantly lowered the latency time of NPD 1 as compared to NPD 2. Regarding the anti-inflammatory effect, both of the tested NPDs demonstrated a significant reduction in paw edema against various inflammatory mediators, as mentioned above; however, the anti-inflammatory effect of NPD 1 was better. The maximal percent inhibition by NPD 1 and 2 was 43.24 (after 60 min) and 45.93 (after 90 min). A considerable effect also resulted from xylene-induced ere edema. Further, a molecular docking study was carried out to investigate the binding modes of the NPD. The docking analysis revealed that the NPD significantly interacted with the COX2 enzyme. Furthermore, molecular dynamics simulation was carried out for the docked complexes. The MD simulation analysis revealed the high stability of the two naproxen derivatives.
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Affiliation(s)
- Naveed Muhammad
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakhtunkhwa, Pakistan
| | - Rashid Khan
- Department of Pharmacy, University of Swabi, Swabi, Khyber Pakhtunkhwa, Pakistan
| | - Faiza Seraj
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Abad Khan
- Department of Pharmacy, University of Swabi, Swabi, Khyber Pakhtunkhwa, Pakistan
| | - Ubaid Ullah
- Department of Pharmacy, University of Swabi, Swabi, Khyber Pakhtunkhwa, Pakistan
| | - Abdul Wadood
- Department of Biochemistry, Abdul Wali Khan University, Mardan, Pakhtunkhwa, Pakistan
| | - Amar Ajmal
- Department of Biochemistry, Abdul Wali Khan University, Mardan, Pakhtunkhwa, Pakistan
| | - Uzma
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakhtunkhwa, Pakistan
| | - Basharat Ali
- Sulaiman Bin Abdullah Aba Al-Khail (SA)- Center for Interdisciplinary Research in Basic Science, International Islamic University, Islamabad, Pakistan
| | - Khalid Mohammed Khan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
- Pakistan Academy of Science, 3-Constitution Avenue, G-5/2, Islamabad, 44000, Pakistan
| | - Noor Ul Ain Nawaz
- Department of Pharmacy, City University of Science and Information Technology Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan
| | - Najla AlMasoud
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84427, Riyadh, 11671, Saudi Arabia
| | - Taghrid S. Alomar
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84427, Riyadh, 11671, Saudi Arabia
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, 23430, Pakistan
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Fotopoulos I, Pontiki E, Hadjipavlou-Litina D. Pharmacochemical Study of Multitarget Amino Acids' Hybrids: Design, Synthesis, In vitro, and In silico Studies. Med Chem 2024; 20:709-720. [PMID: 38347768 PMCID: PMC11348465 DOI: 10.2174/0115734064279653240125081042] [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: 08/29/2023] [Revised: 11/21/2023] [Accepted: 12/13/2023] [Indexed: 03/22/2024]
Abstract
INTRODUCTION Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5, COX-2, pro-inflammatory enzymes, and amino acid neurotransmitters are tightly correlated to neuro-inflammatory pathologies. Developing drugs that interfere with these targets will offer treatment for various diseases. OBJECTIVE Herein, we extend our previous research by synthesizing a series of multitarget hybrids of cinnamic acids with amino acids recognized as neurotransmitters. METHODS The synthesis was based on an In silico study of a library of cinnamic amide hybrids with glycine, γ- aminobutyric, and L - glutamic acids. Drug-likeness and ADMET properties were subjected to In silico analysis. Cinnamic acids were derived from the corresponding aldehydes by Knoevenagel condensation. The synthesis of the amides followed a two-step reaction with 1- hydroxybenzotriazole monohydrate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dry dichloromethane and the corresponding amino acid ester hydrochloride salt in the presence of N,N,-diisopropyl-Nethylamine. RESULTS The structure of the synthesized compounds was confirmed spectrophotometrically. The new compounds, such as lipoxygenase, cyclooxygenase-2, lipid peroxidation inhibitors, and antiinflammatories, were tested in vitro. The compounds exhibited LOX inhibition with IC50 values in the low μM region). CONCLUSION Compounds 18a, 23b, and 11c are strong lipid peroxidation inhibitors (99%, 78%, and 92%). Compound 28c inhibits SLOX-1 with IC50 =8.5 μM whereas 11a and 22a highly inhibit COX-2 (IC50 6 and 5 μM Hybrids 14c and 17c inhibit both enzymes. Compound 29c showed the highest anti-inflammatory activity (75%). The In silico ADMET properties of 14c and 11a support their drug-likeness.
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Affiliation(s)
- Ioannis Fotopoulos
- Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
| | - Eleni Pontiki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
| | - Dimitra Hadjipavlou-Litina
- Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
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Kong RJ, Li YM, Huang JQ, Yan N, Wu YY, Cheng H. Self-Delivery Photodynamic Re-educator Enhanced Tumor Treatment by Inducing Immunogenic Cell Death and Improving Immunosuppressive Microenvironments. ACS APPLIED MATERIALS & INTERFACES 2023; 15:59165-59174. [PMID: 38100370 DOI: 10.1021/acsami.3c13188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
Immunotherapy is known to be a promising strategy in the clinical treatment of malignant tumors, but it has received generally low response rates in various tumors because of the poor immunogenicity and multiple immunosuppressive microenvironments. A self-delivery photodynamic re-educator, denoted as CCXB, is synthesized through the self-assembly of chlorine e6 (Ce6) and celecoxib (CXB). As a carrier-free nanomedicine, CCXB shows a high drug loading rate, improved water stability, superior cellular uptake, and tumor accumulation capability. In comparison with free Ce6, CCXB triggers much stronger photodynamic therapy (PDT) to reduce the proliferation of breast cancer cells and activates robust immune responses via the induction of immunogenic cell death (ICD). Better yet, CXB-mediated cyclooxygenase 2 (COX-2) inhibition can decrease the level of synthesis of prostaglandin E2 (PGE2) to further improve immunosuppressive microenvironments. With the increase of cytotoxic T lymphocytes (CTLs) and decrease of regulatory T cells (Tregs) in tumor, in vivo antitumor immunity is significantly amplified to inhibit the metastasis of breast cancer. This study sheds light on developing drug codelivery systems with collaborative mechanisms for immunotherapy of metastatic tumors.
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Affiliation(s)
- Ren-Jiang Kong
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China
| | - Yan-Mei Li
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China
| | - Jia-Qi Huang
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China
| | - Ni Yan
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China
| | - Ye-Yang Wu
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China
| | - Hong Cheng
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China
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12
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Sahu A, Pradhan D, Veer B, Kumar S, Singh R, Raza K, Rizvi MA, Jain AK, Verma S. In silico screening, synthesis, characterization and biological evaluation of novel anticancer agents as potential COX-2 inhibitors. Daru 2023; 31:119-133. [PMID: 37454036 PMCID: PMC10624798 DOI: 10.1007/s40199-023-00467-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Cyclooxygenase enzyme is frequently overexpressed in various types of cancer and found to play a crucial role in poor prognosis in cancer patients. In current research, we have reported the new COX-2 inhibitors for cancer treatment using computer-aided drug design and experimental validation. METHODS A total of 12,795 compounds from the different databases were used to screen against the COX-2 enzyme. It perceived three new compounds with better binding affinity to the enzyme. Afterwards, physicochemical properties and in silico bioactivity were assessed for efficacy, safety, and structural features required for binding. The molecules were synthesized and confirmed by spectroscopic techniques. Later on, molecules were evaluated for their anti-cancer activity using MCF-7, MDA-MB-231 and SiHa cancer cell lines. RESULTS Compound ZINC5921547 and ZINC48442590 (4a, and 4b) reduced the MCF-7, MDA-MB-231, and SiHa cells proliferation potently than parent compounds. The PG-E2 estimation shown, both compounds act through the COX-2 PGE2 axis. Compound 4a and 4b block the cell cycle at G1-S phase and induce cancer cell death. CONCLUSIONS We concluded that compounds 4a and 4b effectively promotes cancer cell death via COX-2 PGE2 axis, and further in vivo studies can be evaluated for development in both compounds as anticancer agents. The compilation of this information will help us to generate better outcome through robust computational methods. The high-quality experimental results may pave the way for identifying effective drug candidates for cancer treatment.
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Affiliation(s)
- Ankita Sahu
- Tumor Biology, ICMR-National Institute of Pathology, New Delhi, 110029, India
| | - Dibyabhaba Pradhan
- Indian Biological Data Center, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Babita Veer
- Department of Applied Chemistry, Delhi Technological University, New Delhi, 110042, India
| | - Sumit Kumar
- Tumor Biology, ICMR-National Institute of Pathology, New Delhi, 110029, India
| | - Ram Singh
- Department of Applied Chemistry, Delhi Technological University, New Delhi, 110042, India
| | - Khalid Raza
- Department of Computer Science, Jamia Millia Islamia, New Delhi, 110025, India
| | - Moshahid A Rizvi
- Department of Bioscience, Jamia Millia Islamia, New Delhi, 110025, India
| | - Arun Kumar Jain
- Biomedical Informatics Centre, ICMR-National Institute of Pathology, New Delhi, 110029, India
| | - Saurabh Verma
- Tumor Biology, ICMR-National Institute of Pathology, New Delhi, 110029, India.
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13
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Wang J, Qiu F, Zhang Z, Liu Y, Zhou Q, Dai S, Xiang S, Wei C. Clostridium butyricum Alleviates DEHP Plasticizer-Induced Learning and Memory Impairment in Mice via Gut-Brain Axis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:18524-18537. [PMID: 37963287 DOI: 10.1021/acs.jafc.3c03533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2023]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) plasticizer, a well-known environmental and food pollutant, has neurotoxicity. However, it is unknown whether DEHP leads to learning and memory impairment through gut-brain axis and whether Clostridium butyricum can alleviate this impairment. Here, C57BL/6 mice were exposed to DEHP and treated with C. butyricum. Learning and memory abilities were evaluated through the Morris water maze. The levels of synaptic proteins, inflammatory cytokines, and 5-hydroxytryptamine (5-HT) were detected by immunohistochemistry or ELISA. Gut microbiota were analyzed through 16S rRNA sequencing. C. butyricum alleviated DEHP-induced learning and memory impairment and restored synaptic proteins. It significantly relieved DEHP-induced inflammation and recovered 5-HT levels. C. butyricum recovered the richness of the gut microbiota decreased by DEHP, with the Bifidobacterium genus increasing the most. Overall, C. butyricum alleviated DEHP-induced learning and memory impairment due to reduced inflammation and increased 5-HT secretion, which was partly attributed to the recovery of gut microbiota.
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Affiliation(s)
- Jin Wang
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Feng Qiu
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Zilong Zhang
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Yu Liu
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Qian Zhou
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Siyu Dai
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Shuanglin Xiang
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Chenxi Wei
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
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14
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Isbel L, Iskar M, Durdu S, Weiss J, Grand RS, Hietter-Pfeiffer E, Kozicka Z, Michael AK, Burger L, Thomä NH, Schübeler D. Readout of histone methylation by Trim24 locally restricts chromatin opening by p53. Nat Struct Mol Biol 2023:10.1038/s41594-023-01021-8. [PMID: 37386214 DOI: 10.1038/s41594-023-01021-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 05/15/2023] [Indexed: 07/01/2023]
Abstract
The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually diverse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as DNA methylation, do not influence the binding of p53 across the genome. Instead, the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated histone 3 lysine 4 (H3K4), thereby preferentially localizing to those p53 sites that reside in closed chromatin, whereas it is deterred from accessible chromatin by H3K4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to affect gene expression as a function of the local chromatin state. These findings link H3K4 methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors that locally modulate TF function.
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Affiliation(s)
- Luke Isbel
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Murat Iskar
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Sevi Durdu
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Joscha Weiss
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Faculty of Sciences, University of Basel, Basel, Switzerland
| | - Ralph S Grand
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany
| | - Eric Hietter-Pfeiffer
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Faculty of Sciences, University of Basel, Basel, Switzerland
| | - Zuzanna Kozicka
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Faculty of Sciences, University of Basel, Basel, Switzerland
| | - Alicia K Michael
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Biozentrum, University of Basel, Basel, Switzerland
| | - Lukas Burger
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Nicolas H Thomä
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Dirk Schübeler
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
- Faculty of Sciences, University of Basel, Basel, Switzerland.
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15
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Kennedy BM, Harris RE. Cyclooxygenase and Lipoxygenase Gene Expression in the Inflammogenesis of Colorectal Cancer: Correlated Expression of EGFR, JAK STAT and Src Genes, and a Natural Antisense Transcript, RP11-C67.2.2. Cancers (Basel) 2023; 15:cancers15082380. [PMID: 37190308 DOI: 10.3390/cancers15082380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/13/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
We examined the expression of major inflammatory genes, cyclooxygenase-1, 2 (COX1, COX2), arachidonate-5-lipoxygenase (ALOX5), and arachidonate-5-lipoxygenase activating protein (ALOX5AP) among 469 tumor specimens of colorectal cancer in The Cancer Genome Atlas (TCGA). Among 411 specimens without mutations in mismatch repair (MMR) genes, the mean expression of each of the inflammatory genes ranked above the 80th percentile, and the overall mean cyclooxygenase expression (COX1+COX2) ranked in the upper 99th percentile of all genes. Similar levels were observed for 58 cases with MMR mutations. Pearson correlation coefficients exceeding r = 0.70 were observed between COX and LOX mRNA levels with genes of major cell-signaling pathways involved in tumorigenesis (Src, JAK STAT, MAPK, PI3K). We observed a novel association (r = 0.78) between ALOX5 expression and a natural antisense transcript (NAT), RP11-67C2.2, a long non-coding mRNA gene, 462 base pairs in length that is located within the terminal intron of the ALOX5 gene on chromosome 10q11.21. Tumor-promoting genes highly correlated with the expression of COX1, COX2, ALOX5 and ALOX5AP are known to increase mitogenesis, mutagenesis, angiogenesis, cell survival, immunosuppression and metastasis in the inflammogenesis of colorectal cancer. These genes and the novel NAT, RP1167C2.2 are potential molecular targets for chemoprevention and therapy of colorectal cancer.
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Affiliation(s)
- Brian M Kennedy
- Colleges of Public Health and Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, 1841 Neil Avenue, Columbus, OH 43210-1351, USA
| | - Randall E Harris
- Colleges of Public Health and Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, 1841 Neil Avenue, Columbus, OH 43210-1351, USA
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16
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Wu T, Orschell CM. The delayed effects of acute radiation exposure (DEARE): characteristics, mechanisms, animal models, and promising medical countermeasures. Int J Radiat Biol 2023; 99:1066-1079. [PMID: 36862990 PMCID: PMC10330482 DOI: 10.1080/09553002.2023.2187479] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/25/2023] [Accepted: 02/20/2023] [Indexed: 03/04/2023]
Abstract
PURPOSE Terrorist use of nuclear weapons and radiation accidents put the human population at risk for exposure to life-threatening levels of radiation. Victims of lethal radiation exposure face potentially lethal acute injury, while survivors of the acute phase are plagued with chronic debilitating multi-organ injuries for years after exposure. Developing effective medical countermeasures (MCM) for the treatment of radiation exposure is an urgent need that relies heavily on studies conducted in reliable and well-characterized animal models according to the FDA Animal Rule. Although relevant animal models have been developed in several species and four MCM for treatment of the acute radiation syndrome are now FDA-approved, animal models for the delayed effects of acute radiation exposure (DEARE) have only recently been developed, and there are no licensed MCM for DEARE. Herein, we provide a review of the DEARE including key characteristics of the DEARE gleaned from human data as well as animal, mechanisms common to multi-organ DEARE, small and large animal models used to study the DEARE, and promising new or repurposed MCM under development for alleviation of the DEARE. CONCLUSIONS Intensification of research efforts and support focused on better understanding of mechanisms and natural history of DEARE are urgently needed. Such knowledge provides the necessary first steps toward the design and development of MCM that effectively alleviate the life-debilitating consequences of the DEARE for the benefit of humankind worldwide.
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Affiliation(s)
- Tong Wu
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Christie M Orschell
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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17
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Villaseñor VM, Navat Enriquez-Vara J, Urías-Silva JE, del Carmen Lugo-Cervantes E, Luna-Vital DA, Mojica L. Mexican grasshopper (Sphenarium purpurascens) as source of high protein flour: Techno-functional characterization, and in silico and in vitro biological potential. Food Res Int 2022; 162:112048. [DOI: 10.1016/j.foodres.2022.112048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 11/04/2022]
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18
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Song J, Jia Y, Li J, Ding R, Yuan Y, Cai J, Su Y, Hua Q, Zhang Z. LiuweiDihuang improved cognitive functions in SAMP8 mice by inhibiting COX-2 expression and subsequent neuroinflammation. JOURNAL OF ETHNOPHARMACOLOGY 2022; 296:115491. [PMID: 35752263 DOI: 10.1016/j.jep.2022.115491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/10/2022] [Accepted: 06/15/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE LiuweiDihuang (LW) pills was mainly used to treatment of children's fontanelle incomplete closure, enuresis and nervous system development delays and other diseases.Following the deepening of pharmacological research, LW has a good effect on neurological diseases include senile dementia. However, the neuroprotection mechanism of LW on Alzheimer's disease (AD) through regulation of inflammation remains unclear. AIM OF THE STUDY Here, we aimed to explore the effects and mechanism of LW on learning and memory deficits in SAMP8 mice. MATERIALS AND METHODS Mice aged 6 months were treated with LW for 2 months and BV2, C6 and HT22 cells were treated with LW pharmaceutic serum and Lipopolysaccharide (LPS) continuously. Then, cognitive tests were performed, including the Morris water maze and Y maze tests. The mRNA level of cyclooxygenase 2 (COX-2) and pro-inflammatory factors (IL-1β, IL-6 and TNF-α) were examined in cells and the cortex and hippocampus by quantitative RT-PCR. The expression of postsynaptic density protein 95, synaptophysin and various inflammatory factors were detected in the cortex and hippocampus by Western blot. Furthermore, Ionized calcium binding adapter molecule 1, glial fibrillary acidic protein and Aβ were examined in the brain of AD mice by immunofluorescence staining and immunohistochemistry. And synaptic loss and neuronal ultrastructure were observed by transmission electron microscope. RESULTS We found that LW suppressed LPS-induced COX-2 expression in vitro. Importantly, LW dramatically improved spatial learning and memory in SAMP8 mice through inhibiting Aβ accumulation and restoring structural synaptic integrity. Furthermore, LW inhibited the glial activation and neuroinflammation (COX-2, IL-1β, IL-6 and TNF-α) in the cortex and hippocampus of SAMP8 mice. CONCLUSION Taken together, the present data not only indicated that LW is an effective agent on improving the learning and memory deficits through mitigating neuroinflammation but highlighted the LW can be a potential therapeutic drug for AD therapy.
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Affiliation(s)
- Junying Song
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Henan Engineering Research Center for Prevention and Treatment of Neurodegenerative Diseases, Zhengzhou, 450046, PR China; Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Yaquan Jia
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Henan Engineering Research Center for Prevention and Treatment of Neurodegenerative Diseases, Zhengzhou, 450046, PR China
| | - Junlin Li
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Rui Ding
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Yong Yuan
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Henan Engineering Research Center for Prevention and Treatment of Neurodegenerative Diseases, Zhengzhou, 450046, PR China
| | - Ju Cai
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Yunfang Su
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Henan Engineering Research Center for Prevention and Treatment of Neurodegenerative Diseases, Zhengzhou, 450046, PR China
| | - Qian Hua
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, PR China
| | - Zhenqiang Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Henan Engineering Research Center for Prevention and Treatment of Neurodegenerative Diseases, Zhengzhou, 450046, PR China.
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19
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Hajhashemi V, Khodarahmi G, Asadi P, Rajabi H. Evaluation of the antinociceptive effects of a selection of triazine derivatives in mice. Korean J Pain 2022; 35:440-446. [PMID: 36175343 PMCID: PMC9530681 DOI: 10.3344/kjp.2022.35.4.440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/01/2022] [Accepted: 08/12/2022] [Indexed: 11/24/2022] Open
Abstract
Background The authors showed in a previous study that some novel triazine derivatives had an anti-inflammatory effect. The present study was designed to evaluate the antinociceptive effect of five out of nine compounds including two vanillin-triazine (5c and 5d) and three phenylpyrazole-triazine (10a, 10b, 10e) derivatives which showed the best anti-inflammatory effect. Methods Male Swiss mice (25–30 g) were used. To assess the antinociceptive effect, acetic acid-writhing, formalin, and hot plate tests were used after intraperitoneal injection of each compound. Results All compounds significantly (P < 0.001) reduced acetic acid-induced writhing at tested doses (50, 100, and 200 mg/kg). Also, the percent inhibition of writhing in the acetic acid test showed that at the maximum tested dose of these compounds (200 mg/kg), the order of potencies is as follows 10b > 10a > 10e > 5d > 5c. In the formalin test, compounds 5d, 10a, and 10e showed an antinociceptive effect in the acute phase and all compounds were effective in the chronic phase. In the hot plate test, compounds 5c, 5d, and 10a demonstrated an antinociceptive effect. Conclusions The results clearly showed that both vanillin-triazine and phenylpyrazole-triazine derivatives had an antinociceptive effect. Also, some compounds which showed activity in the early phase of formalin test as well as in the hot plate test could control acute pain in addition to chronic or inflammatory pain.
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Affiliation(s)
- Valiollah Hajhashemi
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ghadamali Khodarahmi
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvin Asadi
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamed Rajabi
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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20
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Enamel biomineralization under the effects of indomethacin and celecoxib non-steroidal anti-inflammatory drugs. Sci Rep 2022; 12:15823. [PMID: 36138112 PMCID: PMC9500046 DOI: 10.1038/s41598-022-19583-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
The aim of this study was to explore the effects of nonsteroidal anti-inflammatory drugs on biomineralization of enamel. Sixty C57Bl6 male mice were used, which were assigned into three groups: celecoxib (n = 20) or indomethacin (n = 20) treatment for a period of 28 days or received no medication (control group, n = 20). Visual inspection and microcomputed tomography were used to analyze enamel morphology. Scanning electron microscopy–Energy dispersive X-ray and Knoop microhardness test were used to quantify chemical element content (Ca, P, C, O) and enamel microhardness, respectively. Tissues were collected to investigate the synthesis, activity or nuclear translocation of metalloproteinase-20, transcription factor Runx2, dentin sialoprotein and cyclooxygenase-2 enzyme by means of immunohistochemistry, in situ zymography and indirect immunofluorescence. Treatment with indomethacin and celecoxib reduced the Ca and P content, microhardness and mineral density in enamel. Treatment with nonsteroidal anti-inflammatory drugs caused an accumulation of metalloproteinase-20 and overall increased enzymatic activity in enamel matrix, while the synthesis of the transcription factor Runx2 was inhibited by these drugs. Interestingly, indomethacin inhibited Runx2 translocation to the nucleus whereas celecoxib did not. Those findings show that non-steroidal anti-inflammatory drugs impact the enamel biomineralization and could be involved in the etiology tooth enamel defects if used during the period of tooth formation and mineralization.
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Shah M, Bibi S, Kamal Z, Al-Sabahi JN, Alam T, Ullah O, Murad W, Rehman NU, Al-Harrasi A. Bridging the Chemical Profile and Biomedical Effects of Scutellaria edelbergii Essential Oils. Antioxidants (Basel) 2022; 11:antiox11091723. [PMID: 36139797 PMCID: PMC9496006 DOI: 10.3390/antiox11091723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/21/2022] [Accepted: 08/24/2022] [Indexed: 11/30/2022] Open
Abstract
The present study explored chemical constituents of Scutellaria edelbergii essential oils (SEEO) for the first time, extracted through hydro-distillation, and screened them against the microbes and free radicals scavenging effect, pain-relieving, and anti-inflammatory potential employing standard techniques. The SEEO ingredients were noticed via Gas Chromatography-Mass-Spectrometry (GC-MS) analysis and presented fifty-two bioactive compounds contributed (89.52%) with dominant volatile constituent; 3-oxomanoyl oxide (10.09%), 24-norursa-3,12-diene (8.05%), and methyl 7-abieten-18-oate (7.02%). The MTT assay via 96 well-plate and agar-well diffusion techniques against various microbes was determined for minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), IC50, and zone of inhibitions (ZOIs). The SEEO indicated considerable antimicrobial significance against tested bacterial strains viz. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterococcus faecalis and the fungal strains Fusarium oxysporum and Candida albicans. The free radicals scavenging potential was noticed to be significant in 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) as compared to 2,2′-azino-bis-3-ethylbenzotiazolin-6-sulfonic acid (ABTS) assays with IC50 = 125.0 ± 0.19 µg/mL and IC50 = 153.0 ± 0.31 µg/mL correspondingly; similarly, the antioxidant standard in the DPPH assay was found efficient as compared to ABTS assay. The SEEO also offered an appreciable analgesic significance and presented 54.71% in comparison with standard aspirin, 64.49% reduction in writhes, and an anti-inflammatory potential of 64.13%, as compared to the standard diclofenac sodium inhibition of 71.72%. The SEEO contain bioactive volatile ingredients with antimicrobial, free radical scavenging, pain, and inflammation relieving potentials. Computational analysis validated the anti-inflammatory potential of selected hit “methyl 7-abieten-18-oate” as a COX-2 enzyme inhibitor. Docking results were very good in terms of docked score (−7.8704 kcal/mol) and binding interactions with the functional residues; furthermore, MD simulation for 100 ns has presented a correlation with docking results with minor fluctuations. In silico, ADMET characteristics supported that methyl 7-abieten-18-oate could be recommended for further investigations in clinical tests and could prove its medicinal status as an anti-inflammatory drug.
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Affiliation(s)
- Muddaser Shah
- Department of Botany, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al-Mauz, P.O. Box 33, Nizwa 616, Oman
| | - Shabana Bibi
- Department of Biosciences, Shifa Tameer-e-Millat University, Islamabad 44000, Pakistan
- Yunnan Herbal Laboratory, College of Ecology and Environmental Sciences, Yunnan University, Kunming 650091, China
| | - Zul Kamal
- Department of Pharmacy, Shaheed Benazir Bhutto University, Upper Dir 18000, Pakistan
| | - Jamal Nasser Al-Sabahi
- Central Instrument Laboratory, College of Agriculture and Marine Sciences, Sultan Qaboos University, Muscat 123, Oman
| | - Tanveer Alam
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al-Mauz, P.O. Box 33, Nizwa 616, Oman
| | - Obaid Ullah
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al-Mauz, P.O. Box 33, Nizwa 616, Oman
- Department of Chemistry, University of Chakdara, Chakdara 18800, Pakistan
| | - Waheed Murad
- Department of Botany, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
- Correspondence: (W.M.); (N.U.R.); (A.A.-H.)
| | - Najeeb Ur Rehman
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al-Mauz, P.O. Box 33, Nizwa 616, Oman
- Correspondence: (W.M.); (N.U.R.); (A.A.-H.)
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al-Mauz, P.O. Box 33, Nizwa 616, Oman
- Correspondence: (W.M.); (N.U.R.); (A.A.-H.)
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22
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Lorencetti-Silva F, Sales LS, Lamarque GDCC, Caixeta GA, Arnez MFM, Faccioli LH, Paula-Silva FWG. Effects of inflammation in dental pulp cell differentiation and reparative response. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2022.942714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The responsiveness of the dentin-pulp complex is possible due to the stimulation of dental pulp cells, which begin to synthesize and secrete dentin matrix. The inflammatory process generated by harmful stimuli should be understood as a natural event of the immune response, resulting in the recruitment of hematopoietic cells, which cross the endothelial barrier and reach the site affected by the injury in order to eliminate the damage and provide an appropriate environment for the restoration of homeostasis. The repair process occurs in the presence of adequate blood supply, absence of infection, and with the participation of pro-inflammatory cytokines, growth factors, extracellular matrix components, and other biologically active molecules. Prostaglandins and leukotrienes are bioactive molecules derived from the metabolism of arachidonic acid, as a result of a variable range of cellular stimuli. The aim of this review is to describe the process of formation and biomineralization of the dentin-pulp complex and how pro-inflammatory events can modify this response, with emphasis on the lipid mediators prostaglandins and leukotrienes derived from arachidonic acid metabolism.
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Petean IBF, Silva-Sousa AC, Cronenbold TJ, Mazzi-Chaves JF, Silva LABD, Segato RAB, Castro GAPD, Kuchler EC, Paula-Silva FWG, Damião Sousa-Neto M. Genetic, Cellular and Molecular Aspects involved in Apical Periodontitis. Braz Dent J 2022; 33:1-11. [PMID: 36043561 PMCID: PMC9645190 DOI: 10.1590/0103-6440202205113] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/03/2022] [Indexed: 11/26/2022] Open
Abstract
The development, establishment and repair of apical periodontitis (AP) is
dependent of several factors, which include host susceptibility, microbial
infection, immune response, quality of root canal treatment and organism's
ability to repair. The understanding of genetic contributions to the risk of
developing AP and presenting persistent AP has been extensively explored in
modern Endodontics. Thus, this article aims to provide a review of the
literature regarding the biochemical mediators involved in immune response
signaling, osteoclastogenesis and bone neoformation, as the genetic components
involved in the development and repair of AP. A narrative review of the
literature was performed through a PUBMED/MEDLINE search and a hand search of
the major AP textbooks. The knowledge regarding the cells, receptors and
molecules involved in the host's immune-inflammatory response during the
progression of AP added to the knowledge of bone biology allows the
identification of factors inherent to the host that can interfere both in the
progression and in the repair of these lesions. The main outcomes of studies
evaluated in the review that investigated the correlation between genetic
polymorphisms and AP in the last five years, demonstrate that genetic factors of
the individual are involved in the success of root canal treatment. The
discussion of this review gives subsides that may help to glimpse the
development of new therapies based on the identification of therapeutic targets
and the development of materials and techniques aimed at acting at the molecular
level for clinical, radiographic and histological success of root canal
treatment.
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Affiliation(s)
- Igor Bassi Ferreira Petean
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Brazil
| | - Alice Corrêa Silva-Sousa
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Brazil
| | | | | | - Lea Assed Bezerra da Silva
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Raquel Assed Bezerra Segato
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | | | - Erika Calvano Kuchler
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.,Department of Orthodontics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | | | - Manoel Damião Sousa-Neto
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Brazil
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Zhang L, Li S, Tai Z, Yu C, Xu Z. Gut Microbes Regulate Innate Immunity and Epilepsy. Front Neurosci 2022; 16:870197. [PMID: 35720723 PMCID: PMC9198293 DOI: 10.3389/fnins.2022.870197] [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] [Received: 02/06/2022] [Accepted: 04/13/2022] [Indexed: 12/03/2022] Open
Abstract
Epilepsy is a common chronic brain disease. There are many clinical methods to control epileptic seizures, such as anti-seizure medications (ASMs) or surgical removal of epileptogenic lesions. However, the pathophysiology of epilepsy is still unknown, making it difficult to control or prevent it. The host's immune system monitors gut microbes, interacts with microbes through pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) expressed by innate immune cells, and activates immune responses in the body to kill pathogens and balance the relationship between microbes and host. In addition, inflammatory responses induced by the innate immune system are seen in animal models of epilepsy and temporal lobe epilepsy brain tissue to combat pathogens or injuries. This review summarizes the potential relationship between gut microbes, innate immunity, and epilepsy based on recent research to provide more hints for researchers to explore this field further.
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Affiliation(s)
- Linhai Zhang
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Shuang Li
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhenzhen Tai
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Changyin Yu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Zucai Xu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
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Leme RD, Lamarque GDCC, Bastos LA, Arnez MFM, Paula-Silva FWG. Minimal Intervention Dentistry: Biocompatibility and Mechanism of Action of Products for Chemical-Mechanical Removal of Carious Tissue. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2022.851331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Conventional method for removal of carious tissue using low speed drills usually induce noise and vibration, in addition to thermal and pressure effects that can be harmful to the pulp tissue and cause fear in children. Therefore, several alternative methods are being developed to try to minimize the unpleasant perception of the patient during caries removal. Chemical-mechanical removal of carious tissue goal is to selectively remove the carious lesion, which reduces the amount of bacteria inside the cavity without removing the tissue susceptible to remineralization. This method is also able to minimize the tactile perception by the patient during the manipulation of the lesion compared to the conventional method, and, therefore, it has been widely accepted among phobic patients, children and special needs patients. Due to the close relationship between dentin and pulp tissue, all injuries imposed on this dentin may have repercussions on the underlying pulp connective tissue. The morphological aspects of remaining dentin favor the diffusion of chemical components of dental materials, which can be toxic to the pulp tissue or even negatively interfere in the reparative process. Thus, considering the proximity between the applied material and the underlying pulp tissue, especially in deep cavities, there is a need to assess the biological behavior of dental materials against pulp cells, since aggressions to the pulp tissue can be caused not only by metabolites from microorganisms involved in dental caries but also by components that are released from these products. This subject was explored in this narrative literature review.
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Gad El-Hak HN, Mahmoud HS, Ahmed EA, Elnegris HM, Aldayel TS, Abdelrazek HMA, Soliman MTA, El-Menyawy MAI. Methanolic Phoenix dactylifera L. Extract Ameliorates Cisplatin-Induced Hepatic Injury in Male Rats. Nutrients 2022; 14:1025. [PMID: 35268000 PMCID: PMC8912432 DOI: 10.3390/nu14051025] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 12/20/2022] Open
Abstract
This study investigated the ameliorative potential of methanolic date flesh extract (MDFE) against cisplatin-induced hepatic injury. Twenty male rats (weighing 180-200 g) were allocated into four groups: control; date flesh (DF) group (oral 600 mg/kg MDFE for 21 days); Cis group (7.5 mg/kg i.p. at day 16); and date flesh/cisplatin (DF/Cis) group (oral 600 mg/kg MDFE for 21 days and 7.5 mg/kg i.p. at day 16). Hepatic biochemical parameters in sera, and inflammatory and oxidant/antioxidant hepatic biomarkers were estimated. Hepatic histological changes and the immunohistochemistry of cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and alpha smooth muscle actin (α-SMA) were assessed. Pretreatment with MDFE decreased Cis-triggered liver biochemical parameters, oxidative stress, inflammatory biomarkers, and histological damage. Moreover, MDFE treatment reduced Cis-induced hepatic NF-κB, COX-2, and α-SMA protein expression. MDFE exerted a hepatoprotective effect when used concomitantly with Cis. Its effect was mediated via its antioxidant and anti-inflammatory ingredients.
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Affiliation(s)
- Heba Nageh Gad El-Hak
- Zoology Department, Faculty of Sciences, Suez Canal University, Ismailia 41522, Egypt;
| | - Hany Salah Mahmoud
- Center of Scientific Foundation for Experimental Studies and Research, Ismailia 41511, Egypt;
| | - Eman A. Ahmed
- Department of Pharmacology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Heba M. Elnegris
- Department of Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt;
- Department of Histology and Cell Biology, Faculty of Medicine, Badr University in Cairo, Cairo 11829, Egypt
| | - Tahany Saleh Aldayel
- Department of Physical Sport Sciences, College of Education, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Heba M. A. Abdelrazek
- Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Mohamed T. A. Soliman
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 67614, Saudi Arabia;
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Zhong Z, Liu Z, Zheng R, Chai J, Jiang S. miR-132-3p Modulates DUSP9-Dependent p38/JNK Signaling Pathways to Enhance Inflammation in the Amnion Leading to Labor. Int J Mol Sci 2022; 23:ijms23031864. [PMID: 35163786 PMCID: PMC8836965 DOI: 10.3390/ijms23031864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 12/10/2022] Open
Abstract
Labor is a process of inflammation and hormonal changes involving both fetal and maternal compartments. MicroRNA-132-3p (miR-132-3p) has been reported to be involved in the development of inflammation-related diseases. However, little is known about its potential role in labor onset. This study aimed to explore the mechanism of miR-132-3p in amnion for labor initiation. In the mouse amnion membranes, the expression of miR-132-3p was found to increase gradually during late gestation. In human amniotic epithelial cell line (WISH), upregulation of miR-132-3p was found to increase proinflammatory cytokines and cyclooxygenase 2 (COX2) as well as prostaglandin E2 (PGE2), which was suppressed by miR-132-3p inhibitor. Dual-specificity phosphatase 9 (DUSP9) was identified as a novel target gene of miR-132-3p, which could be negatively regulated by miR-132-3p. DUSP9 was present in the mouse amnion epithelial cells, with a decrease in its abundance at 18.5 days post coitum (dpc) relative to 15.5 dpc. Silencing DUSP9 was found to facilitate the expression of proinflammatory cytokines and COX2 as well as PGE2 secretion in WISH cells, which could be attenuated by p38 inhibitor SB203580 or JNK inhibitor SP600125. Additionally, intraperitoneal injection of pregnant mice with miR-132-3p agomir not only caused preterm birth, but also promoted the abundance of COX2 as well as phosphorylated JNK and p38 levels, and decreased DUSP9 level in mouse amnion membranes. Collectively, miR-132-3p might participate in inflammation and PGE2 release via targeting DUSP9-dependent p38 and JNK signaling pathways to cause preterm birth.
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Gallyas F, Ramadan FHJ, Andreidesz K, Hocsak E, Szabo A, Tapodi A, Kiss GN, Fekete K, Bognar R, Szanto A, Bognar Z. Involvement of Mitochondrial Mechanisms and Cyclooxygenase-2 Activation in the Effect of Desethylamiodarone on 4T1 Triple-Negative Breast Cancer Line. Int J Mol Sci 2022; 23:ijms23031544. [PMID: 35163464 PMCID: PMC8836269 DOI: 10.3390/ijms23031544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/20/2022] [Accepted: 01/26/2022] [Indexed: 12/10/2022] Open
Abstract
Novel compounds significantly interfering with the mitochondrial energy production may have therapeutic value in triple-negative breast cancer (TNBC). This criterion is clearly fulfilled by desethylamiodarone (DEA), which is a major metabolite of amiodarone, a widely used antiarrhythmic drug, since the DEA previously demonstrated anti-neoplastic, anti-metastasizing, and direct mitochondrial effects in B16F10 melanoma cells. Additionally, the more than fifty years of clinical experience with amiodarone should answer most of the safety concerns about DEA. Accordingly, in the present study, we investigated DEA’s potential in TNBC by using a TN and a hormone receptor positive (HR+) BC cell line. DEA reduced the viability, colony formation, and invasive growth of the 4T1 cell line and led to a higher extent of the MCF-7 cell line. It lowered mitochondrial transmembrane potential and induced mitochondrial fragmentation. On the other hand, DEA failed to significantly affect various parameters of the cellular energy metabolism as determined by a Seahorse live cell respirometer. Cyclooxygenase 2 (COX-2), which was upregulated by DEA in the TNBC cell line only, accounted for most of 4T1’s DEA resistance, which was counteracted by the selective COX-2 inhibitor celecoxib. All these data indicate that DEA may have potentiality in the therapy of TNBC.
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Affiliation(s)
- Ferenc Gallyas
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
- Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary
- LERN-UP Nuclear-Mitochondrial Interactions Research Group, 1245 Budapest, Hungary
| | - Fadi H. J. Ramadan
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Kitti Andreidesz
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Eniko Hocsak
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Aliz Szabo
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Antal Tapodi
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Gyongyi N. Kiss
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Katalin Fekete
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Rita Bognar
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
| | - Arpad Szanto
- Urology Clinic, UP Medical Center, University of Pecs Medical School, 7624 Pecs, Hungary;
| | - Zita Bognar
- Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary; (F.G.J.); (F.H.J.R.); (K.A.); (E.H.); (A.S.); (A.T.); (G.N.K.); (K.F.); (R.B.)
- Correspondence: ; Tel.: +36-72-536-276
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Divyambika CV, Sathasivasubramanian S, Vidyarani S, RaviDavid A, Harinee S, Vijayalakshmi R. Clinicopathological Correlation of Cyclooxygenase 2 Expression in Oral Submucous Fibrosis: An Immunohistochemical Study. J Int Soc Prev Community Dent 2021; 11:553-560. [PMID: 34760800 PMCID: PMC8533033 DOI: 10.4103/jispcd.jispcd_136_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/07/2021] [Accepted: 06/30/2021] [Indexed: 12/02/2022] Open
Abstract
Background: Oral submucous fibrosis (OSMF) has a high prevalence in Southeast Asia with increased malignant transformation rates. Numerous biomarkers are currently being investigated to predict the disease prognosis and for early detection of malignant changes. Materials and Methods: A prospective study was conducted comprising 40 subjects with clinically and biopsy-proven OSMF being included in the study as experimental group (n = 28) and patients with no tobacco/betel nut habit, who underwent surgical removal of third molar, being included as control group (n = 12). About 5-μm sections from formalin-fixed paraffin-embedded tissue blocks were obtained for immunohistochemical (IHC) study. The expression of cyclooxygenase 2 (COX 2) was evaluated in the experimental group and compared in morphologically normal oral epithelium. The intensity of stain was assessed at different levels of epithelium (basal, stratum spinosum, superficial level) and connective tissue. Results: Based on IHC expression of COX 2, all the patients of the control group were negative for COX 2, and among the OSMF group, 19 patients (67.9%) were positive and 9 patients (32.1%) were found to be negative for COX 2. The association of COX2 expression on comparison of controls with OSMF was found to be statistically significant (χ2 =21.955; P = 0.000). On comparison of immune expression of COX 2 in different clinical stages based on functional staging, we found significant association of COX 2 expression with the stage of OSMF (χ2 = 7.368; P = 0.025). Conclusion: The significant expression of COX 2 in different clinical stages of OSMF when compared with normal shows the role of COX 2 in the pathogenesis of OSMF and could serve as a potent biomarker for assessing the disease progression.
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Affiliation(s)
- Catakapatri Venugopal Divyambika
- Department of Oral Medicine and Radiology, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, India
| | - Sankarapandian Sathasivasubramanian
- Department of Oral Medicine and Radiology, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, India
| | - Shyamsundar Vidyarani
- Centre for Oral Cancer Prevention, Awareness and Research, Sree Balaji Dental College and Hospital, BIHER University, Pallikaranai, Chennai, India
| | - Austin RaviDavid
- Department of Oral Medicine and Radiology, Rajah Muthiah Dental College, Annamalai University, Chidambaram, India
| | - Srinivasan Harinee
- Department of Oral Medicine and Radiology, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, India
| | - Ramshankar Vijayalakshmi
- Department of Preventive Oncology (Research), Cancer Institute WIA, Adyar, Chennai, Tamil Nadu, India
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Abril-Parreño L, Meade KG, Krogenæs AK, Druart X, Fair S, Cormican P. Conserved and breed-specific differences in the cervical transcriptome of sheep with divergent fertility at the follicular phase of a natural oestrus cycle. BMC Genomics 2021; 22:752. [PMID: 34666676 PMCID: PMC8527727 DOI: 10.1186/s12864-021-08060-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/01/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The outcome of cervical artificial insemination (AI) with frozen-thawed semen in sheep is limited by the inability of sperm to traverse the cervix of some ewe breeds. Previous research has demonstrated that cervical sperm transport is dependent on ewe breed, as sperm can traverse the cervix in greater numbers in some higher fertility ewe breeds. However, the molecular mechanisms underlying ewe breed differences in sperm transport through the cervix remain unknown. In this study, we aimed to characterise the cervical transcriptome of four European ewe breeds with known differences in pregnancy rates following cervical AI using frozen-thawed semen at the follicular phase of a natural oestrous cycle. Cervical post mortem tissue samples were collected from two Irish ewe breeds (Belclare and Suffolk; medium and low fertility, respectively) and from two Norwegian ewe breeds (Norwegian White Sheep (NWS) and Fur; high fertility compared to both Irish breeds) at the follicular phase of a natural oestrous cycle (n = 8 to 10 ewes per breed). RESULTS High-quality RNA extracted from biopsies of the mid-region of the cervix was analysed by RNA-sequencing and Gene Ontology (GO). After stringent filtering (P < 0.05 and FC > 1.5), a total of 11, 1539 and 748 differentially expressed genes (DEGs) were identified in Belclare, Fur and NWS compared to the low fertility Suffolk breed, respectively. Gene ontology analysis identified significantly enriched biological processes involved in muscle contraction, extracellular matrix (ECM) development and the immune response. Gene co-expression analysis revealed similar patterns in muscle contraction and ECM development modules in both Norwegian ewe breeds, which differed to the Irish ewe breeds. CONCLUSIONS These breed-specific biological processes may account for impaired cervical sperm transport through the cervix in sheep during the follicular phase of the reproductive cycle. This novel and comprehensive dataset provides a rich foundation for future targeted initiatives to improve cervical AI in sheep.
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Affiliation(s)
- Laura Abril-Parreño
- Laboratory of Animal Reproduction, Department of Biological Sciences, School of Natural Sciences, Biomaterials Research Cluster, Bernal Institute, Faculty of Science and Engineering, University of Limerick, Limerick, Ireland.,Animal & Bioscience Research Department, Animal & Grassland Research and Innovation Centre, Teagasc, Grange, Co. Meath, Ireland
| | - Kieran G Meade
- School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | | | - Xavier Druart
- UMR 6175 INRA, CNRS-Université de Tours-Haras Nationaux, Station de Physiologie de la Reproduction et des Comportements Institut National de la Recherche Agronomique, Nouzilly, France
| | - Sean Fair
- Laboratory of Animal Reproduction, Department of Biological Sciences, School of Natural Sciences, Biomaterials Research Cluster, Bernal Institute, Faculty of Science and Engineering, University of Limerick, Limerick, Ireland.
| | - Paul Cormican
- Animal & Bioscience Research Department, Animal & Grassland Research and Innovation Centre, Teagasc, Grange, Co. Meath, Ireland
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Petean IBF, Almeida-Junior LA, Arnez MFM, Queiroz AM, Silva RAB, Silva LAB, Faccioli LH, Paula-Silva FWG. Celecoxib treatment dampens LPS-induced periapical bone resorption in a mouse model. Int Endod J 2021; 54:1289-1299. [PMID: 33403674 DOI: 10.1111/iej.13472] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 12/29/2022]
Abstract
AIM To evaluate the efficacy of selective and nonselective inhibitors of cyclooxygenase-2 enzymes in the treatment of experimental apical periodontitis induced by bacterial lipopolysaccharide (LPS) in vivo in a mouse model. METHODOLOGY Thirty-six C57BL/6 mice were used. After access cavity preparation, a solution containing E. coli LPS (1.0 µg µL-1 ) was inoculated into the root canals of the mandibular and maxillary right first molars (n = 72) After 30 days, apical periodontitis was established and the animals were systemically treated with celecoxib, a selective COX-2 inhibitor (15 mg kg-1 ), or indomethacin, a nonselective COX-2 inhibitor (5 mg kg-1 ), for 7 and 14 days. Blocks containing teeth and bone were removed for histopathological and histometric analyses (haematoxylin and eosin), evaluation of osteoclasts numbers (tartrate-resistant acid phosphatase enzyme - TRAP) and immunohistochemistry for RANK, RANKL and OPG. Gene expression was performed using reverse transcription and real-time polymerase chain reaction (qRT-PCR) for RANK, RANKL, OPG, TRAP, MMP-9, cathepsin K and calcitonin receptor. Histopathological, histometric, TRAP, immunohistochemistry and qRT-PCR data were evaluated using Kruskal-Wallis followed by Dunn's test (α = 0.05). RESULTS Systemic administration of celecoxib for 7 and 14 days prevented periapical bone resorption (P < 0.0001), differently from indomethacin that exacerbated bone resorption at 7 days (P < 0.0001) or exerted no effect at 14 days (P = 0.8488). Celecoxib treatment reduced osteoclast formation in apical periodontitis, regardless of the period of treatment (P < 0.0001 for 7 days and P = 0.026 for 14 days). Administration of celecoxib or indomethacin differentially modulated the expression of genes involved in bone resorption. At 7 days, celecoxib and indomethacin treatment significantly inhibited expression of mRNA for cathepsin K (P = 0.0005 and P = 0.016, respectively) without changing TRAP, MMP-9 and calcitonin receptor gene expression. At 14 days, celecoxib significantly inhibited expression of mRNA for MMP-9 (P < 0.0001) and calcitonin receptor (P = 0.004), whilst indomethacin exerted no effect on MMP-9 (P = 0.216) and calcitonin receptor (P = 0.971) but significantly augmented cathepsin K gene expression (P = 0.001). CONCLUSIONS The selective COX-2 inhibitor celecoxib reduced osteoclastogenic signalling and activity that dampened bone resorption in LPS-induced apical periodontitis in mice, with greater efficacy than the nonselective inhibitor indomethacin.
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Affiliation(s)
- I B F Petean
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - L A Almeida-Junior
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - M F M Arnez
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - A M Queiroz
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - R A B Silva
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - L A B Silva
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - L H Faccioli
- Laboratório de Inflamação e Imunologia das Parasitoses, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - F W G Paula-Silva
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brasil.,Laboratório de Inflamação e Imunologia das Parasitoses, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
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Ribeiro-Santos FR, Arnez MFM, de Carvalho MS, da Silva RAB, Politi MPL, de Queiroz AM, Nelson-Filho P, da Silva LAB, Faccioli LH, Paula-Silva FWG. Effect of non-steroidal anti-inflammatory drugs on pulpal and periapical inflammation induced by lipopolysaccharide. Clin Oral Investig 2021; 25:6201-6209. [PMID: 33791868 DOI: 10.1007/s00784-021-03919-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/28/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVES The objective of this study was to evaluate the effect of non-steroidal anti-inflammatory drugs (NSAIDs) in controlling pulpal and periapical inflammation in vivo as a potential coadjutant systemic therapy for pulpitis. MATERIALS AND METHODS A suspension containing E. coli lipopolysaccharide (LPS; 1.0 μg/μL) was inoculated into the pulp chamber of the first molars of C57BL/6 mice (n = 72), and the animals were treated daily with indomethacin or celecoxib throughout the experimental periods. After 7, 14, 21, and 28 days, the tissues were removed for histopathological, histoenzymology, histometric, and immunohistochemical evaluation. RESULTS Inoculation of LPS into the pulp chamber induced the synthesis of the enzyme cyclooxygenase-2 (COX-2) in dental pulp and periapical region. Indomethacin and celecoxib treatment changed the profile of inflammatory cells recruited to dental pulp and to the periapex, which was characterized by a higher mononuclear cell infiltrate, compared to LPS inoculation alone which recruited a higher amount of polymorphonuclear neutrophils. Administration of indomethacin for 28 days resulted in the development of apical periodontitis and increased osteoclast recruitment, unlike celecoxib. CONCLUSIONS NSAIDs indomethacin and celecoxib changed the recruitment of inflammatory cells to a mononuclear profile upon inoculation of LPS into the pup chamber, but indomethacin enhanced periapical bone loss whereas celecoxib did not. CLINICAL RELEVANCE Celecoxib, a selective COX-2 inhibitor, can change the profile of inflammatory cells recruited to the dental pulp challenged with LPS and might a be potential systemic coadjutant for treatment of pulpitis.
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Affiliation(s)
- Fernanda Regina Ribeiro-Santos
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
- Universidade de Pernambuco, Arco Verde, Pernambuco, Brazil
| | - Maya Fernanda Manfrin Arnez
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
| | - Marcio Santos de Carvalho
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
| | - Raquel Assed Bezerra da Silva
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
| | - Marília Pacífico Lucisano Politi
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
| | - Alexandra Mussolino de Queiroz
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
| | - Paulo Nelson-Filho
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
| | - Léa Assed Bezerra da Silva
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil
| | - Lúcia Helena Faccioli
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Francisco Wanderley Garcia Paula-Silva
- School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n. CEP 14040-904, Ribeirão Preto, São Paulo, Brazil.
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
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Neuroprotective and anti-neuroinflammatory effects of ethanolic extract from leaves and stems of Aster glehni. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104400] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Anti-Inflammatory Effects of Antarctic Lichen Umbilicaria antarctica Methanol Extract in Lipopolysaccharide-Stimulated RAW 264.7 Macrophage Cells and Zebrafish Model. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8812090. [PMID: 33644231 PMCID: PMC7902135 DOI: 10.1155/2021/8812090] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 01/19/2021] [Accepted: 02/03/2021] [Indexed: 11/30/2022]
Abstract
Umbilicaria antarctica (UA) is a member of the family Umbilicariaceae. To the best of our knowledge, no studies on its anti-inflammatory effects have been reported yet. In the present study, we examined its ability to suppress inflammatory responses and the molecular mechanisms underlying these abilities using lipopolysaccharide- (LPS-) stimulated RAW 264.7 cells and a zebrafish model of inflammation. We investigated the effects of UA on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated RAW 264.7 cells. To explore the anti-inflammatory mechanisms of UA, we measured the mRNA and protein expression of proinflammatory mediators in LPS-stimulated RAW 264.7 cells using quantitative RT-PCR and western blot analyses, respectively. UA significantly inhibited the production of NO, PGE2, interleukin- (IL-) 6, and tumor necrosis factor- (TNF-) α in the LPS-stimulated RAW 264.7 cells. It also suppressed the mRNA and protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor- (NF-) κB activation in LPS-stimulated RAW 264.7 cells and tail pin-cutting-induced zebrafish model. Collectively, these findings indicate that UA significantly inhibits LPS-stimulated inflammatory responses. These effects were considered to be strongly associated with the suppression of NF-κB activation. Overall, our results demonstrate that UA extract exerts strong anti-inflammatory activities in in vitro and in vivo models and suggest that UA may be an effective novel therapeutic agent for the treatment of inflammatory diseases.
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Faki Y, Er A. Different Chemical Structures and Physiological/Pathological Roles of Cyclooxygenases. Rambam Maimonides Med J 2021; 12:RMMJ.10426. [PMID: 33245277 PMCID: PMC7835113 DOI: 10.5041/rmmj.10426] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
This review describes cyclooxygenase (COX), which synthesizes prostanoids that play an important role in living things. The authors conducted a national and international literature review on the subject. The COX enzyme uses arachidonic acid to form prostanoids, which play a role in several physiological and pathological conditions. This enzyme has different isoforms, mainly COX-1 and COX-2. The constitutive isoform is COX-1, while COX-2 is the inducible isoform. Both are expressed in different tissues and at different levels, but they may also coexist within the same tissue. Both isoforms show essentially the same mode of action, but their substrates and inhibitors may differ. The COX-1 isoform, which plays a role in the continuation of physiological events, has an increased expression level in various carcinomas, and the COX-2 isoform, which is increased in inflammatory conditions, is typically expressed at low physiological levels in some tissues such as the brain, kidney, and uterus. In addition to investigating the efficacies of the COX-1 and COX-2 isoforms, the discovery of potential new COX enzymes and their effect continues. This review also looks at the roles of the COX enzyme in certain physiological and pathological conditions.
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Affiliation(s)
| | - Ayse Er
- To whom correspondence should be addressed. E-mail:
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36
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Horishny VY, Zadorozhnii PV, Horishnia IV, Matiychuk VS. Synthesis, Anti-Inflammatory Activity and Molecular Docking Studies of 1,4,5,6-Tetrahydropyrimidine-2-Carboxamides. PHARMACEUTICAL SCIENCES 2020. [DOI: 10.34172/ps.2020.100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. The widespread use of NSAIDs is associated with a number of serious side effects and complications observed for both selective and non-selective COX inhibitors. Therefore, the search for new COX inhibitors, which along with their effectiveness will have minimal side effects, is a very important and urgent task. Methods: This work studied the synthesis of new 1,4,5,6-tetrahydropyrimidine-2-carboxamides based on the reaction of 2-morpholin-4-yl-N-(het)aryl-2-thioxoacetamides with 1,3-diaminopropane. All obtained compounds were tested for anti-inflammatory activity in vitro and in silico conditions. All synthesized 1,4,5,6-tetrahydropyrimidine-2-carboxamides were tested for influence on the course of the exudative phase of the inflammatory process based on the carrageenan model of paw edema of laboratory nonlinear heterosexual white rats weighing 220-250 g, using Diclofenac as a reference. Optimization of the geometry of the studied structures and molecular docking was carried out using the ArgusLab 4.0.1 software package. Results: The target products were obtained with yields of 71-98% and easily isolated from the reaction mixture. The best anti-inflammatory activity was found in N-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine-2-carboxamide and in N-[4-chloro-3-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydropyrimidine-2-carboxamide, suppression of the inflammatory response was 46.7 and 46.4%, respectively. The results of molecular docking with COX-1 and COX-2 enzymes were in good agreement with the experimental data, R2 ˃ 0.92 and R2 ˃ 0.83, respectively. Conclusion: The compounds under study were shown to be promising as potential anti-inflammatory agents.
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Affiliation(s)
- Volodymyr Ya. Horishny
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv, 79010, Ukraine
| | - Pavlo V. Zadorozhnii
- Department of Pharmacy and Technology of Organic Substances, Ukrainian State University of Chemical Technology, Gagarin Ave., 8, Dnipro 49005, Ukraine
| | - Ivanna V. Horishnia
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv, 79010, Ukraine
| | - Vasyl S. Matiychuk
- Department of Organic Chemistry, Ivan Franko National University of Lviv, 6 Kyryla і Mefodia, Lviv, 79005, Ukraine
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Abdul Rahman M, Tan ML, Johnson SP, Hollows RJ, Chai WL, Mansell JP, Yap LF, Paterson IC. Deregulation of lysophosphatidic acid metabolism in oral cancer promotes cell migration via the up-regulation of COX-2. PeerJ 2020; 8:e10328. [PMID: 33240646 PMCID: PMC7666559 DOI: 10.7717/peerj.10328] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 10/19/2020] [Indexed: 12/24/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and accounts for 300,000 new cases yearly. The five-year survival rate is approximately 50% and the major challenges to improving patient prognosis include late presentation, treatment resistance, second primary tumours and the lack of targeted therapies. Therefore, there is a compelling need to develop novel therapeutic strategies. In this study, we have examined the effect of lysophosphatidic acid (LPA) on OSCC cell migration, invasion and response to radiation, and investigated the contribution of cyclooxygenase-2 (COX-2) in mediating the tumour promoting effects of LPA. Using the TCGA data set, we show that the expression of the lipid phosphate phosphatases (LPP), LPP1 and LPP3, was significantly down-regulated in OSCC tissues. There was no significant difference in the expression of the ENPP2 gene, which encodes for the enzyme autotaxin (ATX) that produces LPA, between OSCCs and control tissues but ENPP2 levels were elevated in a subgroup of OSCCs. To explore the phenotypic effects of LPA, we treated OSCC cell lines with LPA and showed that the lipid enhanced migration and invasion as well as suppressed the response of the cells to irradiation. We also show that LPA increased COX-2 mRNA and protein levels in OSCC cell lines and inhibition of COX-2 activity with the COX-2 inhibitor, NS398, attenuated LPA-induced OSCC cell migration. Collectively, our data show for the first time that COX-2 mediates some of the pro-tumorigenic effects of LPA in OSCC and identifies the ATX-LPP-LPA-COX-2 pathway as a potential therapeutic target for this disease.
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Affiliation(s)
- Mariati Abdul Rahman
- Department of Oral and Craniofacial Sciences, University of Malaya, Kuala Lumpur, Malaysia.,Department of Craniofacial Diagnostics and Biosciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - May Leng Tan
- Department of Oral and Craniofacial Sciences, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Robert J Hollows
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Wen Lin Chai
- Department of Restorative Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Jason P Mansell
- Department of Applied Sciences, University of the West of England, Bristol, United Kingdom
| | - Lee Fah Yap
- Department of Oral and Craniofacial Sciences, University of Malaya, Kuala Lumpur, Malaysia
| | - Ian C Paterson
- Department of Oral and Craniofacial Sciences, University of Malaya, Kuala Lumpur, Malaysia.,Oral Cancer Research and Coordinating Centre, University of Malaya, Kuala Lumpur, Malaysia
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Akhtar W, Marella A, Alam MM, Khan MF, Akhtar M, Anwer T, Khan F, Naematullah M, Azam F, Rizvi MA, Shaquiquzzaman M. Design and synthesis of pyrazole-pyrazoline hybrids as cancer-associated selective COX-2 inhibitors. Arch Pharm (Weinheim) 2020; 354:e2000116. [PMID: 33015829 DOI: 10.1002/ardp.202000116] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 08/22/2020] [Accepted: 09/11/2020] [Indexed: 12/25/2022]
Abstract
In continuation of our previous work on cancer and inflammation, 15 novel pyrazole-pyrazoline hybrids (WSPP1-15) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in 1 H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (HA , HM , and HX ) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF-7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5-Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC50 values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC50 value of more than 50 µM. The derivatives were also evaluated for their in vitro anti-inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti-inflammatory activities were further studied for COX-2 inhibition. The manifestation of a higher COX-2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX-2 also exhibited a better spectrum of activity against various cancer cell lines.
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Affiliation(s)
- Wasim Akhtar
- Drug Design and Medicinal Chemistry Laboratory, Jamia Hamdard, New Delhi, India
| | - Akranth Marella
- Fryer Global Regulatory Solutions and Services, Hyderabad, Telangana, India
| | | | - Mohemmed F Khan
- Drug Design and Medicinal Chemistry Laboratory, Jamia Hamdard, New Delhi, India
| | - Mymoona Akhtar
- Drug Design and Medicinal Chemistry Laboratory, Jamia Hamdard, New Delhi, India
| | - Tariq Anwer
- Department of Pharmacology, College of Pharmacy, Jazan University, Gizan, Saudi Arabia
| | - Farah Khan
- Department of Biochemistry, Jamia Hamdard, New Delhi, India
| | - Md Naematullah
- Department of Biochemistry, Jamia Hamdard, New Delhi, India
| | - Faizul Azam
- Department of Pharmaceutical Chemistry & Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah, Saudi Arabia
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Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol 2020; 180:114147. [PMID: 32653589 PMCID: PMC7347500 DOI: 10.1016/j.bcp.2020.114147] [Citation(s) in RCA: 827] [Impact Index Per Article: 165.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/03/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022]
Abstract
Owing to the efficacy in reducing pain and inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most popularly used medicines confirming their position in the WHO's Model List of Essential Medicines. With escalating musculoskeletal complications, as evident from 2016 Global Burden of Disease data, NSAID usage is evidently unavoidable. Apart from analgesic, anti-inflammatory and antipyretic efficacies, NSAIDs are further documented to offer protection against diverse critical disorders including cancer and heart attacks. However, data from multiple placebo-controlled trials and meta-analyses studies alarmingly signify the adverse effects of NSAIDs in gastrointestinal, cardiovascular, hepatic, renal, cerebral and pulmonary complications. Although extensive research has elucidated the mechanisms underlying the clinical hazards of NSAIDs, no review has extensively collated the outcomes on various multiorgan toxicities of these drugs together. In this regard, the present review provides a comprehensive insight of the existing knowledge and recent developments on NSAID-induced organ damage. It precisely encompasses the current understanding of structure, classification and mode of action of NSAIDs while reiterating on the emerging instances of NSAID drug repurposing along with pharmacophore modification aimed at safer usage of NSAIDs where toxic effects are tamed without compromising the clinical benefits. The review does not intend to vilify these 'wonder drugs'; rather provides a careful understanding of their side-effects which would be beneficial in evaluating the risk-benefit threshold while rationally using NSAIDs at safer dose and duration.
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Affiliation(s)
- Samik Bindu
- Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal 736101 India
| | - Somnath Mazumder
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India
| | - Uday Bandyopadhyay
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India; Division of Molecular Medicine, Bose Institute, P-1/12, CIT Rd, Scheme VIIM, Kankurgachi, Kolkata, West Bengal 700054 India.
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40
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Hermann S, Brandes F, Kirchner B, Buschmann D, Borrmann M, Klein M, Kotschote S, Bonin M, Reithmair M, Kaufmann I, Schelling G, Pfaffl MW. Diagnostic potential of circulating cell-free microRNAs for community-acquired pneumonia and pneumonia-related sepsis. J Cell Mol Med 2020; 24:12054-12064. [PMID: 32916773 PMCID: PMC7578906 DOI: 10.1111/jcmm.15837] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 02/07/2023] Open
Abstract
Cell-free microRNAs (miRNAs) are transferred in disease state including inflammatory lung diseases and are often packed into extracellular vesicles (EVs). To assess their suitability as biomarkers for community-acquired pneumonia (CAP) and severe secondary complications such as sepsis, we studied patients with CAP (n = 30), sepsis (n = 65) and healthy volunteers (n = 47) subdivided into a training (n = 67) and a validation (n = 75) cohort. After precipitating crude EVs from sera, associated small RNA was profiled by next-generation sequencing (NGS) and evaluated in multivariate analyses. A subset of the thereby identified biomarker candidates was validated both technically and additionally by reverse transcription quantitative real-time PCR (RT-qPCR). Differential gene expression (DGE) analysis revealed 29 differentially expressed miRNAs in CAP patients when compared to volunteers, and 25 miRNAs in patients with CAP, compared to those with sepsis. Sparse partial-least discriminant analysis separated groups based on 12 miRNAs. Three miRNAs proved as a significant biomarker signature. While expression levels of miR-1246 showed significant changes with an increase in overall disease severity from volunteers to CAP and to sepsis, miR-193a-5p and miR-542-3p differentiated patients with an infectious disease (CAP or sepsis) from volunteers. Cell-free miRNAs are potentially novel biomarkers for CAP and may help to identify patients at risk for progress to sepsis, facilitating early intervention and treatment.
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Affiliation(s)
- Stefanie Hermann
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Florian Brandes
- Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Benedikt Kirchner
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Dominik Buschmann
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Melanie Borrmann
- Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Matthias Klein
- Department of Neurology, University Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
| | | | | | - Marlene Reithmair
- Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Ines Kaufmann
- Department of Anesthesia, Klinikum Neuperlach, Munich City Hospitals, Munich, Germany
| | - Gustav Schelling
- Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Michael W Pfaffl
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
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41
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Tyagi A, Kamal MA, Poddar NK. Integrated Pathways of COX-2 and mTOR: Roles in Cell Sensing and Alzheimer's Disease. Front Neurosci 2020; 14:693. [PMID: 32742252 PMCID: PMC7364283 DOI: 10.3389/fnins.2020.00693] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022] Open
Abstract
Cyclooxygenases (COX) are enzymes catalyzing arachidonic acid into prostanoids. COX exists in three isoforms: COX-1, 2, and 3. COX-1 and COX-2 have been widely studied in order to explore and understand their involvement in Alzheimer’s disease (AD), a progressive neuroinflammatory dementia. COX-2 was traditionally viewed to be expressed only under pathological conditions and to have detrimental effects in AD pathophysiology and neurodegeneration. However, an increasing number of reports point to much more complex roles of COX-2 in AD. Mammalian/mechanistic target of rapamycin (mTOR) has been considered as a hub which integrates multiple signaling cascades, some of which are also involved in AD progression. COX-2 and mTOR are both involved in environmental sensing, growth, and metabolic processes of the cell. They are also known to act in cooperation in many different cancers and thus, their role together in normal cellular functions as well as AD has been explored in this review. Some of the therapeutic approaches targeting COX-2 and mTOR in AD and cancer are also discussed.
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Affiliation(s)
- Arti Tyagi
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
| | - Mohammad A Kamal
- King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Enzymoics, Hebersham, NSW, Australia
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42
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Jalalvand M, Shahsavari G, Sheikhian A, Ganji A, Mosayebi G. In vitro Anti-inflammatory Effects of Satureja Kkhuzestanica Essential Oil Compared to Carvacrol. INTERNATIONAL JOURNAL OF BASIC SCIENCE IN MEDICINE 2020. [DOI: 10.34172/ijbsm.2020.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Introduction: Satureja khozestanica grows mainly in the southwest part of Iran as a native plant. This edible herb contains various compounds including the S. Khuzestanica essential oil (SKEO) and monoterpene known as Carvacrol. Previous studies have shown the anti-inflammatory effects of S. Khuzestanica without mentioning the exact mechanism of its function. Given that prostaglandin synthesis, which is one of the main mediators of inflammation, is regulated by the cyclooxygenase-2 (COX2) gene, the present study investigated the effects of SKEO and Carvacrol on the expression of the COX2 gene in the stimulated-J774A.1 macrophage cell line. Methods: To this end, fresh aerial parts of the plant were processed to prepare SKEO. Then, different doses of SKEO and Carvacrol (i.e., 0.004%, 0.008%, and 0.016% v/v) were used to treat with the lipopolysaccharides (LPS)-stimulated cell line for eight hours. After RNA extraction, the real-time polymerase chain reaction technique was applied for gene expression analysis. Results: In the LPS-stimulated J774A.1 macrophage cell line, COX2 gene expression reduced significantly in a dose-dependent manner (0.004%, 0.008%, and 0.016%, P = 0.024, P = 0.021, and P = 0.013 v/v of SKEO, respectively) by SKEO, and the effect of Carvacrol was less powerful (0.008% and 0.016%, P = 0.027 and P = 0.038 v/v, respectively) compared to SKEO. Finally, the comparison between SKEO and Carvacrol showed higher significant inhibitory effects of SKEO on COX2 gene expression in comparison with Carvacrol in 0.004% v/v concentration (P = 0.037). Conclusion: In general, SKEO significantly reduced COX2 gene expression, thus it can be suggested that its anti-inflammatory effect may result from the inhibition of the synthesis of this pro-inflammatory gene.
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Affiliation(s)
- Masumeh Jalalvand
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
| | - Gholamreza Shahsavari
- Department of Biochemistry, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Ali Sheikhian
- Department of Immunology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Ali Ganji
- Department of Microbiology and Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Ghasem Mosayebi
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
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43
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The investigation of the protective effects of nimesulide on experimental testicular ischemia-reperfusion injury in rats. Rev Int Androl 2020; 18:55-62. [DOI: 10.1016/j.androl.2018.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 08/13/2018] [Accepted: 08/31/2018] [Indexed: 12/24/2022]
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44
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Di Dato V, Barbarinaldi R, Amato A, Di Costanzo F, Fontanarosa C, Perna A, Amoresano A, Esposito F, Cutignano A, Ianora A, Romano G. Variation in prostaglandin metabolism during growth of the diatom Thalassiosira rotula. Sci Rep 2020; 10:5374. [PMID: 32214130 PMCID: PMC7096440 DOI: 10.1038/s41598-020-61967-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 02/28/2020] [Indexed: 02/03/2023] Open
Abstract
Prostaglandins (PGs) are hormone-like mediators in many physiological and pathological processes that are present in all vertebrates, in some terrestrial and aquatic invertebrates, and have also been identified in some macroalgae. They have recently been reported also in marine microalgae but their role as chemical mediators is largely unknown. Here we studied the expression pattern of the PG biosynthetic pathway during different growth phases of the centric diatom Thalassiosira rotula and assessed the release of PGs in the surrounding environment for the first time. We show that enzymes responsible for PGs formation such as cyclooxygenase, prostaglandin E synthase 2-like and prostaglandin F synthase are mainly expressed at the end of the exponential phase and that PGs are released especially during the stationary and senescent phases, suggesting a possible signaling function for these compounds. Phylogenetic analysis of the limiting enzyme, COX, indicate the presence in diatoms of more than one enzyme related to the oxidative metabolism of fatty acids belonging to the peroxidase-cyclooxygenase superfamily. These findings suggest a more complex evolution and diversity of metabolic pathways leading to the synthesis of lipid mediators in diatoms.
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Affiliation(s)
- Valeria Di Dato
- Stazione Zoologica Anton Dohrn, Villa Comunale, 80121, Napoli, Italy.
| | | | - Alberto Amato
- Laboratoire de Physiologie Cellulaire Végétale, Université Grenoble Alpes, CEA, CNRS, INRA, IRIG-LPCV 38054, Grenoble Cedex 9, France
| | | | - Carolina Fontanarosa
- Dipartimento di Scienze Chimiche, Università degli Studi di Napoli, Monte Sant'Angelo, 80126, Napoli, Italy
| | - Anna Perna
- Stazione Zoologica Anton Dohrn, Villa Comunale, 80121, Napoli, Italy
| | - Angela Amoresano
- Dipartimento di Scienze Chimiche, Università degli Studi di Napoli, Monte Sant'Angelo, 80126, Napoli, Italy
| | | | - Adele Cutignano
- Istituto di Chimica Biomolecolare-CNR, Via Campi Flegrei 34, 80078, Pozzuoli, Napoli, Italy
| | - Adrianna Ianora
- Stazione Zoologica Anton Dohrn, Villa Comunale, 80121, Napoli, Italy
| | - Giovanna Romano
- Stazione Zoologica Anton Dohrn, Villa Comunale, 80121, Napoli, Italy
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45
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El-Husseiny WM, El-Sayed MAA, El-Azab AS, AlSaif NA, Alanazi MM, Abdel-Aziz AAM. Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition. J Enzyme Inhib Med Chem 2020; 35:744-758. [PMID: 32183576 PMCID: PMC7144195 DOI: 10.1080/14756366.2020.1740695] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3–14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13–17.95 μM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC50=6.44 μM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC50=0.68 μM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC50=1.55 μM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.
Highlights Antitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated. The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors. Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition. Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.
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Affiliation(s)
- Walaa M El-Husseiny
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Magda A-A El-Sayed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt
| | - Adel S El-Azab
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Nawaf A AlSaif
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed M Alanazi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Alaa A-M Abdel-Aziz
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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46
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Pei H, Xue L, Tang M, Tang H, Kuang S, Wang L, Ma X, Cai X, Li Y, Zhao M, Peng A, Ye H, Chen L. Alkaloids from Black Pepper ( Piper nigrum L.) Exhibit Anti-Inflammatory Activity in Murine Macrophages by Inhibiting Activation of NF-κB Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:2406-2417. [PMID: 32031370 DOI: 10.1021/acs.jafc.9b07754] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Black pepper (Piper nigrum L.) has been commonly utilized in food preparation and traditional medicine in several countries. Seven new amide alkaloids, pipernigramides A-G (3, 10, 38, and 41-44), a new piperic ester, pipernigrester A (48), along with 47 known compounds were isolated from the EtOH extract of P. nigrum. The inhibitory effects on nitric oxide (NO) of all compounds were then evaluated. Among the tested compounds, three of them (42-44) significantly inhibited inducible nitric oxide synthase (iNOS)-mediated NO (IC50 = 4.74 ± 0.18, 4.08 ± 0.19, and 3.71 ± 0.32 μM, respectively), and IL-1β, IL-6, TNF-α, and PGE2 release in RAW 264.7 cells stimulated by lipopolysaccharide. Moreover, 42-44 suppressed IκB degradation and further inhibited the cytosol-nucleus translocation of the p65 subunit by targeting IKK-β. In the carrageenan-induced paw edema test, 42-44 demonstrated anti-inflammatory effects as well. These results indicate that all three compounds from P.nigrum have the potential anti-inflammatory effects.
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Affiliation(s)
- Heying Pei
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Linlin Xue
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Minghai Tang
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Huan Tang
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Shuang Kuang
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Lun Wang
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China.,School of Chemical Engineering , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Xu Ma
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Xiaoying Cai
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Yan Li
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China.,School of Chemical Engineering , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Min Zhao
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Aihua Peng
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Haoyu Ye
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
| | - Lijuan Chen
- Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China
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47
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Di Dato V, Ianora A, Romano G. Identification of Prostaglandin Pathway in Dinoflagellates by Transcriptome Data Mining. Mar Drugs 2020; 18:md18020109. [PMID: 32069885 PMCID: PMC7073720 DOI: 10.3390/md18020109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 12/28/2022] Open
Abstract
Dinoflagellates, a major class of marine eukaryote microalgae composing the phytoplankton, are widely recognised as producers of a large variety of toxic molecules, particularly neurotoxins, which can also act as potent bioactive pharmacological mediators. In addition, similarly to other microalgae, they are also good producers of polyunsaturated fatty acids (PUFAs), important precursors of key molecules involved in cell physiology. Among PUFA derivatives are the prostaglandins (Pgs), important physiological mediators in several physiological and pathological processes in humans, also used as “biological” drugs. Their synthesis is very expensive because of the elevated number of reaction steps required, thus the search for new Pgs production methods is of great relevance. One possibility is their extraction from microorganisms (e.g., diatoms), which have been proved to produce the same Pgs as humans. In the present study, we took advantage of the available transcriptomes for dinoflagellates in the iMicrobe database to search for the Pgs biosynthetic pathway using a bioinformatic approach. Here we show that dinoflagellates express nine Pg-metabolism related enzymes involved in both Pgs synthesis and reduction. Not all of the enzymes were expressed simultaneously in all the species analysed and their expression was influenced by culturing conditions, especially salinity of the growth medium. These results confirm the existence of a biosynthetic pathway for these important molecules in unicellular microalgae other than diatoms, suggesting a broad diffusion and conservation of the Pgs pathway, which further strengthen their importance in living organisms.
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48
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Coy-Barrera E. Discrimination of Naturally-Occurring 2-Arylbenzofurans as Cyclooxygenase-2 Inhibitors: Insights into the Binding Mode and Enzymatic Inhibitory Activity. Biomolecules 2020; 10:E176. [PMID: 31979339 PMCID: PMC7072606 DOI: 10.3390/biom10020176] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/12/2020] [Accepted: 01/20/2020] [Indexed: 01/04/2023] Open
Abstract
2-arylbenzofuran-containing compounds are chemical entities that can be naturally produced by several organisms. A wide-range of activities is described for several compounds of this kind and they are, therefore, valuable moieties for a lead finding from nature. Although there are in-vitro data about the activity of 2-arylbenzofuran-related compounds against cyclooxygenase (COX) enzymes, the molecular level of these COX-inhibiting constituents had not been deeply explored. Thus, 58 2-arylbenzofurans were initially screened through molecular docking within the active site of nine COX-2 crystal structures. The resulting docking scores were statistically analyzed and good reproducibility and convergence were found to discriminate the best-docked compounds. Discriminated compounds exhibited the best performance in molecular dynamics simulations as well as the most-favorable binding energies and the lowest in-vitro IC50 values for COX-2 inhibition. A three-dimensional quantitative activity-structure relationship (3D-QSAR) was also demonstrated, which showed some crucial structural requirements for enhanced enzyme inhibition. Therefore, four hits are proposed as lead structures for the development of COX-2 inhibitors based on 2-arylbenzofurans in further studies.
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Affiliation(s)
- Ericsson Coy-Barrera
- Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Cajicá 250247, Colombia
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49
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Wong SK, Kamisah Y, Mohamed N, Muhammad N, Masbah N, Mohd Fahami NA, Mohamed IN, Shuid AN, Mohd Saad Q, Abdullah A, Mohamad NV, Ibrahim NI, Pang KL, Chow YY, Thong BKS, Subramaniam S, Chan CY, Ima-Nirwana S, Chin KY. Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence. Nutrients 2020; 12:259. [PMID: 31963885 PMCID: PMC7019837 DOI: 10.3390/nu12010259] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 12/14/2022] Open
Abstract
Tocotrienol (T3) is a subfamily of vitamin E known for its wide array of medicinal properties. This review aimed to summarize the health benefits of T3, particularly in prevention or treatment of non-communicable diseases (NCDs), including cardiovascular, musculoskeletal, metabolic, gastric, and skin disorders, as well as cancers. Studies showed that T3 could prevent various NCDs, by suppressing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the mevalonate pathway, inflammatory response, oxidative stress, and alternating hormones. The efficacy of T3 in preventing/treating these NCDs is similar or greater compared to tocopherol (TF). TF may lower the efficacy of T3 because the efficacy of the combination of TF and T3 was lower than T3 alone in some studies. Data investigating the effects of T3 on osteoporosis, arthritis, and peptic ulcers in human are limited. The positive outcomes of T3 treatment obtained from the preclinical studies warrant further validation from clinical trials.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Kuala Lumpur, Malaysia; (S.K.W.); (Y.K.); (N.M.); (N.M.); (N.M.); (N.A.M.F.); (I.N.M.); (A.N.S.); (Q.M.S.); (A.A.); (N.-V.M.); (N.I.I.); (K.-L.P.); (Y.Y.C.); (B.K.S.T.); (S.S.); (C.Y.C.); (S.I.-N.)
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50
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Sheng J, Sun H, Yu FB, Li B, Zhang Y, Zhu YT. The Role of Cyclooxygenase-2 in Colorectal Cancer. Int J Med Sci 2020; 17:1095-1101. [PMID: 32410839 PMCID: PMC7211146 DOI: 10.7150/ijms.44439] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer is the third common cancer in this world, accounting for more than 1 million cases each year. However, detailed etiology and mechanism of colorectal cancer have not been fully understood. For example, cyclooxygenase-2 (COX-2) and its product prostaglandin E2 (PGE2) have been closely linked to its occurrence, progression and prognosis. However, the mechanisms on how COX-2 and PGE2-mediate the pathogenesis of colorectal cancer are obscure. In this review, we have summarized recent advances in studies of pathogenesis and control in colorectal cancer to assist further advances in the research for the cure of the cancer. In addition, the knowledge gained may also guide the audiences for reduction of the risk and control of this deadly disease.
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Affiliation(s)
- Juan Sheng
- Department of Gastroenterology, the Second People's Hospital of Yunnan Province, Kunming, Yunnan 650021, China
| | - Hong Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Fu-Bing Yu
- Department of Gastroenterology, the Second People's Hospital of Yunnan Province, Kunming, Yunnan 650021, China
| | - Bo Li
- Department of General Surgery, The Second People's Hospital of Yunnan Province, Kunming, Yunnan 650021, China
| | - Yuan Zhang
- Tissue Tech Inc, Miami, Florida 33032, USA
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