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Wu Y, Guo F, Li J, Shi W, Song L, Liu J. Curcumin ameliorates heatstroke-induced lung injury by activating the PI3K/AKT pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4617-4632. [PMID: 39521756 DOI: 10.1007/s00210-024-03572-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
Heatstroke (HS) poses a significant threat to public health. Curcumin, a polyphenolic compound, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the potential therapeutic effects of curcumin on HS-induced lung injury and to elucidate its underlying molecular mechanisms. We utilized network pharmacology to predict the potential targets of curcumin and determine its possible protective effects against HS. Molecular docking was performed to assess the affinity of curcumin to proteins. Forty mice were used for in vivo experiments to evaluate the therapeutic effects of curcumin, divided into four groups (n = 10 per group): normal control (NC), high-temperature control (HTC), low-dose curcumin heatstroke (H100c, 100 mg/kg/day), and high-dose curcumin heatstroke (H200c, 200 mg/kg/day). Furthermore, we evaluated lung pathology, ultrastructural alterations, and protein expression levels of key molecules. Molecular docking indicated a high binding affinity between curcumin and PIK3R1, AKT, and CASP3. In vivo experiments confirm that curcumin pretreatment significantly mitigates HS-induced lung tissue pathology and ultrastructural damage, with the H200c group showing notably greater improvement. Furthermore, curcumin pretreatment markedly enhances the activation of the PI3K/AKT pathway and suppresses the expression of cleaved caspase3, particularly in the H200c group. Our study suggests curcumin may alleviate HS-induced lung injury via the PI3K/AKT pathway, but limitations exist. We did not test key protein knockdown/overexpression, and PI3K/AKT may not be the only pathway. Human and mouse pharmacokinetic differences could affect clinical translation.
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Affiliation(s)
- Yizhan Wu
- Department of Graduate School, Xinjiang Medical University, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Fei Guo
- Department of Emergency Trauma Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang Uygur Autonomous Region, China
| | - Jiajia Li
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Wenhui Shi
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Laiyang Song
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Jiangwei Liu
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China.
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Baharara H, Kesharwani P, Johnston TP, Sahebkar A. Therapeutic potential of phytochemicals for cystic fibrosis. Biofactors 2023; 49:984-1009. [PMID: 37191383 DOI: 10.1002/biof.1960] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 05/01/2023] [Indexed: 05/17/2023]
Abstract
The aim of this review was to review and discuss various phytochemicals that exhibit beneficial effects on mutated membrane channels, and hence, improve transmembrane conductance. These therapeutic phytochemicals may have the potential to decrease mortality and morbidity of CF patients. Four databases were searched using keywords. Relevant studies were identified, and related articles were separated. Google Scholar, as well as gray literature (i.e., information that is not produced by commercial publishers), were also checked for related articles to locate/identify additional studies. The relevant databases were searched a second time to ensure that recent studies were included. In conclusion, while curcumin, genistein, and resveratrol have demonstrated effectiveness in this regard, it should be emphasized that coumarins, quercetin, and other herbal medicines also have beneficial effects on transporter function, transmembrane conductivity, and overall channel activity. Additional in vitro and in vivo studies should be conducted on mutant CFTR to unequivocally define the mechanism by which phytochemicals alter transmembrane channel function/activity, since the results of the studies evaluated in this review have a high degree of heterogenicity and discrepancy. Finally, continued research be undertaken to clearly define the mechanism(s) of action and the therapeutic effects that therapeutic phytochemicals have on the symptoms observed in CF patients in an effort to reduce mortality and morbidity.
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Affiliation(s)
- Hamed Baharara
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai, India
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - AmirHossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Talebi S, Day AS, Safarian M, Sayedi SJ, Jaafari MR, Abbasi Z, Barghchi H, Kianifar HR. Adjunctive nano-curcumin therapy improves inflammatory and clinical indices in children with cystic fibrosis: A randomized clinical trial. Food Sci Nutr 2023; 11:3348-3357. [PMID: 37324924 PMCID: PMC10261803 DOI: 10.1002/fsn3.3323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 03/01/2023] [Accepted: 03/04/2023] [Indexed: 03/30/2023] Open
Abstract
Inflammation may develop due to internal dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein or external factors in patients with cystic fibrosis (CF). This prospective randomized clinical trial aimed to ascertain the effects of nano-curcumin as an anti-inflammatory agent and a CFTR modulator on clinical and inflammatory markers in children with CF. Children with CF were randomly assigned to receive daily curcumin or a placebo for 3 months. The primary outcome measure was to evaluate inflammatory indices, nasopharyngeal swab analysis, and clinical assessments via spirometry, anthropometric measurements, and quality of life (QOL) analysis. Sixty children were included. Intra-group changes comparison showed that curcumin decreased the level of high-sensitivity C-reactive protein (hs-CRP) (median: -0.31 mg/L, IQR: -1.53 to 0.81; p = .01) and fecal calprotectin level (-29 μg/g, -57.5 to 11.5; p = .03), also increased the level of interleukin (IL)-10 (6.1 pg/mL, 4.5-9; p = .01). Moreover, curcumin improved the overall QOL and the subscales of the questionnaire. Inter-group changes comparison depicted the number of Pseudomonas colonies reduced by about 52% in the curcumin group and gained weight by about 16% (p > .05). Nano-curcumin seems to be considered as an effective nutritional supplement on hs-CRP, IL-10, fecal calprotectin levels, and improving QOL in patients with CF.
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Affiliation(s)
- Saeedeh Talebi
- Department of Nutrition, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Andrew S. Day
- Department of PediatricsUniversity of OtagoChristchurchNew Zealand
| | - Mahammad Safarian
- Department of Nutrition, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Seyed Javad Sayedi
- Department of PediatricsMashhad University of Medical SciencesMashhadIran
| | - Mahmood Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran
| | - Zahra Abbasi
- Akbar Clinical Research and Development UnitMashhad University of Medical SciencesMashhadIran
| | - Hanieh Barghchi
- Department of Nutrition, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
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4
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Trandafir LM, Frăsinariu OE, Țarcă E, Butnariu LI, Leon Constantin MM, Moscalu M, Temneanu OR, Melinte Popescu AS, Popescu MGM, Stârcea IM, Cojocaru E, Moisa SM. Can Bioactive Food Substances Contribute to Cystic Fibrosis-Related Cardiovascular Disease Prevention? Nutrients 2023; 15:314. [PMID: 36678185 PMCID: PMC9860597 DOI: 10.3390/nu15020314] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/30/2022] [Accepted: 01/06/2023] [Indexed: 01/11/2023] Open
Abstract
Advances in cystic fibrosis (CF) care have significantly improved the quality of life and life expectancy of patients. Nutritional therapy based on a high-calorie, high-fat diet, antibiotics, as well as new therapies focused on CFTR modulators change the natural course of the disease. They do so by improving pulmonary function and growing BMI. However, the increased weight of such patients can lead to unwanted long-term cardiovascular effects. People with CF (pwCF) experience several cardiovascular risk factors. Such factors include a high-fat diet and increased dietary intake, altered lipid metabolism, a decrease in the level of fat-soluble antioxidants, heightened systemic inflammation, therapeutic interventions, and diabetes mellitus. PwCF must pay special attention to food and eating habits in order to maintain a nutritional status that is as close as possible to the proper physiological one. They also have to benefit from appropriate nutritional counseling, which is essential in the evolution and prognosis of the disease. Growing evidence collected in the last years shows that many bioactive food components, such as phytochemicals, polyunsaturated fatty acids, and antioxidants have favorable effects in the management of CF. An important positive effect is cardiovascular prevention. The possibility of preventing/reducing cardiovascular risk in CF patients enhances both quality of life and life expectancy in the long run.
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Affiliation(s)
- Laura Mihaela Trandafir
- Department of Mother and Child Medicine–Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Otilia Elena Frăsinariu
- Department of Mother and Child Medicine–Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Elena Țarcă
- Department of Surgery II-Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Lăcrămioara Ionela Butnariu
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | | | - Mihaela Moscalu
- Department of Preventive Medicine and Interdisciplinarity, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Oana Raluca Temneanu
- Department of Mother and Child Medicine–Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Alina Sinziana Melinte Popescu
- Department of General Nursing, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania
| | - Marian George Melinte Popescu
- Department of General Nursing, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania
| | - Iuliana Magdalena Stârcea
- Department of Mother and Child Medicine–Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Elena Cojocaru
- Department of Morphofunctional Sciences I–Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Stefana Maria Moisa
- Department of Mother and Child Medicine–Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
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Fossa P, Uggeri M, Orro A, Urbinati C, Rondina A, Milanesi M, Pedemonte N, Pesce E, Padoan R, Ford RC, Meng X, Rusnati M, D’Ursi P. Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing. Int J Mol Sci 2022; 23:ijms232012274. [PMID: 36293130 PMCID: PMC9602983 DOI: 10.3390/ijms232012274] [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: 08/25/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
Cystic fibrosis is a hereditary disease mainly caused by the deletion of the Phe 508 (F508del) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. Cystic fibrosis remains a potentially fatal disease, but it has become treatable as a chronic condition due to some CFTR-rescuing drugs that, when used in combination, increase in their therapeutic effect due to a synergic action. Also, dietary supplementation of natural compounds in combination with approved drugs could represent a promising strategy to further alleviate cystic fibrosis symptoms. On these bases, we screened by in silico drug repositioning 846 small synthetic or natural compounds from the AIFA database to evaluate their capacity to interact with the highly druggable lumacaftor binding site of F508del-CFTR. Among the identified hits, nicotinamide (NAM) was predicted to accommodate into the lumacaftor binding region of F508del-CFTR without competing against the drug but rather stabilizing its binding. The effective capacity of NAM to bind F508del-CFTR in a lumacaftor-uncompetitive manner was then validated experimentally by surface plasmon resonance analysis. Finally, the capacity of NAM to synergize with lumacaftor increasing its CFTR-rescuing activity was demonstrated in cell-based assays. This study suggests the possible identification of natural small molecules devoid of side effects and endowed with the capacity to synergize with drugs currently employed for the treatment of cystic fibrosis, which hopefully will increase the therapeutic efficacy with lower doses.
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Affiliation(s)
- Paola Fossa
- Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132 Genoa, Italy
| | - Matteo Uggeri
- Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132 Genoa, Italy
- Institute for Biomedical Technologies, National Research Council (ITB-CNR), 20054 Segrate, Italy
| | - Alessandro Orro
- Institute for Biomedical Technologies, National Research Council (ITB-CNR), 20054 Segrate, Italy
| | - Chiara Urbinati
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Alessandro Rondina
- Institute for Biomedical Technologies, National Research Council (ITB-CNR), 20054 Segrate, Italy
| | - Maria Milanesi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | | | - Emanuela Pesce
- UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Rita Padoan
- Department of Pediatrics, Regional Support Centre for Cystic Fibrosis, Children’s Hospital—ASST Spedali Civili, University of Brescia, 25123 Brescia, Italy
| | - Robert C. Ford
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
| | - Xin Meng
- Cellular Degradation Systems Laboratory, The Francis Crick Institute, London NW1 1AT, UK
| | - Marco Rusnati
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
- Correspondence: (M.R.); (P.D.)
| | - Pasqualina D’Ursi
- Institute for Biomedical Technologies, National Research Council (ITB-CNR), 20054 Segrate, Italy
- Correspondence: (M.R.); (P.D.)
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6
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Wong SL, Awatade NT, Astore MA, Allan KM, Carnell MJ, Slapetova I, Chen PC, Capraro A, Fawcett LK, Whan RM, Griffith R, Ooi CY, Kuyucak S, Jaffe A, Waters SA. Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity. iScience 2022; 25:103710. [PMID: 35072004 PMCID: PMC8761696 DOI: 10.1016/j.isci.2021.103710] [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: 08/26/2021] [Revised: 11/27/2021] [Accepted: 12/28/2021] [Indexed: 12/30/2022] Open
Abstract
Characterization of I37R, a mutation located in the lasso motif of the CFTR chloride channel, was conducted by theratyping several CFTR modulators from both potentiator and corrector classes. Intestinal current measurements in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids, and short circuit current measurements in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype demonstrated that the I37R-CFTR results in a residual function defect amenable to treatment with potentiators and type III, but not type I, correctors. Molecular dynamics of I37R using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavorable strengthening of the interactions between the lasso motif, the regulatory (R) domain, and the transmembrane domain 2 (TMD2). Structural and functional characterization of the I37R-CFTR mutation increases understanding of CFTR channel regulation and provides a potential pathway to expand drug access to CF patients with ultra-rare genotypes.
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Affiliation(s)
- Sharon L. Wong
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
| | - Nikhil T. Awatade
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
| | - Miro A. Astore
- School of Physics, University of Sydney, Sydney, Australia
| | - Katelin M. Allan
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
| | - Michael J. Carnell
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, Australia
| | - Iveta Slapetova
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, Australia
| | - Po-chia Chen
- School of Physics, University of Sydney, Sydney, Australia
| | - Alexander Capraro
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
| | - Laura K. Fawcett
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
- Department of Respiratory Medicine, Sydney Children's Hospital, Randwick, Australia
| | - Renee M. Whan
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, Australia
| | | | - Chee Y. Ooi
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
- Department of Gastroenterology, Sydney Children's Hospital, Randwick, Australia
| | - Serdar Kuyucak
- School of Physics, University of Sydney, Sydney, Australia
| | - Adam Jaffe
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
- Department of Respiratory Medicine, Sydney Children's Hospital, Randwick, Australia
| | - Shafagh A. Waters
- School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia
- Department of Respiratory Medicine, Sydney Children's Hospital, Randwick, Australia
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7
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Coco JC, Ataide JA, Sake JA, Tambourgi EB, Ehrhardt C, Mazzola PG. In vitro antioxidant and wound healing properties of baru nut extract ( Dipteryx alata Vog.) in pulmonary epithelial cells for therapeutic application in chronic pulmonary obstructive disease (COPD). Nat Prod Res 2021; 36:4475-4481. [PMID: 34618614 DOI: 10.1080/14786419.2021.1984909] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Baru nuts (Dipteryx alata Vog.) are a native species from Brazil, rich in phenols and other antioxidants, with high socioeconomic value and possible pharmaceutical applications. Here we investigated baru nut ethanolic extract (BNEE) antioxidant and wound healing activities in human NCI-H441 and A549 lung epithelial cell lines for a possible use in conditions related to oxidative stress and wound healing impairments, such as chronic obstructive pulmonary disease (COPD). BNEE was characterised with high DPPH free radical scavenging activity and high total phenolics content, amongst them gallic acid, that was identified and quantified by HPLC. BNEE was not cytotoxic at concentrations studied, reduced the levels of reactive oxygen species before and during oxidative stress and increased wound healing in cell monolayers. These are the first steps to investigate the beneficial properties of baru in diseases related to oxidative stress and wound healing impairments such as COPD.
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Affiliation(s)
- Julia Cedran Coco
- Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil.,School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | | | - Johannes A Sake
- School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | | | - Carsten Ehrhardt
- School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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8
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Talebi S, Safarian M, Jaafari MR, Sayedi SJ, Abbasi Z, Ranjbar G, Kianifar HR. The effects of nano-curcumin as a nutritional strategy on clinical and inflammatory factors in children with cystic fibrosis: the study protocol for a randomized controlled trial. Trials 2021; 22:292. [PMID: 33879218 PMCID: PMC8056493 DOI: 10.1186/s13063-021-05224-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 03/25/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cystic fibrosis (CF) is a genetic disorder, which is caused by the CFTR protein defects. Along with CFTR dysfunction, inflammation plays a key role in the disease outcomes. Inflammation may develop due to the internal dysfunction of the CFTR protein or external factors. Curcumin affects the CFTR protein function primarily as a corrector and potentiator and secondary as an anti-inflammatory and antimicrobial agent. The present study aims to assess the impact of nano-curcumin on clinical and inflammatory markers in children with CF. METHODS This prospective, double blind control trial will be conducted at the Akbar Children's Hospital in Mashhad, Iran. Children with CF will be enrolled based on the eligibility criteria. Placebo and curcumin with the maximum dose of 80 mg considering the body surface of the patients will be administrated for 3 months. The primary outcome is to evaluate inflammation based on serum interleukin-6, interleukin-10, and hs-CRP, stool calprotectin, and neutrophil count of nasopharyngeal swab. The secondary outcome involved clinical assessment via spirometry, anthropometrics, and quality of life. They will be assessed before and after 3 months. DISCUSSION Due to the multifarious effects of curcumin on CF disease, it could be proposed as a nutritional strategy in the treatment of cystic fibrosis. TRIAL REGISTRATION Iranian Registry of Clinical Trials IRCT20200705048018N1 . Registered on July 10, 2020.
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Affiliation(s)
- Saeedeh Talebi
- Department of Nutrition, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahammad Safarian
- Department of Nutrition, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmood Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Javad Sayedi
- Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Abbasi
- Akbar clinical research and development unit, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Golnaz Ranjbar
- Department of Nutrition, Faculty of Medicine, Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Kianifar
- Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran.
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9
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Berkers G, van der Meer R, van Mourik P, Vonk AM, Kruisselbrink E, Suen SW, Heijerman HG, Majoor CJ, Koppelman GH, Roukema J, Janssens HM, de Rijke YB, Kemper EM, Beekman JM, van der Ent CK, de Jonge HR. Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation. J Cyst Fibros 2020; 19:955-961. [PMID: 32499204 DOI: 10.1016/j.jcf.2020.04.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 04/21/2020] [Accepted: 04/23/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.
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Affiliation(s)
- Gitte Berkers
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Renske van der Meer
- Department of Pulmonology, Haga Teaching Hospital, The Hague, the Netherlands
| | - Peter van Mourik
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Annelotte M Vonk
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Evelien Kruisselbrink
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Sylvia Wf Suen
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Harry Gm Heijerman
- Department of Pulmonology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Christof J Majoor
- Department of Respiratory Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Gerard H Koppelman
- Department of Pediatric Pulmonology and Pediatric Allergology and GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands
| | - Jolt Roukema
- Department of Pediatric Pulmonology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Hettie M Janssens
- Department of Pediatrics, division of Respiratory Medicine and Allergology, Erasmus Medical Center/Sophia Children's Hospital, University Hospital Rotterdam, the Netherlands
| | - Yolanda B de Rijke
- Department of Clinical Chemistry, Erasmus Medical Center, University Hospital Rotterdam, the Netherlands
| | - E Marleen Kemper
- Department of Pharmacy, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Jeffrey M Beekman
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Cornelis K van der Ent
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
| | - Hugo R de Jonge
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Hospital Rotterdam, the Netherlands
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10
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Tosco A, Villella VR, Raia V, Kroemer G, Maiuri L. Cystic Fibrosis: New Insights into Therapeutic Approaches. CURRENT RESPIRATORY MEDICINE REVIEWS 2020. [DOI: 10.2174/1573398x15666190702151613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Since the identification of Cystic Fibrosis (CF) as a disease in 1938 until 2012, only
therapies to treat symptoms rather than etiological therapies have been used to treat the disease. Over
the last few years, new technologies have been developed, and gene editing strategies are now
moving toward a one-time cure. This review will summarize recent advances in etiological therapies
that target the basic defect in the CF Transmembrane Receptor (CFTR), the protein that is mutated in
CF. We will discuss how newly identified compounds can directly target mutated CFTR to improve
its function. Moreover, we will discuss how proteostasis regulators can modify the environment in
which the mutant CFTR protein is synthesized and decayed, thus restoring CFTR function. The
future of CF therapies lies in combinatory therapies that may be personalized for each CF patient.
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Affiliation(s)
- Antonella Tosco
- Department of Translational Medical Sciences, Pediatric Unit, Regional Cystic Fibrosis Center, Federico II University, Naples 80131, Italy
| | - Valeria R. Villella
- Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan 20132, Italy
| | - Valeria Raia
- Department of Translational Medical Sciences, Pediatric Unit, Regional Cystic Fibrosis Center, Federico II University, Naples 80131, Italy
| | - Guido Kroemer
- Equipe11 labellisee Ligue Nationale Contrele Cancer, Centre de Recherche des Cordeliers, Paris, France
| | - Luigi Maiuri
- Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan 20132, Italy
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11
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Cho DY, Skinner D, Zhang S, Lazrak A, Lim DJ, Weeks CG, Banks CG, Han CK, Kim SK, Tearney GJ, Matalon S, Rowe SM, Woodworth BA. Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion. J Ginseng Res 2019; 45:66-74. [PMID: 33437158 PMCID: PMC7790903 DOI: 10.1016/j.jgr.2019.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 08/30/2019] [Accepted: 09/06/2019] [Indexed: 11/26/2022] Open
Abstract
Background Abnormal chloride (Cl-) transport has a detrimental impact on mucociliary clearance in both cystic fibrosis (CF) and non-CF chronic rhinosinusitis. Ginseng is a medicinal plant noted to have anti-inflammatory and antimicrobial properties. The present study aims to assess the capability of red ginseng aqueous extract (RGAE) to promote transepithelial Cl- secretion in nasal epithelium. Methods Primary murine nasal septal epithelial (MNSE) [wild-type (WT) and transgenic CFTR-/-], fisher-rat-thyroid (FRT) cells expressing human WT CFTR, and TMEM16A-expressing human embryonic kidney cultures were utilized for the present experiments. Ciliary beat frequency (CBF) and airway surface liquid (ASL) depth measurements were performed using micro-optical coherence tomography (μOCT). Mechanisms underlying transepithelial Cl- transport were determined using pharmacologic manipulation in Ussing chambers and whole-cell patch clamp analysis. Results RGAE (at 30μg/mL of ginsenosides) significantly increased Cl- transport [measured as change in short-circuit current (ΔISC = μA/cm2)] when compared with control in WT and CFTR-/- MNSE (WT vs control = 49.8±2.6 vs 0.1+/-0.2, CFTR-/- = 33.5±1.5 vs 0.2±0.3, p < 0.0001). In FRT cells, the CFTR-mediated ΔISC attributed to RGAE was small (6.8 ± 2.5 vs control, 0.03 ± 0.01, p < 0.05). In patch clamp, TMEM16A-mediated currents were markedly improved with co-administration of RGAE and uridine 5-triphosphate (8406.3 +/- 807.7 pA) over uridine 5-triphosphate (3524.1 +/- 292.4 pA) or RGAE alone (465.2 +/- 90.7 pA) (p < 0.0001). ASL and CBF were significantly greater with RGAE (6.2+/-0.3 μm vs control, 3.9+/-0.09 μm; 10.4+/-0.3 Hz vs control, 7.3 ± 0.2 Hz; p < 0.0001) in MNSE. Conclusion RGAE augments ASL depth and CBF by stimulating Cl- secretion through CaCC, which suggests therapeutic potential in both CF and non-CF chronic rhinosinusitis.
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Affiliation(s)
- Do-Yeon Cho
- Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States.,Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Daniel Skinner
- Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Shaoyan Zhang
- Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Ahmed Lazrak
- Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States.,Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Dong Jin Lim
- Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Christopher G Weeks
- Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Catherine G Banks
- Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Chang Kyun Han
- Korea Ginseng Research Institute, Korea Ginseng Corporation, Daejeon, Republic of Korea
| | - Si-Kwan Kim
- Department of Biomedical Chemistry, Konkuk University, Chungju, Republic of Korea
| | - Guillermo J Tearney
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, United States
| | - Sadis Matalon
- Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States.,Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Steven M Rowe
- Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States.,Departments of Medicine, Pediatrics, Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Bradford A Woodworth
- Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States.,Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States
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12
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Sadowska B, Wójcik U, Krzyżanowska-Kowalczyk J, Kowalczyk M, Stochmal A, Rywaniak J, Burzyńska J, Różalska B. The Pros and Cons of Cystic Fibrosis (CF) Patient Use of Herbal Supplements Containing Pulmonaria officinalis L. Extract: the Evidence from an In Vitro Study on Staphylococcus aureus CF Clinical Isolates. Molecules 2019; 24:E1151. [PMID: 30909529 PMCID: PMC6471470 DOI: 10.3390/molecules24061151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/18/2019] [Accepted: 03/20/2019] [Indexed: 11/17/2022] Open
Abstract
The justification for the use of herbal supplements with Pulmonaria officinalis L. extract (POE) in the case of staphylococcal lung colonization/infections characteristic for cystic fibrosis (CF), was examined in vitro. The impact of POE phenolic-rich fraction on the virulence attributes of CF-associated Staphylococcus aureus (S. aureus) clinical strains has been assessed, including pathogen adhesion, biofilm formation on native and protein-conditioned surfaces (mucin, elastin), mature biofilm eradication, staphylococcal protein A expression, α-toxin release, and S. a. adhesion to A549 cells. Cytotoxicity of the extract to lung epithelial cells was also investigated. It was found that POE has bacteriostatic effects at MIC 1⁻2 mg/mL, recognized as of limited efficacy, but at MIC/subMICs it targeted virulence not viability. It usually decreased S. aureus adhesion and less frequently inhibited biofilm formation on native and protein-conditioned surfaces. Observed effect seems to be related to significant reduction by POE of sortase A activity. However, in some cases POE favored the creation of biofilm by staphylococci and S. aureus adhesion to the lung epithelium was not limited. On the other side POE caused significant decrease of S. a. α-toxin synthesis and slightly weakened the expression of SpA. When used at supraMICs POE eradicated mature biofilm, but in some cases with unsatisfying outcomes. Promisingly, POE has been recognized as a safe product, with no cytotoxicity up to 4 mg/mL. These results reflect the positive, negative or neutral anti-staphylococcal properties of POE. It seems that POE may be beneficial as a prophylactic, but not as a therapeutic or supportive agent in the area of CF-integrative medicine. However, introduction the official recommendations needs further in vivo studies.
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Affiliation(s)
- Beata Sadowska
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
| | - Urszula Wójcik
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
| | - Justyna Krzyżanowska-Kowalczyk
- Department of Biochemistry, Institute of Soil Science and Plant Cultivation, State Research Institute, Czartoryskich 8, 24-100 Pulawy, Poland.
| | - Mariusz Kowalczyk
- Department of Biochemistry, Institute of Soil Science and Plant Cultivation, State Research Institute, Czartoryskich 8, 24-100 Pulawy, Poland.
| | - Anna Stochmal
- Department of Biochemistry, Institute of Soil Science and Plant Cultivation, State Research Institute, Czartoryskich 8, 24-100 Pulawy, Poland.
| | - Joanna Rywaniak
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
| | - Julia Burzyńska
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
| | - Barbara Różalska
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
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13
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Hoppe S, Breves G, Klinger S. Calcium-induced chloride secretion is decreased by Resveratrol in ileal porcine tissue. BMC Res Notes 2018; 11:719. [PMID: 30309374 PMCID: PMC6182809 DOI: 10.1186/s13104-018-3825-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/08/2018] [Indexed: 11/16/2022] Open
Abstract
Objective Chloride (Cl−) secretion is crucial for intestinal fluid secretion. Therefore, effects of the polyphenol Resveratrol (RSV) on Cl− secretion have been investigated. In a previous study, we observed effects of RSV on forskolin-induced Cl− secretion in the porcine jejunum but not the ileum although RSV itself induced a transepithelial ion current that may represent Cl− secretion in the ileum. The aim of this study was to gain further insights regarding the effects of RSV on characteristics of Cl− secretion in the porcine ileum using the Ussing chamber technique (recording of short circuit currents (Isc) as a measure for epithelial net ion transfer). Results RSV increased the Isc in the porcine ileum but not in the porcine jejunum as is already known. This increase was absent in a Cl−-free buffer system, indicating that RSV indeed induces Cl− secretion. However, the carbachol-induced Isc was significantly inhibited by RSV indicating an inhibition of Ca2+-induced Cl− secretion. The cellular basis for these contradictory, segment specific results of RSV on Cl− secretion has to be subjected to further studies. The results also underline, that is difficult to generalize effects of RSV between different intestinal locations, organs, cell culture models or species. Electronic supplementary material The online version of this article (10.1186/s13104-018-3825-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Susanne Hoppe
- Department of Physiology, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany
| | - Gerhard Breves
- Department of Physiology, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany
| | - Stefanie Klinger
- Department of Physiology, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany.
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14
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Lord R, Fairbourn N, Mylavarapu C, Dbeis A, Bowman T, Chandrashekar A, Banayat T, Hodges CA, Al-Nakkash L. Consuming Genistein Improves Survival Rates in the Absence of Laxative in ΔF508-CF Female Mice. Nutrients 2018; 10:E1418. [PMID: 30282922 PMCID: PMC6213472 DOI: 10.3390/nu10101418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 09/11/2018] [Accepted: 09/26/2018] [Indexed: 11/16/2022] Open
Abstract
Genistein is a naturally occurring isoflavone found in soy. Genistein has been shown to increase the open probability of the most common cystic fibrosis (CF) disease-associated mutation, ∆F508-CFTR. Mice homozygous for the ∆F508 mutation are characterized with severe intestinal disease and require constant laxative treatment for survival. This pathology mimics the intestinal obstruction (meconium ileus) seen in some cystic fibrosis patients. This study tested whether dietary supplementation with genistein would reduce the dependence of the ∆F508 CF mouse model on laxatives for survival, thereby improving mortality rates. At weaning (21 days), homozygous ∆F508 mice were maintained on one of three diet regimens for a period of up to 65 days: normal diet, normal diet plus colyte, or genistein diet. Survival rates for males were as follows: standard diet (38%, n = 21), standard diet plus colyte (83%, n = 42) and genistein diet (60%, n = 15). Survival rates for females were as follows: standard diet (47%, n = 19), standard diet plus colyte (71%, n = 38), and genistein diet (87%, n = 15). Average weight of male mice fed genistein diet increased by ~2.5 g more (p = 0.006) compared to those with colyte treatment. Genistein diet did not change final body weight of females. Expression of intestinal SGLT-1 increased 2-fold (p = 0.0005) with genistein diet in females (no change in males, p = 0.722). Expression of GLUT2 and GLUT5 was comparable between all diet groups. Genistein diet reduced the number of goblet cells per micrometer of crypt depth in female (p = 0.0483), yet was without effect in males (p = 0.7267). The results from this study demonstrate that supplementation of diet with genistein for ~45 days increases the survival rate of female ∆F508-CF mice (precluding the requirement for laxatives), and genistein only improves weight gain in males.
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Affiliation(s)
- Ryan Lord
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
| | - Nathan Fairbourn
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
| | - Charisma Mylavarapu
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
| | - Ammer Dbeis
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
| | - Taylor Bowman
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
| | - Archana Chandrashekar
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
| | - Tatum Banayat
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
| | - Craig A Hodges
- Department of Genetics & Genome Sciences & Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, 830 BRB, Cleveland, OH 44106, USA.
| | - Layla Al-Nakkash
- Department of Physiology, AZCOM, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
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15
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Tosco A, Villella VR, Castaldo A, Kroemer G, Maiuri L, Raia V. Repurposing therapies for the personalised treatment of cystic fibrosis. Expert Opin Orphan Drugs 2018. [DOI: 10.1080/21678707.2018.1483231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Antonella Tosco
- Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Valeria R. Villella
- European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | - Alice Castaldo
- Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Guido Kroemer
- Equipe11 labellisée Ligue Nationale Contrele Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
- Université Paris Descartes, Paris, Sorbonne Paris Cité, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
- Pôle de Biologie, HôpitalEuropéen Georges Pompidou, AP-HP, Paris, France
| | - Luigi Maiuri
- European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
- Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
| | - Valeria Raia
- Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples, Italy
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16
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Gámez A, Yuste-Checa P, Brasil S, Briso-Montiano Á, Desviat L, Ugarte M, Pérez-Cerdá C, Pérez B. Protein misfolding diseases: Prospects of pharmacological treatment. Clin Genet 2017; 93:450-458. [DOI: 10.1111/cge.13088] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/16/2017] [Accepted: 06/27/2017] [Indexed: 12/21/2022]
Affiliation(s)
- A. Gámez
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
| | - P. Yuste-Checa
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
| | - S. Brasil
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
| | - Á. Briso-Montiano
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
| | - L.R. Desviat
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
| | - M. Ugarte
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
| | - C. Pérez-Cerdá
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
| | - B. Pérez
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria IdiPAZ; Madrid Spain
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17
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Ranucci G, Polishchuck R, Iorio R. Wilson's disease: Prospective developments towards new therapies. World J Gastroenterol 2017; 23:5451-5456. [PMID: 28852304 PMCID: PMC5558108 DOI: 10.3748/wjg.v23.i30.5451] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 04/11/2017] [Accepted: 07/22/2017] [Indexed: 02/06/2023] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure.
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18
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DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress. PLoS One 2017; 12:e0179456. [PMID: 28662078 PMCID: PMC5491010 DOI: 10.1371/journal.pone.0179456] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 05/29/2017] [Indexed: 11/23/2022] Open
Abstract
Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates. UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident protein involved in an initial step in the N-glycosylation pathway. The aim of the present study was to examine the effect of six variants in DPAGT1 detected in patients with DPAGT1-CDG, and the role of endoplasmic reticulum stress, as part of the search for therapeutic strategies to use against DPAGT1-CDG. The effect of the six mutations, i.e., c.358C>A (p.Leu120Met), c.791T>G (p.Val264Gly), c.901C>T (p.Arg301Cys), c.902G>A (p.Arg301His), c.1154T>G (p.Leu385Arg), and of the novel mutation c.329T>C (p.Phe110Ser), were examined via the analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. In addition, the transient expression of different mutations was analysed in COS-7 cells. The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane. The unfolded protein response (UPR; the response to ER stress) was found not to be active in patient-derived fibroblasts, unlike that seen in cells from patients with PMM2-CDG or DPM1-CDG. Even so, the fibroblasts of patients with DPAGT1-CDG seemed to be more sensitive to the stressor tunicamycin. The present work improves our knowledge of DPAGT1-CDG and provides bases for developing tailored splicing and folding therapies.
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19
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Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA. The Essential Medicinal Chemistry of Curcumin. J Med Chem 2017; 60:1620-1637. [PMID: 28074653 PMCID: PMC5346970 DOI: 10.1021/acs.jmedchem.6b00975] [Citation(s) in RCA: 1187] [Impact Index Per Article: 148.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
![]()
Curcumin
is a constituent (up to ∼5%) of the traditional
medicine known as turmeric. Interest in the therapeutic use of turmeric
and the relative ease of isolation of curcuminoids has led to their
extensive investigation. Curcumin has recently been classified as
both a PAINS (pan-assay interference compounds) and an IMPS (invalid
metabolic panaceas) candidate. The likely false activity of curcumin
in vitro and in vivo has resulted in >120
clinical trials of curcuminoids against several diseases. No double-blinded,
placebo controlled clinical trial of curcumin has been successful.
This manuscript reviews the essential medicinal chemistry of curcumin
and provides evidence that curcumin is an unstable, reactive, nonbioavailable
compound and, therefore, a highly improbable lead. On the basis of
this in-depth evaluation, potential new directions for research on
curcuminoids are discussed.
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Affiliation(s)
- Kathryn M Nelson
- Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States
| | - Jayme L Dahlin
- Department of Pathology, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States
| | - Jonathan Bisson
- Center for Natural Product Technologies, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States
| | - James Graham
- Center for Natural Product Technologies, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States
| | - Guido F Pauli
- Center for Natural Product Technologies, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.,Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States
| | - Michael A Walters
- Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States
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20
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Castellani C, Assael BM. Cystic fibrosis: a clinical view. Cell Mol Life Sci 2017; 74:129-140. [PMID: 27709245 PMCID: PMC11107741 DOI: 10.1007/s00018-016-2393-9] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 09/28/2016] [Indexed: 02/07/2023]
Abstract
Cystic fibrosis (CF), a monogenic disease caused by mutations in the CFTR gene on chromosome 7, is complex and greatly variable in clinical expression. Airways, pancreas, male genital system, intestine, liver, bone, and kidney are involved. The lack of CFTR or its impaired function causes fat malabsorption and chronic pulmonary infections leading to bronchiectasis and progressive lung damage. Previously considered lethal in infancy and childhood, CF has now attained median survivals of 50 years of age, mainly thanks to the early diagnosis through neonatal screening, recognition of mild forms, and an aggressive therapeutic attitude. Classical treatment includes pancreatic enzyme replacement, respiratory physiotherapy, mucolitics, and aggressive antibiotic therapy. A significant proportion of patients with severe symptoms still requires lung or, less frequently, liver transplantation. The great number of mutations and their diverse effects on the CFTR protein account only partially for CF clinical variability, and modifier genes have a role in modulating the clinical expression of the disease. Despite the increasing understanding of CFTR functioning, several aspects of CF need still to be clarified, e.g., the worse outcome in females, the risk of malignancies, the pathophysiology, and best treatment of comorbidities, such as CF-related diabetes or CF-related bone disorder. Research is focusing on new drugs restoring CFTR function, some already available and with good clinical impact, others showing promising preliminary results that need to be confirmed in phase III clinical trials.
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Affiliation(s)
- Carlo Castellani
- Verona Cystic Fibrosis Centre, Piazzale Stefani 1, 37126, Verona, Italy.
| | - Baroukh M Assael
- Adult Cystic Fibrosis Center, Via Francesco Sforza, 20100, Milano, Italy
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21
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Schmidt BZ, Haaf JB, Leal T, Noel S. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol 2016; 8:127-140. [PMID: 27703398 PMCID: PMC5036583 DOI: 10.2147/cpaa.s100759] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients. This review highlights the current development in pharmacological modulators of CFTR, which aim at rescuing the expression and/or function of mutated CFTR. While only Kalydeco® and Orkambi® are currently available to patients, many other families of CFTR modulators are undergoing preclinical and clinical investigations. Drug repositioning and personalized medicine are particularly detailed in this review as they represent the most promising strategies for restoring CFTR function in CF.
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Affiliation(s)
- Béla Z Schmidt
- Stem Cell Biology and Embryology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven
| | - Jérémy B Haaf
- Louvain Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium
| | - Teresinha Leal
- Louvain Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium
| | - Sabrina Noel
- Louvain Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium
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