Pub Date : 2023-01-06DOI: 10.3390/futurepharmacol3010004
Gamze Varan, Serhat Unal
Cells, the basic structures of all living organisms, reside in an extracellular matrix consisting of a complex three-dimensional architecture and interact with neighboring cells both mechanically and biochemically. Cell–cell and cell–extracellular matrix interactions form a three-dimensional network that maintains tissue specificity and homeostasis. Important biological processes in a cell cycle are regulated by principles organized by the microenvironment surrounding the cell. The conventional cell culture methods failed to mimic in vivo-like structural organization and are insufficient to examine features such as connectivity of cells, cellular morphology, viability, proliferation, differentiation, gene and protein expression, response to stimuli, and drug/vaccine metabolism. Three-dimensional cell culture studies are very important in terms of reducing the need for in vivo studies and creating an intermediate step. Three-dimensional cell culture methods have attracted attention in the literature in recent years, especially in examining the cellular distribution of organs in the presence of infectious diseases, elucidating the pathogenic mechanism of action of viruses, and examining virus–host interactions. This review highlights the use and importance of three-dimensional cell culture methods in the design and characterization of novel vaccine formulations and the pathogenesis of infectious diseases.
{"title":"Three-Dimensional Cell Culture Methods in Infectious Diseases and Vaccine Research","authors":"Gamze Varan, Serhat Unal","doi":"10.3390/futurepharmacol3010004","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010004","url":null,"abstract":"Cells, the basic structures of all living organisms, reside in an extracellular matrix consisting of a complex three-dimensional architecture and interact with neighboring cells both mechanically and biochemically. Cell–cell and cell–extracellular matrix interactions form a three-dimensional network that maintains tissue specificity and homeostasis. Important biological processes in a cell cycle are regulated by principles organized by the microenvironment surrounding the cell. The conventional cell culture methods failed to mimic in vivo-like structural organization and are insufficient to examine features such as connectivity of cells, cellular morphology, viability, proliferation, differentiation, gene and protein expression, response to stimuli, and drug/vaccine metabolism. Three-dimensional cell culture studies are very important in terms of reducing the need for in vivo studies and creating an intermediate step. Three-dimensional cell culture methods have attracted attention in the literature in recent years, especially in examining the cellular distribution of organs in the presence of infectious diseases, elucidating the pathogenic mechanism of action of viruses, and examining virus–host interactions. This review highlights the use and importance of three-dimensional cell culture methods in the design and characterization of novel vaccine formulations and the pathogenesis of infectious diseases.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89688388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-04DOI: 10.3390/futurepharmacol3010002
Kaihui Lu, Y. Yip
Obesity is associated with a significantly increased risk of cardiovascular and metabolic diseases such as diabetes mellitus. Recently, a growing body of evidence shows that phytochemicals, especially many flavonoids, place an inhibitory regulatory effect on adipogenesis, obesity and diabetes. With computer-aided drug discovery, the action modes of more and more bioactive flavonoids are being identified and confirmed at the molecular level. Citrus fruit peels are particularly rich in bioactive flavonoids which have demonstrated strong therapeutic potentials in regulating lipid metabolisms. However, they are usually thrown away after consuming the flesh, sometimes even causing environmental problems. Thus, extraction of useful flavonoids from citrus fruit waste for pharmaceutical industry could be a profitable and environmentally friendly solution in the future, advocating the concepts of circular economy and sustainable society. The aim of this review is to summarize current evidence on the antiobesity and antidiabetic potentials of identified bioactive flavonoids extracted from the peels of citrus fruits. Our results suggest that various citrus fruit peels could be potential sources for novel drugs and nutraceuticals. Combining experimental data and artificial intelligence methods to study citrus flavonoids would facilitate the discovery of novel drugs against obesity and obesity-related metabolic diseases.
{"title":"Therapeutic Potential of Bioactive Flavonoids from Citrus Fruit Peels toward Obesity and Diabetes Mellitus","authors":"Kaihui Lu, Y. Yip","doi":"10.3390/futurepharmacol3010002","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010002","url":null,"abstract":"Obesity is associated with a significantly increased risk of cardiovascular and metabolic diseases such as diabetes mellitus. Recently, a growing body of evidence shows that phytochemicals, especially many flavonoids, place an inhibitory regulatory effect on adipogenesis, obesity and diabetes. With computer-aided drug discovery, the action modes of more and more bioactive flavonoids are being identified and confirmed at the molecular level. Citrus fruit peels are particularly rich in bioactive flavonoids which have demonstrated strong therapeutic potentials in regulating lipid metabolisms. However, they are usually thrown away after consuming the flesh, sometimes even causing environmental problems. Thus, extraction of useful flavonoids from citrus fruit waste for pharmaceutical industry could be a profitable and environmentally friendly solution in the future, advocating the concepts of circular economy and sustainable society. The aim of this review is to summarize current evidence on the antiobesity and antidiabetic potentials of identified bioactive flavonoids extracted from the peels of citrus fruits. Our results suggest that various citrus fruit peels could be potential sources for novel drugs and nutraceuticals. Combining experimental data and artificial intelligence methods to study citrus flavonoids would facilitate the discovery of novel drugs against obesity and obesity-related metabolic diseases.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74812281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-21DOI: 10.3390/futurepharmacol3010001
Waratta Hemtong, Aporn Chuncharunee, G. Sreekanth
Wound healing is the restorative process of skin or tissue injury, composed of the inflammatory, proliferative, maturation, and remodeling phases. The current study aimed to examine the efficacy of ASPP 092 (a well-characterized diarylheptanoid from Curcuma comosa Roxb) in modulating wound healing. Full-thickness excision wounds were made in rats and treated with either ASPP 092 (dose: 1 mg/mL and 2 mg/mL) or mupirocin (bioequivalent formulation). A control group treated with the vehicle (gel base) was also maintained. The healing efficacy of ASPP 092 was evaluated based on gross appearance, wound closure, and histopathology on days 3, 7, and 12 post-wounding. The expression of cyclooxygenase-2 (COX-2) among the groups was also determined on day 3 post-wounding. Our results suggest that ASPP 092 treatment accelerated wound healing, as evidenced by rapid wound closure, re-epithelialization, and granulation of tissue formation with fewer inflammatory cells. More fibroblasts, collagen fibers, and blood vessels originated with reduced COX-2 expression in the wounds, demonstrating the anti-inflammatory potential of ASPP 092 in experimental wounds. In conclusion, our findings, for the first time, preliminarily identified the potential of ASPP 092 in accelerating wound healing; however, more detailed studies on its mechanism of action in wound healing are required.
{"title":"Topical Application of ASPP 092, a Diarylheptanoid Isolated from Curcuma comosa Roxb, Accelerates Wound Healing","authors":"Waratta Hemtong, Aporn Chuncharunee, G. Sreekanth","doi":"10.3390/futurepharmacol3010001","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010001","url":null,"abstract":"Wound healing is the restorative process of skin or tissue injury, composed of the inflammatory, proliferative, maturation, and remodeling phases. The current study aimed to examine the efficacy of ASPP 092 (a well-characterized diarylheptanoid from Curcuma comosa Roxb) in modulating wound healing. Full-thickness excision wounds were made in rats and treated with either ASPP 092 (dose: 1 mg/mL and 2 mg/mL) or mupirocin (bioequivalent formulation). A control group treated with the vehicle (gel base) was also maintained. The healing efficacy of ASPP 092 was evaluated based on gross appearance, wound closure, and histopathology on days 3, 7, and 12 post-wounding. The expression of cyclooxygenase-2 (COX-2) among the groups was also determined on day 3 post-wounding. Our results suggest that ASPP 092 treatment accelerated wound healing, as evidenced by rapid wound closure, re-epithelialization, and granulation of tissue formation with fewer inflammatory cells. More fibroblasts, collagen fibers, and blood vessels originated with reduced COX-2 expression in the wounds, demonstrating the anti-inflammatory potential of ASPP 092 in experimental wounds. In conclusion, our findings, for the first time, preliminarily identified the potential of ASPP 092 in accelerating wound healing; however, more detailed studies on its mechanism of action in wound healing are required.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77915509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-16DOI: 10.3390/futurepharmacol2040041
T. Hanrahan, R. Chan, D. Tassone, N. Ding, C. Basnayake, J. Schulberg, A. Vasudevan, M. Kamm, M. De Gregorio, D. V. van Langenberg, O. Niewiadomski
Background: Despite proven efficacy of biologics in inflammatory bowel disease (IBD), many exhibit primary non-response or secondary loss of response and switch to subsequent biologic(s). Here, we identified early predictors of second- and/or third-line biologic persistence in IBD, in a real-world cohort of patients. Methods: A retrospective multicentre cohort study was conducted on patients receiving second- and/or third-line biologics for IBD from 2005–2021. Cox regression was applied to identify factors predictive of longer cumulative biologic persistence prior to treatment failure. Results: Of 179 patients who received ≥2 biologics, 159 (88.8%) received an anti-tumour necrosis factor (anti-TNF) first-line. There was a significantly increased likelihood of longer treatment persistence in recipients who received an anti-TNF first, versus those that received a non-anti-TNF agent first (p < 0.01). A diagnosis of CD (OR 7.1, 95% CI [2.3–21.7], p < 0.01), and endoscopic remission achieved on the first biologic (OR 10.4 [1.3–79.9], p = 0.03) were positive predictors of longer biologic persistence, whilst advancing age at IBD diagnosis (OR 0.97 [0.94–0.99], p = 0.04) and primary non-response to initial biologic (OR 0.3 [0.1–0.7], p < 0.01) were inversely associated with biologic persistence. Conclusions: These real-world data demonstrate multiple, simple to identify factors that offer the potential for early objectively assessed response to first-line biologic to predict future biologic persistence.
背景:尽管已证实生物制剂对炎症性肠病(IBD)有效，但许多生物制剂表现出原发性无反应或继发性反应丧失，并转而使用后续生物制剂。在这里，我们在现实世界的患者队列中确定了IBD的二线和/或三线生物学持久性的早期预测因素。方法:一项回顾性多中心队列研究对2005-2021年接受二线和/或三线生物制剂治疗IBD的患者进行了研究。应用Cox回归来确定治疗失败前更长的累积生物学持久性的预测因素。结果:179例接受≥2种生物制剂治疗的患者中，159例(88.8%)接受了一线抗肿瘤坏死因子(anti-TNF)治疗。首先接受抗肿瘤坏死因子治疗的患者与首先接受非抗肿瘤坏死因子治疗的患者相比，治疗持续时间较长的可能性显著增加(p < 0.01)。诊断为CD (OR 7.1, 95% CI [2.3-21.7]， p < 0.01)和内镜下首次生物治疗缓解(OR 10.4 [1.3-79.9]， p = 0.03)是生物治疗持续时间较长的积极预测因素，而IBD诊断时年龄越大(OR 0.97 [0.94-0.99]， p = 0.04)和最初生物治疗无反应(OR 0.3 [0.1-0.7]， p < 0.01)与生物治疗持续时间呈负相关。结论:这些真实世界的数据证明了多种简单识别的因素，这些因素提供了早期客观评估一线生物药物反应的潜力，以预测未来的生物持久性。
{"title":"Persistence of Second and Third-Line Biologics in Inflammatory Bowel Disease: A Multi-Centre Cohort Study","authors":"T. Hanrahan, R. Chan, D. Tassone, N. Ding, C. Basnayake, J. Schulberg, A. Vasudevan, M. Kamm, M. De Gregorio, D. V. van Langenberg, O. Niewiadomski","doi":"10.3390/futurepharmacol2040041","DOIUrl":"https://doi.org/10.3390/futurepharmacol2040041","url":null,"abstract":"Background: Despite proven efficacy of biologics in inflammatory bowel disease (IBD), many exhibit primary non-response or secondary loss of response and switch to subsequent biologic(s). Here, we identified early predictors of second- and/or third-line biologic persistence in IBD, in a real-world cohort of patients. Methods: A retrospective multicentre cohort study was conducted on patients receiving second- and/or third-line biologics for IBD from 2005–2021. Cox regression was applied to identify factors predictive of longer cumulative biologic persistence prior to treatment failure. Results: Of 179 patients who received ≥2 biologics, 159 (88.8%) received an anti-tumour necrosis factor (anti-TNF) first-line. There was a significantly increased likelihood of longer treatment persistence in recipients who received an anti-TNF first, versus those that received a non-anti-TNF agent first (p < 0.01). A diagnosis of CD (OR 7.1, 95% CI [2.3–21.7], p < 0.01), and endoscopic remission achieved on the first biologic (OR 10.4 [1.3–79.9], p = 0.03) were positive predictors of longer biologic persistence, whilst advancing age at IBD diagnosis (OR 0.97 [0.94–0.99], p = 0.04) and primary non-response to initial biologic (OR 0.3 [0.1–0.7], p < 0.01) were inversely associated with biologic persistence. Conclusions: These real-world data demonstrate multiple, simple to identify factors that offer the potential for early objectively assessed response to first-line biologic to predict future biologic persistence.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87606112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-10DOI: 10.3390/futurepharmacol2040040
E. Winter, I. V. van Geijlswijk, I. Akkerdaas, M. Sturkenboom, R. Gehring
Tramadol is a veterinary analgesic for dogs. In this study, the steady-state pharmacokinetics of a sustained-release (SR) tablet (Tramagetic OD®) and immediate-release capsules (IR) were compared. In a crossover design, six dogs received five doses of IR 50 mg four times a day (qid), or two doses of SR 200 mg once a day (sid). Eight blood samples were collected per dog, per formulation, up to 6 and 24 h after the last dose, respectively. Serum concentrations of tramadol and its metabolites were measured with LC-MS/MS. Metabolite M1 levels were below the lower limit of quantification (LLOQ) in all samples. The non-compartmental analysis of the time–concentration data showed a later Tmax with the SR formulation (median 6.00 h (3.00–9.00)) and a lower Cmax/D (median 7.74 µg/L/mg/kg (0.09–25.3)) compared to the IR formulation (median Tmax 1.75 h (0.75–2.00) and median Cmax/D 11.1 µg/L/mg/kg (4.8–70.4)). AUCtau/D after SR administration was 55.5 h × kg × µg/L/mg (0–174.1) compared to 29.8 h × kg × µg/L/mg (12.2–140.8) after IR administration. The terminal elimination half-lives were 2.38 h (1.77–6.22) and 1.70 h (0.95–2.11) for the SR and IR formulations, respectively. Strong conclusions cannot be drawn from this study because of the high percentage of samples that were below LLOQ and the great interindividual variability, but these results suggest that Tramagetic OD can be administered less frequently in dogs.
曲马多是一种犬用兽药。本研究比较了一种缓释片(Tramagetic OD®)和速释胶囊(IR)的稳态药代动力学。在交叉设计中，6只狗接受5次剂量的IR 50 mg，每天4次(qid)，或2次剂量的SR 200 mg，每天1次(sid)。在最后一次给药后的6和24小时，每只狗分别采集8份血液样本。采用LC-MS/MS法测定曲马多及其代谢产物的血清浓度。所有样品的代谢产物M1水平均低于定量下限(LLOQ)。时间-浓度数据的非区隔分析显示，与IR制剂(Tmax中值1.75 h(0.75-2.00)和Cmax/D中值11.1µg/L/mg/kg(4.8-70.4))相比，SR制剂的Tmax中值较晚(中值6.00 h (3.00-9.00))， Cmax/D中值7.74µg/L/mg/kg(0.09-25.3))。SR给药后AUCtau/D为55.5 h × kg ×µg/L/mg (0 ~ 174.1)， IR给药后AUCtau/D为29.8 h × kg ×µg/L/mg(12.2 ~ 140.8)。SR和IR配方的末端消除半衰期分别为2.38 h(1.77 ~ 6.22)和1.70 h(0.95 ~ 2.11)。由于低于LLOQ的样本比例很高，而且个体间差异很大，因此无法从这项研究中得出强有力的结论，但这些结果表明，在狗身上施用Tramagetic OD的频率较低。
{"title":"Tramadol Steady-State Pharmacokinetics of Immediate-Release Capsules and Sustained-Release Tablets in Dogs","authors":"E. Winter, I. V. van Geijlswijk, I. Akkerdaas, M. Sturkenboom, R. Gehring","doi":"10.3390/futurepharmacol2040040","DOIUrl":"https://doi.org/10.3390/futurepharmacol2040040","url":null,"abstract":"Tramadol is a veterinary analgesic for dogs. In this study, the steady-state pharmacokinetics of a sustained-release (SR) tablet (Tramagetic OD®) and immediate-release capsules (IR) were compared. In a crossover design, six dogs received five doses of IR 50 mg four times a day (qid), or two doses of SR 200 mg once a day (sid). Eight blood samples were collected per dog, per formulation, up to 6 and 24 h after the last dose, respectively. Serum concentrations of tramadol and its metabolites were measured with LC-MS/MS. Metabolite M1 levels were below the lower limit of quantification (LLOQ) in all samples. The non-compartmental analysis of the time–concentration data showed a later Tmax with the SR formulation (median 6.00 h (3.00–9.00)) and a lower Cmax/D (median 7.74 µg/L/mg/kg (0.09–25.3)) compared to the IR formulation (median Tmax 1.75 h (0.75–2.00) and median Cmax/D 11.1 µg/L/mg/kg (4.8–70.4)). AUCtau/D after SR administration was 55.5 h × kg × µg/L/mg (0–174.1) compared to 29.8 h × kg × µg/L/mg (12.2–140.8) after IR administration. The terminal elimination half-lives were 2.38 h (1.77–6.22) and 1.70 h (0.95–2.11) for the SR and IR formulations, respectively. Strong conclusions cannot be drawn from this study because of the high percentage of samples that were below LLOQ and the great interindividual variability, but these results suggest that Tramagetic OD can be administered less frequently in dogs.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81097906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-09DOI: 10.3390/futurepharmacol2040039
Vijay Kumar, Caitlin E. Bauer, John H. Stewart Iv
Gynecological cancers, including endometrial adenocarcinoma, significantly contribute to cancer incidence and mortality worldwide. The immune system plays a significant role in endometrial cancer pathogenesis. NK cells, a component of innate immunity, are among the critical innate immune cells in the uterus crucial in menstruation, embryonic development, and fighting infections. NK cell number and function influence endometrial cancer development and progression. Hence, it becomes crucial to understand the role of local (uterine) NK cells in uterine cancer. Uterine NK (uNK) cells behave differently than their peripheral counterparts; for example, uNK cells are more regulated by sex hormones than peripheral NK cells. A deeper understanding of NK cells in uterine cancer may facilitate the development of NK cell-targeted therapies. This review synthesizes current knowledge on the uterine immune microenvironment and NK cell-targeted uterine cancer therapeutics.
{"title":"Chasing Uterine Cancer with NK Cell-Based Immunotherapies","authors":"Vijay Kumar, Caitlin E. Bauer, John H. Stewart Iv","doi":"10.3390/futurepharmacol2040039","DOIUrl":"https://doi.org/10.3390/futurepharmacol2040039","url":null,"abstract":"Gynecological cancers, including endometrial adenocarcinoma, significantly contribute to cancer incidence and mortality worldwide. The immune system plays a significant role in endometrial cancer pathogenesis. NK cells, a component of innate immunity, are among the critical innate immune cells in the uterus crucial in menstruation, embryonic development, and fighting infections. NK cell number and function influence endometrial cancer development and progression. Hence, it becomes crucial to understand the role of local (uterine) NK cells in uterine cancer. Uterine NK (uNK) cells behave differently than their peripheral counterparts; for example, uNK cells are more regulated by sex hormones than peripheral NK cells. A deeper understanding of NK cells in uterine cancer may facilitate the development of NK cell-targeted therapies. This review synthesizes current knowledge on the uterine immune microenvironment and NK cell-targeted uterine cancer therapeutics.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89488171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-08DOI: 10.3390/futurepharmacol2040038
Yezan M. Salamoun, Kishore Polireddy, Yu Kyoung Cho, R. Funk
Although methotrexate (MTX) is the first line disease-modifying therapy used in the treatment of autoimmune arthritis, it is limited by its unpredictable and variable response profile and lack of therapeutic biomarkers to predict or monitor therapeutic response. The purpose of this work is to evaluate the utility of red blood cell (RBC) metabolite profiles to screen for molecular biomarkers associated with MTX response. Methods: Utilizing the collagen-induced arthritis mouse model, DBA/1J mice were treated with subcutaneous MTX (20 mg/kg/week) and RBC samples were collected and analyzed by semi-targeted global metabolomic profiling and analyzed by univariate analysis. Results: MTX treatment normalized the following RBC metabolite levels that were found to be altered by disease induction: N-methylisoleucine, nudifloramide, phenylacetylglycine, 1-methyl-L-histidine, PC 42:1, PE 36:4e, PC 42:3, PE 36:4e (16:0e/20:4), and SM d34:0. Changes in the RBC metabolome weakly but significantly correlated with changes in the plasma metabolome following MTX treatment (ρ = 0.24, p = 1.1 × 10−13). The RBC metabolome resulted in the detection of nine significant discriminatory biomarkers, whereas the plasma metabolome resulted in two. Overall, the RBC metabolome yielded more highly sensitive and specific biomarkers of MTX response compared to the plasma metabolome. N-methylisoleucine was found to be highly discriminatory in both plasma and RBCs. Conclusions: Our results suggest that RBCs represent a promising biological matrix for metabolomics and future studies should consider the RBC metabolome in their biomarker discovery strategy.
{"title":"Metabolomic Profiling of Red Blood Cells to Identify Molecular Markers of Methotrexate Response in the Collagen Induced Arthritis Mouse Model","authors":"Yezan M. Salamoun, Kishore Polireddy, Yu Kyoung Cho, R. Funk","doi":"10.3390/futurepharmacol2040038","DOIUrl":"https://doi.org/10.3390/futurepharmacol2040038","url":null,"abstract":"Although methotrexate (MTX) is the first line disease-modifying therapy used in the treatment of autoimmune arthritis, it is limited by its unpredictable and variable response profile and lack of therapeutic biomarkers to predict or monitor therapeutic response. The purpose of this work is to evaluate the utility of red blood cell (RBC) metabolite profiles to screen for molecular biomarkers associated with MTX response. Methods: Utilizing the collagen-induced arthritis mouse model, DBA/1J mice were treated with subcutaneous MTX (20 mg/kg/week) and RBC samples were collected and analyzed by semi-targeted global metabolomic profiling and analyzed by univariate analysis. Results: MTX treatment normalized the following RBC metabolite levels that were found to be altered by disease induction: N-methylisoleucine, nudifloramide, phenylacetylglycine, 1-methyl-L-histidine, PC 42:1, PE 36:4e, PC 42:3, PE 36:4e (16:0e/20:4), and SM d34:0. Changes in the RBC metabolome weakly but significantly correlated with changes in the plasma metabolome following MTX treatment (ρ = 0.24, p = 1.1 × 10−13). The RBC metabolome resulted in the detection of nine significant discriminatory biomarkers, whereas the plasma metabolome resulted in two. Overall, the RBC metabolome yielded more highly sensitive and specific biomarkers of MTX response compared to the plasma metabolome. N-methylisoleucine was found to be highly discriminatory in both plasma and RBCs. Conclusions: Our results suggest that RBCs represent a promising biological matrix for metabolomics and future studies should consider the RBC metabolome in their biomarker discovery strategy.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77121829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-06DOI: 10.3390/futurepharmacol2040037
R. Rajkumar
Anxiety disorders are among the most common mental disorders worldwide and often respond incompletely to existing treatments. Selenium, a micronutrient that is a component of several biologically active selenoproteins, is also involved in several aspects of brain functioning and may exert antidepressant and anxiolytic effects through multiple pathways. The current paper is a scoping review of translational, observational, and interventional evidence on the potential role of selenium and its compounds in the management of anxiety and related disorders. Evidence from animal models suggests that this approach may be promising. Though evidence from observational studies in humans is inconsistent and affected by several confounding factors, the available evidence from randomized controlled trials suggests that selenium supplementation may be beneficial in the management of certain anxiety-related conditions, such as anxiety in medically ill patients, prevention of anxiety following exposure to traumatic stress, and obsessive-compulsive disorder. This paper provides a critical evaluation of the existing evidence base, including unanswered questions that could serve as the focus of further research, and outlines the potential benefits and risks associated with the use of selenium in anxiety disorders.
{"title":"Selenium and Its Compounds in the Treatment of Anxiety and Related Disorders: A Scoping Review of Translational and Clinical Research","authors":"R. Rajkumar","doi":"10.3390/futurepharmacol2040037","DOIUrl":"https://doi.org/10.3390/futurepharmacol2040037","url":null,"abstract":"Anxiety disorders are among the most common mental disorders worldwide and often respond incompletely to existing treatments. Selenium, a micronutrient that is a component of several biologically active selenoproteins, is also involved in several aspects of brain functioning and may exert antidepressant and anxiolytic effects through multiple pathways. The current paper is a scoping review of translational, observational, and interventional evidence on the potential role of selenium and its compounds in the management of anxiety and related disorders. Evidence from animal models suggests that this approach may be promising. Though evidence from observational studies in humans is inconsistent and affected by several confounding factors, the available evidence from randomized controlled trials suggests that selenium supplementation may be beneficial in the management of certain anxiety-related conditions, such as anxiety in medically ill patients, prevention of anxiety following exposure to traumatic stress, and obsessive-compulsive disorder. This paper provides a critical evaluation of the existing evidence base, including unanswered questions that could serve as the focus of further research, and outlines the potential benefits and risks associated with the use of selenium in anxiety disorders.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80030383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-06DOI: 10.3390/futurepharmacol2040036
Sashi Debnath, A. Agarwal, N. R. Kumar, Anjan Bedi
Selenium is one of the eight necessary trace elements humans require for active health balance. It contributes in several ways to the proper functioning of selenoprotein. Selenium has received enormous interest recently due to its therapeutic potential against a number of ailments. To date, numerous chemical compounds containing selenium have been investigated for the therapy of cancer and other disorders. Unifying the selenium atom into chemical components (typically organic) greatly increased their bioactivities. We foresee that the structure–property relationship of recently developed materials could significantly decrease the laborious work of background research to achieve target-oriented drug design in coming years. This review summarizes the research progress in the last 10 to 15 years and the application of selenium-containing compounds in the design and synthesis of those materials for potential antioxidant and anticancer agents.
{"title":"Selenium-Based Drug Development for Antioxidant and Anticancer Activity","authors":"Sashi Debnath, A. Agarwal, N. R. Kumar, Anjan Bedi","doi":"10.3390/futurepharmacol2040036","DOIUrl":"https://doi.org/10.3390/futurepharmacol2040036","url":null,"abstract":"Selenium is one of the eight necessary trace elements humans require for active health balance. It contributes in several ways to the proper functioning of selenoprotein. Selenium has received enormous interest recently due to its therapeutic potential against a number of ailments. To date, numerous chemical compounds containing selenium have been investigated for the therapy of cancer and other disorders. Unifying the selenium atom into chemical components (typically organic) greatly increased their bioactivities. We foresee that the structure–property relationship of recently developed materials could significantly decrease the laborious work of background research to achieve target-oriented drug design in coming years. This review summarizes the research progress in the last 10 to 15 years and the application of selenium-containing compounds in the design and synthesis of those materials for potential antioxidant and anticancer agents.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76378364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-22DOI: 10.3390/futurepharmacol2040035
M. Eadie
Despite the availability over the past decade of a number of new pharmaceutical agents with different mechanisms of action from those of the drugs used previously, the contemporary drug therapy of migraine attacks falls rather short of what would be desirable, while the pharmacological attempt to prevent further attacks appears to prove unsatisfactory about as often as it is successful. The present paper explores reasons for these shortcomings in both the earlier and the current drug therapy of the disorder. Significant major contributory factors appear to be an incomplete understanding of the underlying pathogenic mechanisms of the various stages of the migraine attack, less than optimal pharmacokinetic characteristics of many of the drugs used, and migraine sufferers failing to employ the available drugs to their best advantage. New drugs developed in the light of a more complete understanding of the molecular basis of migraine pathogenesis, together with awareness of pharmacokinetic desiderata in relation to treating and preventing migraine attacks, may go some way towards remedying the situation, but patient decision making may prove more difficult to modify.
{"title":"Potentially Remediable Shortcomings in the Contemporary Drug Treatment of Migraine","authors":"M. Eadie","doi":"10.3390/futurepharmacol2040035","DOIUrl":"https://doi.org/10.3390/futurepharmacol2040035","url":null,"abstract":"Despite the availability over the past decade of a number of new pharmaceutical agents with different mechanisms of action from those of the drugs used previously, the contemporary drug therapy of migraine attacks falls rather short of what would be desirable, while the pharmacological attempt to prevent further attacks appears to prove unsatisfactory about as often as it is successful. The present paper explores reasons for these shortcomings in both the earlier and the current drug therapy of the disorder. Significant major contributory factors appear to be an incomplete understanding of the underlying pathogenic mechanisms of the various stages of the migraine attack, less than optimal pharmacokinetic characteristics of many of the drugs used, and migraine sufferers failing to employ the available drugs to their best advantage. New drugs developed in the light of a more complete understanding of the molecular basis of migraine pathogenesis, together with awareness of pharmacokinetic desiderata in relation to treating and preventing migraine attacks, may go some way towards remedying the situation, but patient decision making may prove more difficult to modify.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75554033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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