Insomnia is a sleep disorder in which you have trouble falling and/or staying asleep. This research aims to evaluate the sedative effects of fraxin (FX) on sleeping mice induced by thiopental sodium (TS). In addition, a molecular docking study was conducted to investigate the molecular processes underlying these effects. The study used adult male Swiss albino mice and administered FX (10 and 20 mg/kg, i.p.) and diazepam (DZP) (2 mg/kg) either separately or in combination within the different groups to examine their modulatory effects. After a period of 30 min, the mice that had been treated were administered (TS: 20 mg/kg, i.p.) to induce sleep. The onset of sleep for the mice and the length of their sleep were manually recorded. Additionally, a computational analysis was conducted to predict the role of gamma-aminobutyric acid (GABA) receptors in the sleep process and evaluate their pharmacokinetics and toxicity. The outcomes indicated that FX extended the length of sleep and reduced the time it took to fall asleep. When the combined treatment of FX and DZP showed synergistic sedative action. Also, FX had a binding affinity of −7.2 kcal/mol, while DZP showed −8.4 kcal/mol. The pharmacokinetic investigation of FX demonstrated favorable drug-likeness and strong pharmacokinetic characteristics. Ultimately, FX demonstrated a strong sedative impact in the mouse model, likely via interacting with the GABAA receptor pathways.
{"title":"Assessment of sedative activity of fraxin: In vivo approach along with receptor binding affinity and molecular interaction with GABAergic system","authors":"Sonaly Akter Mukty, Rubel Hasan, Md. Shimul Bhuia, Anik Kumar Saha, Umme Sadea Rahman, Mst Muslima Khatun, Sumaya Akter Bithi, Siddique Akber Ansari, Irfan Aamer Ansari, Muhammad Torequl Islam","doi":"10.1002/ddr.22250","DOIUrl":"10.1002/ddr.22250","url":null,"abstract":"<p>Insomnia is a sleep disorder in which you have trouble falling and/or staying asleep. This research aims to evaluate the sedative effects of fraxin (FX) on sleeping mice induced by thiopental sodium (TS). In addition, a molecular docking study was conducted to investigate the molecular processes underlying these effects. The study used adult male Swiss albino mice and administered FX (10 and 20 mg/kg, i.p.) and diazepam (DZP) (2 mg/kg) either separately or in combination within the different groups to examine their modulatory effects. After a period of 30 min, the mice that had been treated were administered (TS: 20 mg/kg, i.p.) to induce sleep. The onset of sleep for the mice and the length of their sleep were manually recorded. Additionally, a computational analysis was conducted to predict the role of gamma-aminobutyric acid (GABA) receptors in the sleep process and evaluate their pharmacokinetics and toxicity. The outcomes indicated that FX extended the length of sleep and reduced the time it took to fall asleep. When the combined treatment of FX and DZP showed synergistic sedative action. Also, FX had a binding affinity of −7.2 kcal/mol, while DZP showed −8.4 kcal/mol. The pharmacokinetic investigation of FX demonstrated favorable drug-likeness and strong pharmacokinetic characteristics. Ultimately, FX demonstrated a strong sedative impact in the mouse model, likely via interacting with the GABA<sub>A</sub> receptor pathways.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zohreh Jahanafrooz, Fatemeh Oroojalian, Ahad Mokhtarzadeh, Abbas Rahdar, Ana M. Díez-Pascual
Nanovaccines have been designed to overcome the limitations associated with conventional vaccines. Effective delivery methods such as engineered carriers or smart nanoparticles (NPs) are critical requisites for inducing self-tolerance and optimizing vaccine immunogenicity with minimum side effects. NPs can be used as adjuvants, immunogens, or nanocarriers to develop nanovaccines for efficient antigen delivery. Multiloaded nanovaccines carrying multiple tumor antigens along with immunostimulants can effectively increase immunity against tumor cells. They can be biologically engineered to boost interactions with dendritic cells and to allow a gradual and constant antigen release. Modifying NPs surface properties, using high-density lipoprotein-mimicking nanodiscs, and developing nano-based artificial antigen-presenting cells such as dendritic cell-derived-exosomes are amongst the new developed technologies to enhance antigen-presentation and immune reactions against tumor cells. The present review provides an overview on the different perspectives, improvements, and barriers of successful clinical application of current cancer therapeutic and vaccination options. The immunomodulatory effects of different types of nanovaccines and the nanoparticles incorporated into their structure are described. The advantages of using nanovaccines to prevent and treat common illnesses such as AIDS, malaria, cancer and tuberculosis are discussed. Further, potential paths to develop optimal cancer vaccines are described. Given the immunosuppressive characteristics of both cancer cells and the tumor microenvironment, applying immunomodulators and immune checkpoint inhibitors in combination with other conventional anticancer therapies are necessary to boost the effectiveness of the immune response.
{"title":"Nanovaccines: Immunogenic tumor antigens, targeted delivery, and combination therapy to enhance cancer immunotherapy","authors":"Zohreh Jahanafrooz, Fatemeh Oroojalian, Ahad Mokhtarzadeh, Abbas Rahdar, Ana M. Díez-Pascual","doi":"10.1002/ddr.22244","DOIUrl":"10.1002/ddr.22244","url":null,"abstract":"<p>Nanovaccines have been designed to overcome the limitations associated with conventional vaccines. Effective delivery methods such as engineered carriers or smart nanoparticles (NPs) are critical requisites for inducing self-tolerance and optimizing vaccine immunogenicity with minimum side effects. NPs can be used as adjuvants, immunogens, or nanocarriers to develop nanovaccines for efficient antigen delivery. Multiloaded nanovaccines carrying multiple tumor antigens along with immunostimulants can effectively increase immunity against tumor cells. They can be biologically engineered to boost interactions with dendritic cells and to allow a gradual and constant antigen release. Modifying NPs surface properties, using high-density lipoprotein-mimicking nanodiscs, and developing nano-based artificial antigen-presenting cells such as dendritic cell-derived-exosomes are amongst the new developed technologies to enhance antigen-presentation and immune reactions against tumor cells. The present review provides an overview on the different perspectives, improvements, and barriers of successful clinical application of current cancer therapeutic and vaccination options. The immunomodulatory effects of different types of nanovaccines and the nanoparticles incorporated into their structure are described. The advantages of using nanovaccines to prevent and treat common illnesses such as AIDS, malaria, cancer and tuberculosis are discussed. Further, potential paths to develop optimal cancer vaccines are described. Given the immunosuppressive characteristics of both cancer cells and the tumor microenvironment, applying immunomodulators and immune checkpoint inhibitors in combination with other conventional anticancer therapies are necessary to boost the effectiveness of the immune response.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inflammatory diseases including rheumatoid arthritis are major health problems. Although different techniques and drugs are clinically available for the diagnosis and therapy of the disease, novel approaches regarding radiolabeled drug delivery systems are researched. Hence, in the present study, it was aimed to design, prepare, and characterize 99mTc-radiolabeled and tofacitinib citrate-encapsulated microsphere loaded poloxamer in situ gel formulations for the intra-articular treatment. Among nine different microsphere formulations, MS/TOFA-9 was chosen as the most proper one due to particle size, high encapsulation efficiency, and in vitro drug release behavior. Poloxamer 338 at a concentration of 15% was used to prepare in situ gel formulations. For intra-articular administration, microspheres were dispersed in an in situ gel containing 15% Poloxamer 338 and characterized in terms of gelation temperature, viscosity, rheological, mechanical, and spreadability properties. After the determination of the safe dose for MS/TOFA-9 and PLX-MS/TOFA-9 as 40 µL/mL in the cell culture study performed on healthy cells, the high anti-inflammatory effects were due to significant cellular inhibition of fibroblasts. In the radiolabeling studies with 99mTc, the optimum radiolabeling condition was determined as 200 ppm SnCl2 and 0.5 mg ascorbic acid, and both 99mTc-MS/TOFA-9 and 99mTc-PLX-MS/TOFA-9 exhibited high cellular binding capacity. In conclusion, although further in vivo experiments are required, PLX-MS/TOFA-9 was found to be a promising agent for intra-articular injection in rheumatoid arthritis.
{"title":"99mTc-labeled, tofacitinib citrate encapsulated chitosan microspheres loaded in situ gel formulations for intra-articular treatment of rheumatoid arthritis","authors":"Merve Karpuz, Husniye Hande Aydin, Emre Ozgenc, Gulsah Erel-Akbaba, Evren Atlihan-Gundogdu, Zeynep Senyigit","doi":"10.1002/ddr.22247","DOIUrl":"10.1002/ddr.22247","url":null,"abstract":"<p>Inflammatory diseases including rheumatoid arthritis are major health problems. Although different techniques and drugs are clinically available for the diagnosis and therapy of the disease, novel approaches regarding radiolabeled drug delivery systems are researched. Hence, in the present study, it was aimed to design, prepare, and characterize <sup>99m</sup>Tc-radiolabeled and tofacitinib citrate-encapsulated microsphere loaded poloxamer in situ gel formulations for the intra-articular treatment. Among nine different microsphere formulations, MS/TOFA-9 was chosen as the most proper one due to particle size, high encapsulation efficiency, and in vitro drug release behavior. Poloxamer 338 at a concentration of 15% was used to prepare in situ gel formulations. For intra-articular administration, microspheres were dispersed in an in situ gel containing 15% Poloxamer 338 and characterized in terms of gelation temperature, viscosity, rheological, mechanical, and spreadability properties. After the determination of the safe dose for MS/TOFA-9 and PLX-MS/TOFA-9 as 40 µL/mL in the cell culture study performed on healthy cells, the high anti-inflammatory effects were due to significant cellular inhibition of fibroblasts. In the radiolabeling studies with <sup>99m</sup>Tc, the optimum radiolabeling condition was determined as 200 ppm SnCl<sub>2</sub> and 0.5 mg ascorbic acid, and both <sup>99m</sup>Tc-MS/TOFA-9 and <sup>99m</sup>Tc-PLX-MS/TOFA-9 exhibited high cellular binding capacity. In conclusion, although further in vivo experiments are required, PLX-MS/TOFA-9 was found to be a promising agent for intra-articular injection in rheumatoid arthritis.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abu Sufiyan Chhipa, Ayush Sharma, Srashti Verma, Snehal S. Patel
Tilorone dihydrochloride (tilorone) is an orally active interferon inducer with anticancer effects. The present study aimed to evaluate the anticancer effects of tilorone in breast cancer. MTT assay was done to measure the proliferation of MCF-7 and MDA-MB-231 breast cancer cells after treatment with tilorone. Mammary carcinogenesis was induced by subcutaneous injection (35 mg/kg, 0.5 mL) of dimethylbenz[a]anthracene (DMBA) in mammary pads of Sprague Dawley (SD) rats. Tumors were allowed to grow for 16 weeks till their sizes reached to 550–700 mm3, and then treated with 10 and 20 mg/kg of tilorone and standard drug doxorubicin (4 mg/kg) twice a week for 3 weeks. Normal and disease-control animals received normal saline. Tumor volumes and body weights were measured. Tumors were isolated to measure the levels of interferon-β (IFN-β), vascular endothelial growth factor-A (VEGF-A), P53 and inflammatory markers by enzyme-linked immunosorbent assay (ELISA). Serum biochemistry, lipid peroxidation (LPO) and antioxidant enzymes were measured by standard methods. Histopathology and immunohistochemistry (IHC) of P53 was done in tumor sections. Tilorone reduced the proliferation of MCF-7 and MDA-MB-231 cells with IC50 concentrations at 34.08 µM and 14.27 µM, respectively. Tilorone treatment showed reduced tumor volume, and increased survival with no significant changes in the body weights. Tilorone treatment also decreased levels of inflammatory markers and VEGF-A and increased IFN-β and P53 levels. Further, treatment with tilorone also decreased LPO and increased antioxidants levels. Histopathology of tumor sections showed normalizing morphology of treated animals. IHC of tumor sections showed increased levels of P53. In conclusion, tilorone has potential anticancer effects against breast cancer.
{"title":"Therapeutic effects of tilorone on mammary carcinogenesis through downregulation of pro-inflammatory cytokines and oxidative stress","authors":"Abu Sufiyan Chhipa, Ayush Sharma, Srashti Verma, Snehal S. Patel","doi":"10.1002/ddr.22246","DOIUrl":"10.1002/ddr.22246","url":null,"abstract":"<p>Tilorone dihydrochloride (tilorone) is an orally active interferon inducer with anticancer effects. The present study aimed to evaluate the anticancer effects of tilorone in breast cancer. MTT assay was done to measure the proliferation of MCF-7 and MDA-MB-231 breast cancer cells after treatment with tilorone. Mammary carcinogenesis was induced by subcutaneous injection (35 mg/kg, 0.5 mL) of dimethylbenz[<i>a</i>]anthracene (DMBA) in mammary pads of Sprague Dawley (SD) rats. Tumors were allowed to grow for 16 weeks till their sizes reached to 550–700 mm<sup>3</sup>, and then treated with 10 and 20 mg/kg of tilorone and standard drug doxorubicin (4 mg/kg) twice a week for 3 weeks. Normal and disease-control animals received normal saline. Tumor volumes and body weights were measured. Tumors were isolated to measure the levels of interferon-β (IFN-β), vascular endothelial growth factor-A (VEGF-A), P53 and inflammatory markers by enzyme-linked immunosorbent assay (ELISA). Serum biochemistry, lipid peroxidation (LPO) and antioxidant enzymes were measured by standard methods. Histopathology and immunohistochemistry (IHC) of P53 was done in tumor sections. Tilorone reduced the proliferation of MCF-7 and MDA-MB-231 cells with IC<sub>50</sub> concentrations at 34.08 µM and 14.27 µM, respectively. Tilorone treatment showed reduced tumor volume, and increased survival with no significant changes in the body weights. Tilorone treatment also decreased levels of inflammatory markers and VEGF-A and increased IFN-β and P53 levels. Further, treatment with tilorone also decreased LPO and increased antioxidants levels. Histopathology of tumor sections showed normalizing morphology of treated animals. IHC of tumor sections showed increased levels of P53. In conclusion, tilorone has potential anticancer effects against breast cancer.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zainah Al-Qahtani, Hayder M. Al-kuraishy, Naif H. Ali, Yaser Hosny Ali Elewa, Gaber El-Saber Batiha
The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D.
参与从色氨酸(Trp)合成烟酰胺腺嘌呤二核苷酸(NAD)的犬尿氨酸途径(KP)在胰岛素抵抗(IR)和 2 型糖尿病(T2D)的发展过程中错综复杂。心血管代谢紊乱引起的炎症反应可通过增加 KP 诱导 IR 的发生。然而,犬尿氨酸(Kynurenine,KYN)是犬尿酸(Kynurenic acid,KA)的前体,在体育锻炼后会增加,并参与降低 IR。因此,KP 代谢物 KA 和 KYN 具有抗糖尿病作用,而其他代谢物则具有致糖尿病作用。KP 调节剂,无论是抑制剂还是激活剂,都会以双向的方式影响 T2D 患者的血糖稳态和胰岛素敏感性,要么是保护性的,要么是有害的,这与 KP 的作用无关。然而,二甲双胍通过抑制炎症信号通路可以减少 T2D 中 KP 的激活。这些研究结果表明,KP 在 T2D 中的作用还存在很大争议。因此,本微综述旨在阐明 KP 如何诱导 IR 和 T2D 的发生。此外,本综述还旨在探究抗糖尿病药物二甲双胍对 KP 的机理作用,以及 KP 调节剂如何影响 T2D 的发病机制。
{"title":"Kynurenine pathway in type 2 diabetes: Role of metformin","authors":"Zainah Al-Qahtani, Hayder M. Al-kuraishy, Naif H. Ali, Yaser Hosny Ali Elewa, Gaber El-Saber Batiha","doi":"10.1002/ddr.22243","DOIUrl":"10.1002/ddr.22243","url":null,"abstract":"<p>The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fatih Tok, Nimet Baltaş, Burçin İrem Abas, Gizem Tatar Yılmaz, Süleyman Kaya, Bedia Koçyiğit-Kaymakçıoğlu, Özge Çevik
In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 μm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.
{"title":"Design, synthesis, molecular modeling, in vitro evaluation of novel piperidine-containing hydrazone derivatives as cholinesterase inhibitors","authors":"Fatih Tok, Nimet Baltaş, Burçin İrem Abas, Gizem Tatar Yılmaz, Süleyman Kaya, Bedia Koçyiğit-Kaymakçıoğlu, Özge Çevik","doi":"10.1002/ddr.22240","DOIUrl":"10.1002/ddr.22240","url":null,"abstract":"<p>In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, <b>N12</b> exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC<sub>50</sub> values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC<sub>50</sub> = 38.842 ± 0.053 µM for Donepezil). Among the compounds, <b>N7</b> and <b>N6</b> are much more effective derivatives than the standard compound donepezil with IC<sub>50</sub> values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, <b>N6</b> has the highest BChE inhibition with an IC<sub>50</sub> value of 13.505 μm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of <b>N6</b>, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound <b>N6</b>.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RETRACTION: J. Rajendran, P. Pachaiappan and S. Subramaniyan, “Dose-dependent Chemopreventive Effects of Citronellol in DMBA-Induced Breast Cancer Among Rats,” Drug Development Research 80, no. 6 (2019): 867-876, https://doi.org/10.1002/ddr.21570.
The above article, published online on 16 July 2019 in Wiley Online Library (wileyonlinelibrary.com), and a corresponding Corrigendum, published on 10 June 2020 (https://doi.org/10.1002/ddr.21703), has been retracted by agreement between the journal Editor-in-Chief, Steven Fletcher; and Wiley Periodicals, LLC. The retraction has been agreed due to an overlap between images presented in Figure 3a and 3 f. Despite the previously produced Corrigendum, the overlap between Figure 3a and 3 f still remains. The authors were unable to provide a satisfactory explanation or provide an acceptable replacement for Figure 3 f. As a result, the editors have lost confidence in the results and conclusions presented in this study. The authors disagree with the retraction.
撤回:J. Rajendran, P. Pachaiappan and S. Subramaniyan, "Dose-dependent Chemopreventive Effects of Citronellol in DMBA-Induced Breast Cancer Among Rats," Drug Development Research 80, no. 6 (2019): 867-876, https://doi.org/10.1002/ddr.21570.上述文章于 2019 年 7 月 16 日在线发表于 Wiley Online Library (wileyonlinelibrary.com),并于 2020 年 6 月 10 日发表了相应的 Corrigendum (https://doi.org/10.1002/ddr.21703),经期刊主编 Steven Fletcher 和 Wiley Periodicals, LLC 协议,上述文章已被撤回。同意撤稿的原因是图 3a 和图 3 f 中的图像有重叠。尽管之前已经做了更正,但图 3a 和 3 f 之间的重叠仍然存在。作者无法提供令人满意的解释,也无法提供可接受的图 3 f 替代品。因此,编者对本研究的结果和结论失去了信心。作者不同意撤稿。
{"title":"RETRACTION: “Dose-dependent Chemopreventive Effects of Citronellol in DMBA-Induced Breast Cancer Among Rats”","authors":"","doi":"10.1002/ddr.22238","DOIUrl":"10.1002/ddr.22238","url":null,"abstract":"<p><b>RETRACTION:</b> J. Rajendran, P. Pachaiappan and S. Subramaniyan, “Dose-dependent Chemopreventive Effects of Citronellol in DMBA-Induced Breast Cancer Among Rats,” <i>Drug Development Research</i> 80, no. 6 (2019): 867-876, https://doi.org/10.1002/ddr.21570.</p><p>The above article, published online on 16 July 2019 in Wiley Online Library (wileyonlinelibrary.com), and a corresponding Corrigendum, published on 10 June 2020 (https://doi.org/10.1002/ddr.21703), has been retracted by agreement between the journal Editor-in-Chief, Steven Fletcher; and Wiley Periodicals, LLC. The retraction has been agreed due to an overlap between images presented in Figure 3a and 3 f. Despite the previously produced Corrigendum, the overlap between Figure 3a and 3 f still remains. The authors were unable to provide a satisfactory explanation or provide an acceptable replacement for Figure 3 f. As a result, the editors have lost confidence in the results and conclusions presented in this study. The authors disagree with the retraction.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaowen Wang, Linyu Su, Chong Niu, Xiao Li, Ruijie Wang, Bo Li, Sha Liu, Yuwen Xu
The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, “undruggable” KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the “undruggable” KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.
{"title":"Targeted degradation of KRAS protein in non-small cell lung cancer: Therapeutic strategies using liposomal PROTACs with enhanced cellular uptake and pharmacokinetic profiles","authors":"Xiaowen Wang, Linyu Su, Chong Niu, Xiao Li, Ruijie Wang, Bo Li, Sha Liu, Yuwen Xu","doi":"10.1002/ddr.22241","DOIUrl":"10.1002/ddr.22241","url":null,"abstract":"<p>The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, “undruggable” KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the “undruggable” KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yasaman Kiani Doustvaghe, Azadeh Haeri, Mahsa Mollapour Sisakht, Mohammad Amir Amirkhani, Hossein Vatanpour
Recombinant human epidermal growth factor (rhEGF) is widely utilized as an antiaging compound in wound-healing therapies and cosmetic purposes. However, topical administration of rhEGF has limited treatment outcomes because of its poor percutaneous penetration and rapid proteinase degradation. To overcome these obstacles, this study aims to develop and characterize rhEGF-containing conventional liposomes (rhEGF-CLs) and transferosomes (rhEGF-TFs) as efficient dermal carriers. Physicochemical characterization such as particle size, zeta potential (ZP), morphology, encapsulation efficiency (EE%), and release properties of nanocarriers as well as in vitro cytotoxicity in human dermal fibroblast (HDF) and human embryonic kidney (HEK293) cell lines were investigated. rhEGF-TFs at the rhEGF concentration ranging from 0.05 to 1.0 μg/mL were chosen as the optimum formulation due to the desired release profile, acceptable EE%, optimal cell proliferation, and minimal cytotoxicity compared to the control and free rhEGF. However, higher concentrations caused a decrease in cell viability. The ratio 20:80 of Tween 80 to lipid was optimal for rhEGF-TFs-2, which had an average diameter of 233.23 ± 2.64 nm, polydispersity index of 0.33 ± 0.05, ZP of −15.46 ± 0.29 mV, and EE% of 60.50 ± 1.91. The formulations remained stable at 5°C for at least 1 month. TEM and SEM microscopy revealed that rhEGF-TFs-2 had a regular shape and unilamellar structure. In vitro drug release studies confirmed the superiority of rhEGF-TFs-2 in terms of optimal cumulative release of rhEGF approximately 82% within 24 h. Franz diffusion cell study showed higher rhEGF-TFs-2 skin permeation compared to free rhEGF solution. Taken together, we concluded that rhEGF-TFs can be used as a promising formulation for wound healing and skin regeneration products.
{"title":"Recombinant human epidermal growth factor-loaded liposomes and transferosomes for dermal delivery: Development, characterization, and cytotoxicity evaluation","authors":"Yasaman Kiani Doustvaghe, Azadeh Haeri, Mahsa Mollapour Sisakht, Mohammad Amir Amirkhani, Hossein Vatanpour","doi":"10.1002/ddr.22234","DOIUrl":"10.1002/ddr.22234","url":null,"abstract":"<p>Recombinant human epidermal growth factor (rhEGF) is widely utilized as an antiaging compound in wound-healing therapies and cosmetic purposes. However, topical administration of rhEGF has limited treatment outcomes because of its poor percutaneous penetration and rapid proteinase degradation. To overcome these obstacles, this study aims to develop and characterize rhEGF-containing conventional liposomes (rhEGF-CLs) and transferosomes (rhEGF-TFs) as efficient dermal carriers. Physicochemical characterization such as particle size, zeta potential (ZP), morphology, encapsulation efficiency (EE%), and release properties of nanocarriers as well as in vitro cytotoxicity in human dermal fibroblast (HDF) and human embryonic kidney (HEK293) cell lines were investigated. rhEGF-TFs at the rhEGF concentration ranging from 0.05 to 1.0 μg/mL were chosen as the optimum formulation due to the desired release profile, acceptable EE%, optimal cell proliferation, and minimal cytotoxicity compared to the control and free rhEGF. However, higher concentrations caused a decrease in cell viability. The ratio 20:80 of Tween 80 to lipid was optimal for rhEGF-TFs-2, which had an average diameter of 233.23 ± 2.64 nm, polydispersity index of 0.33 ± 0.05, ZP of −15.46 ± 0.29 mV, and EE% of 60.50 ± 1.91. The formulations remained stable at 5°C for at least 1 month. TEM and SEM microscopy revealed that rhEGF-TFs-2 had a regular shape and unilamellar structure. In vitro drug release studies confirmed the superiority of rhEGF-TFs-2 in terms of optimal cumulative release of rhEGF approximately 82% within 24 h. Franz diffusion cell study showed higher rhEGF-TFs-2 skin permeation compared to free rhEGF solution. Taken together, we concluded that rhEGF-TFs can be used as a promising formulation for wound healing and skin regeneration products.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jana Tchekalarova, Daniela Pechlivanova, Miroslav Rangelov, Nadezda Todorova, Tsveta Stoyanova, Borislav Assenov, Petar Todorov
The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.
最近合成了新型肉桂酸(CA)(H4-CA、H5-CA 和 H7-CA)和咖啡酸(KA)(H4-KA、H5-KA 和 H7-KA)半啡类似物,并对它们的反式异构体进行了抗癫痫和抗痛觉活性测试。本研究测试了这些化合物的顺式形式,并在小鼠癫痫发作和痛觉试验中与其反式异构体进行了比较。顺式-H5-CA 和 H7-CA 化合物对精神运动性癫痫发作有疗效,而反式异构体则无效。顺式和反式 KA 异构体在 6-Hz 试验中均无效。在最大电击(MES)试验中,顺式异构体的抗癫痫活性分别优于反式 CA 和 KA 共轭物。卡巴阿片受体(KOR)拮抗剂可逆转顺式-H5-CA和顺式-H5-KA对癫痫发作传播的抑制作用。纳洛酮和纳吲哚不起作用。CA 共轭物的顺式异构体和顺式-H7-KA 产生的抗痛觉作用明显强于其反式异构体。顺式-H5-CA的抗痛觉作用在福尔马林试验的急性期被纳洛酮阻断,在炎症期被纳洛酮和KOR拮抗剂阻断。阿片受体阻断剂不会取消 KA 共轭物的抗镇痛作用。所测试的共轭物均未影响热痛觉阈值。对接分析的结果还表明,CA和KA共轭物的顺式异构体与阿片受体的活性存在一种模型特异性机制。我们的研究结果为进一步开发新型阿片类抗癫痫和抗痛觉治疗药物铺平了道路。
{"title":"A novel cinnamic and caffeic acid-conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers","authors":"Jana Tchekalarova, Daniela Pechlivanova, Miroslav Rangelov, Nadezda Todorova, Tsveta Stoyanova, Borislav Assenov, Petar Todorov","doi":"10.1002/ddr.22236","DOIUrl":"10.1002/ddr.22236","url":null,"abstract":"<p>The novel cinnamic acid (CA) (<b>H4-CA, H5-CA</b>, and <b>H7-CA</b>) and caffeic acid (KA) (<b>H4-KA, H5-KA</b>, and <b>H7-KA</b>) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-<b>H5-CA</b> and <b>H7-CA</b> compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-<b>H5-CA</b> and the cis-<b>H5-KA</b> was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-<b>H7-KA</b> produced significantly stronger antinociceptive effects than their trans-isomers. The cis-<b>H5-CA</b> antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}