Medicine in Drug Discovery最新文献

{"title":"Low-dose aspirin increases olfactory sensitivity in association with enhanced neurogenesis and reduced activity of AChE in the experimental aging mice","authors":"Jemi Feiona Vergil Andrews ,&nbsp;Divya Bharathi Selvaraj ,&nbsp;Abhinav Bhavani Radhakrishnan ,&nbsp;Mahesh Kandasamy","doi":"10.1016/j.medidd.2024.100191","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100191","url":null,"abstract":"<div><p>This study examined the effect of aspirin on olfactory discrimination and neurogenesis in experimental aging mice. The results from the buried food test (BFT) and odour preference test (OPT) indicated that aspirin treatment enhanced the olfactory functions in the experimental animals. The immunohistochemical assessment revealed increased amounts of doublecortin (DCX)-positive immature neurons and bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive new neurons in the olfactory bulb (OB) of aspirin-treated animals compared to the control group. Besides, aspirin treatment resulted in a decreased number of ionized calcium-binding adaptor molecule (Iba)-1 positive microglia, a main cellular element of neuroinflammation in the brain compared to the control group. In addition, the increased activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in OB of the aspirin-treated mice were evident. Acetylcholinesterase (AChE) is a key enzyme that hydrolyses acetylcholine (ACh), an important neurotransmitter, involved in cognition, and olfaction. While the enhanced activity of AChE has been linked to the severity of dementia and OB defects, the biochemical assessments indicated reduced activity of AChE in OB-derived homogenates of the aspirin-treated experimental animals than that of the control group. Taken together, this study validates the proneurogenic, cholinergic, and anti-neuroinflammatory properties of aspirin in the OB which can be considered in boosting neural regeneration and management of olfactory deficits in aging and various disorders.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100191"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000162/pdfft?md5=d6da6542d0e2d61ba6fea2736a369852&pid=1-s2.0-S2590098624000162-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140894878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lesson from nature: Zataria multiflora nanostructured lipid carrier topical gel formulation against Candida-associated onychomycosis, a randomized double-blind placebo-controlled clinical trial","authors":"Maryam Moazeni ,&nbsp;Hamidreza Kelidari ,&nbsp;Yaser Nasirzadehfard ,&nbsp;Tahereh Shokohi ,&nbsp;Behrad Roohi ,&nbsp;Zohreh Hajheidari ,&nbsp;Armaghan Kazeminejad ,&nbsp;Shima Parsay ,&nbsp;Kofi Asare-Addo ,&nbsp;Ali Nokhodchi","doi":"10.1016/j.medidd.2024.100187","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100187","url":null,"abstract":"<div><h3>Purpose</h3><p>The increasing resistance to onychomycosis treatment globally is a major concern as it results in treatment failures. This research aimed to investigate the effectiveness of incorporating nanostructured lipid carriers (NLCs) in a gel formulation for treating mild to moderate <em>Candida</em>-associated onychomycosis using <em>Zataria multiflora</em> (Zt) essential oils.</p></div><div><h3>Methods</h3><p>The characteristics of <em>Zataria multiflora</em>-loaded nanostructured lipid carriers (Zt-NLCs) were validated using a carbopol gel (1 % w/w). <em>In vitro</em> tests were conducted using CLSI M60 standards to evaluate the susceptibility of ten commonly encountered dermatophyte species to antifungal agents. A clinical study was conducted involving 40 volunteers randomly assigned to two groups: one receiving the Zt-NLCs gel and the other receiving a placebo, using a double-blind, placebo-controlled design. The objective was to assess clinical manifestations and mycological findings after topical application for 2 and 4 weeks. The causative agents' species were identified using a PCR-RFLP method.</p></div><div><h3>Results</h3><p>The preparation of Zt-NLCs gel resulted in a uniform suspension of spherical nanoparticles with favourable characteristics and no cytotoxic effects. Zt-NLCs demonstrated significant inhibitory effects on fungal growth and effectively improved clinical and mycological criteria in comparison to the placebo group (p &lt; 0.005), even after 2 weeks of treatment. The <em>C. albicans</em> complex was recognized as the predominant species isolated from the patients using PCR-RFLP.</p></div><div><h3>Conclusion</h3><p>The administration of Zt-NLCs gel for two weeks showed significant efficacy in disease management, as reported by both dermatologists and mycologists and therefore shows its potential use as a treatment against <em>Candidal</em> onychomycosis.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100187"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000125/pdfft?md5=d7a1baaf0ba6618dfae2bc5073b9b1a7&pid=1-s2.0-S2590098624000125-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140540763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy: Playing an important role in diabetes and its complications","authors":"Ning Wang ,&nbsp;Yinghua Zhou ,&nbsp;Ebenezeri Erasto Ngowi ,&nbsp;Aijun Qiao","doi":"10.1016/j.medidd.2024.100188","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100188","url":null,"abstract":"<div><p>Diabetes, a chronic disease significantly affects peoples’ health and quality of life. It is a major contributor of severe health complications, such as blindness, kidney failure, heart attacks, strokes, and lower limb amputations. Autophagy is a complex cellular process regulated by specific genes. It is responsible for degrading intracellular proteins and organelles within lysosomes, a process which is crucial for maintaining internal cellular balance and clearing damaged or obsolete cellular components. In the context of diabetes, autophagy plays a key role in maintaining blood glucose homeostasis, particularly through the regulation of insulin secretion and sensitivity. Additionally, autophagy aids in preserving the survival and function of pancreatic beta (β)-cells by eliminating harmful proteins within these cells, which is vital for the prevention and treatment of diabetes. Despite the key role autophagy plays in these aspects, its exact mechanisms and effects in diabetes are still complex and not fully understood. Therefore, further research is needed to deeply explore the specific mechanisms and potential therapeutic applications of autophagy in diabetes. This review explores autophagy's classification, mechanisms, role in diabetic pathogenesis and complications, and its potential in treatment strategies of disease.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100188"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000137/pdfft?md5=9de6380dcfdce6966162377ed09f1f05&pid=1-s2.0-S2590098624000137-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140548813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Albumin is a reliable drug-delivering molecule: Highlighting points in cancer therapy","authors":"Akmal M. Asrorov ,&nbsp;Nurkhodja Mukhamedov ,&nbsp;Muzaffar Kayumov ,&nbsp;Ansor Sh. Yashinov ,&nbsp;Ahmidin Wali ,&nbsp;Abulimiti Yili ,&nbsp;Sharafitdin Ya. Mirzaakhmedov ,&nbsp;Yongzhuo Huang","doi":"10.1016/j.medidd.2024.100186","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100186","url":null,"abstract":"<div><p>As the most abundant protein in the blood, albumin binds and transports hydrophilic, hydrophobic, and lipophilic molecules required for the growth and development of cells and tissues. Due to the surface location of charged groups and the inner hydrophobic site, it transports proteins, peptides, amino acids, fatty acids, nutrients, and other biomolecules. It is a multi-domain protein involved in various functions of the blood, including the contribution to oncotic pressure. Because of its unique sequence and structure, albumin can be efficiently utilized to develop drug delivery systems against various diseases, including cancer. As a protein, rich in both negative and positive charges on the surface, it attracts great attention in the drug delivery discipline. Inner hydrophobic sites were proven to be an efficient location for delivering hydrophobic and lipophilic drugs. Albumin binding domains, widely distributed among receptors and matricellular molecules, ease its penetration into cells. A high ratio of cysteine provides stability to the molecule and causes thiol-disulfide interactions, which play an essential role in drug release. In this work, we highlighted several points of albumin nature as a drug-carrying molecule regarding biochemical and physical properties: self-assembling, formation of covalent bonds, formation of <em>in situ</em> albumin corona, etc. Research publications were searched in the NCBI database by various keywords related to sections/subsections to review the related topic. Tens of research works have been dedicated to enhancing the therapeutic efficacy of anticancer drugs using albumin in the last two decades and contributed to clarifying the mechanistic action of albumin. We discussed its mechanisms of action in drug delivery in the first section. In another section, we reviewed the enhanced antitumor/anticancer efficacies of those fabricated DDSs in terms of albumin contribution. The results of <em>in vitro</em> and <em>in vivo</em> experiments were merged into that section consisting of subsections of DDSs of individual anticancer means. Clinical trials of three drugs were reviewed as a separate section. The approaches used to enhance the efficacy of albumin-based DDSs were reviewed in the last section. The final section is devoted to strategies that could significantly improve albumin efficacy in cancer drug delivery.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100186"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000113/pdfft?md5=32645bf86f88d9d6d9d5ae5e0f58f3e4&pid=1-s2.0-S2590098624000113-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140327685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights from clinical trials: New evidence supports surgical interventions over drug therapies for atrial fibrillation","authors":"Akshat D. Modi ,&nbsp;Akriti Sharma ,&nbsp;Dharmeshkumar M. Modi","doi":"10.1016/j.medidd.2024.100182","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100182","url":null,"abstract":"<div><p>Atrial fibrillation (AF) is one of the world’s most prevalent cardiac arrhythmias. It poses a heavy burden on patients, physicians and the global healthcare system as it is one of the top leading causes of cardiovascular death. Researchers have spent numerous years conducting clinical trials to investigate the effectiveness, cost and practicality of treatment for patients suffering from AF. The primary treatment strategy for AF (acute, chronic, persistent, paroxysmal, non-valvular, nonrheumatic, and rapid) involves the use of antiarrhythmic drugs (AAD) and anticoagulant drugs (ACD) to manage heart rate and rhythm, as well as to prevent strokes. This review aims to discuss clinical trials that compared AADs (class Ia: quinidine; class Ic: flecainide, propafenone; class III: sotalol, amiodarone) and ACDs (vitamin K antagonist: warfarin; factor Xa inhibitor: apixaban, rivaroxaban; thrombin inhibitor: dabigatran) with cardiovascular surgical interventions (i.e., catheter ablation, cryoballoon ablation, ablation and DDDR pacemaker, electrical cardioversion, and left atrial appendage occlusion) to treat various types of AF in patients with a diverse history of cardiovascular diseases and medical history. This study provides a review of clinical trials on this topic and enables healthcare professionals to determine the best-suited treatment for their patients.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100182"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000071/pdfft?md5=5469dfbaebe3790d3ff06cec0bea85b0&pid=1-s2.0-S2590098624000071-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140014024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the kinetic features of orexin receptor antagonists at orexin receptors, transduction systems and receptor binding","authors":"Daniel Hoyer ,&nbsp;Laura H. Jacobson","doi":"10.1016/j.medidd.2024.100190","DOIUrl":"10.1016/j.medidd.2024.100190","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Orexin receptor antagonists are on the market or under development for the treatment of insomnia and a number of other neuropsychiatric disorders. Currently, suvorexant, lemborexant and daridorexant, three dual orexin receptor antagonists (DORAs) have received market approval by regulatory authorities in the USA, Australia, Europe and/or Japan for the treatment of insomnia. More DORAs and Selective Orexin Receptor Antagonists (SORAs) in addition to orexin receptor agonists are in various stages of preclinical and clinical development: for instance, 1SORAs (selective orexin 1 receptor antagonists) are being developed for the treatment of anxiety, panic, eating disorders, whereas 2SORAs (selective orexin 2 receptor antagonists) are in late clinical stage for the treatment of insomnia and insomnia-related depression. On the other hand, selective orexin 2 receptor agonists are in clinical trials for the treatment of narcolepsy with (NT1) or without cataplexy (NT2) and other aspects of extreme day time sleepiness.&lt;/p&gt;&lt;p&gt;Traditionally, the medium to high throughput screening procedures used to screen / characterize orexin receptor antagonists or agonists (and for that matter ligands acting on a variety of potential drug targets), frequently ignore two aspects of new drugs candidates: possible functional selectivity (biased agonism or antagonism) and intrinsic receptor-ligand kinetic properties (i.e. association and dissociation features at the target level), since most screening protocols are conducted under short incubation time conditions with usually a single functional readout. Here, we report on strategies to characterise orexin receptor ligands (agonists or antagonists) in radioligand binding and calcium mobilization assays (e.g. using the FLIPR ® /Fluorescent Imaging Plate Reader assay) and for a few select DORAs, on ERK activation. We studied clinically effective and/or tool orexin receptor antagonists (almorexant, suvorexant, filorexant, SB-649868, MK1064…), which have been or are being evaluated in clinical trials or are on the market, in these signalling pathways with an emphasis on kinetics. Thus, we investigated calcium mobilization and pERK elevation triggered by orexin A (OXA) in HEK293 cells stably transfected with human OX&lt;sub&gt;1&lt;/sub&gt;R or OX&lt;sub&gt;2&lt;/sub&gt;R. We confirmed that the ligands behave as antagonists in either assay. Most ligands do not show significant functional selectivity between the two pathways, except MK-1064, which inhibits calcium mobilization about 35 times more potently than ERK phosphorylation. We also estimated the kinetic properties of the antagonists in radioligand binding, calcium mobilization and pERK assays. The results of radioligand binding and calcium mobilization assays indicate consistently that several of the tested antagonists bind to/dissociate from either or the two orexin receptors very slowly, with equilibrium reached only after several hours. Thus, SB-649868 is a very slow binder at the OX&lt;su","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100190"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000150/pdfft?md5=b1feee5aa6e995c5dbe01943f9c05654&pid=1-s2.0-S2590098624000150-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141136060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanomedicine-based drug delivery strategies for the treatment of atherosclerosis","authors":"Yongfang Lin ,&nbsp;Ruibo Lin ,&nbsp;Han-Bin Lin ,&nbsp;Shiyang Shen","doi":"10.1016/j.medidd.2024.100189","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100189","url":null,"abstract":"<div><p>Atherosclerosis, a highly prevalent cardiovascular disease, has significantly contributed to morbidity and mortality worldwide. Despite the availability of various treatment options in clinical practice, complete reversal of the atherosclerotic pathological process remains challenging. Traditional anti-arteriosclerosis drugs often suffer from poor solubility, limited targeting ability and obvious adverse effects. Additionally, novel therapeutics such as genetic and protein-based drugs inherently suffer from instability issues, thereby compromising their actual curative efficacy and impeding further clinical application. Recently, nanomedicine-based drug delivery strategies have emerged as promising approaches for treating atherosclerosis due to their ability to specifically transport various drugs to target cells, microstructures and specific molecules within lesion sites. These advanced features enhance drug properties and bioavailability while minimizing off-target effects. Moreover, numerous studies have demonstrated that nanomedicine not only inhibits plaque progression but also reduces lesional areas and eventually reverses atherosclerosis. The utilization of nanomedicine is considered an important therapeutic tactic for further mitigating residual risks associated with atherosclerosis. This review provides a comprehensive overview of emerging nanomedicine-based strategies for targeted delivery of anti-atherosclerosis drugs, elucidating their distinct mechanisms and highlighting their remarkable efficacy in combating atherosclerosis. Additionally, critical challenges and future perspectives associated with the development and application of anti-arteriosclerosis nanomedicine are thoroughly discussed.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100189"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000149/pdfft?md5=b0905b911586f9255095ff830b97cd8e&pid=1-s2.0-S2590098624000149-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functions and inhibitors of CHK1 in cancer therapy","authors":"Kailong Jiang ,&nbsp;Minjie Deng ,&nbsp;Wenjing Du ,&nbsp;Tao Liu ,&nbsp;Jia Li ,&nbsp;Yubo Zhou","doi":"10.1016/j.medidd.2024.100185","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100185","url":null,"abstract":"<div><p>CHK1 plays a crucial role in cancer biology as it modulates cell cycle checkpoint activation and DNA repair. Furthermore, a number of other cellular functions of CHK1 are also gradually discovered. Based on these biological functions, CHK1 has been regarded as a potential target for cancer therapy, but regrettably no CHK1 inhibitors have been marketed up to now. The incorporation of effective biomarkers or combined combinations is expected to promote the development process of CHK1 inhibitors. This paper reviews the latest research progress on the functions and inhibitors of CHK1.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"22 ","pages":"Article 100185"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000101/pdfft?md5=d4ae51553b195636583049ba38db534f&pid=1-s2.0-S2590098624000101-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140350979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and characterization of multi-target nanoparticles for co-drug delivery","authors":"Farnaz Ahmadi-Nouraldinvand ,&nbsp;Shima Bourang ,&nbsp;Solmaz Azizi ,&nbsp;Mohsen Noori ,&nbsp;Mehran Noruzpour ,&nbsp;Hashem Yaghoubi","doi":"10.1016/j.medidd.2024.100177","DOIUrl":"https://doi.org/10.1016/j.medidd.2024.100177","url":null,"abstract":"<div><p>Self-assembly of various amphipathic copolymers is a simple method that allows the preparation of complex nanoparticles with several useful properties. Therefore, the aim of this research was to develop nanoparticles with better biocompatibility, biodegradability, and prolonged circulation time in the bloodstream to deliver drugs and genes into breast cancer tissues in a controlled and targeted manner. In this study, the copolymers PLA-chitosan- PEG -folic acid (COPA), PLA-chitosan- PEG -glucose (COPB), COPA &amp; COPB (COPAB) and chitosan- PLA-PEG FA /Glu/VEGF/siRNA/PTX (NPsAB/siRNA/Paclitaxel) were synthesized, to control the release of paclitaxel (PTX) and siRNA and the circulation time of nanoparticles in blood. This was confirmed by ¹H NMR and FTIR spectroscopy. The particle size, zeta potential and morphology of NPsAB /siRNA/PTX were studied by DLS and TEM, respectively. The results showed that the NPsAB/siRNA/PTX had spherical morphology with particle size and zeta potential about 200 nm and −7.8 mV, respectively. In vitro cytotoxicity assay results showed that the nanoparticles had good biocompatibility and low toxicity. Also demonstrated that NPsAB in the serum medium improved the efficiency of drug and siRNA delivery more than two-fold compared to COPA, COPB, and COPAB nanoparticles. Due to results the release pattern of siRNA and PTX from NPsAB nanoparticles under an acidic environment was significantly higher than that of their release rate in a neutral medium. Therefore, due to the acidity of tumor tissue, this property of NPsAB nanoparticles seems to be useful in the treatment of cancer.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"21 ","pages":"Article 100177"},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098624000022/pdfft?md5=a8afc8c94e0691a696c4a49e30a460e6&pid=1-s2.0-S2590098624000022-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139699878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of novel liver-targeting glucocorticoid prodrugs","authors":"Yazheng Wang,&nbsp;Dandan Guo,&nbsp;Rebecca Winkler,&nbsp;Xiaohong Lei,&nbsp;Xiaojing Wang,&nbsp;Jennifer Messina,&nbsp;Juntao Luo,&nbsp;Hong Lu","doi":"10.1016/j.medidd.2023.100172","DOIUrl":"https://doi.org/10.1016/j.medidd.2023.100172","url":null,"abstract":"<div><h3>Background</h3><p>Glucocorticoids (GCs) are widely used in the treatment of inflammatory liver diseases and sepsis, but GC’s various side effects on extrahepatic tissues limit their clinical benefits. Liver-targeting GC therapy may have multiple advantages over systemic GC therapy. The purpose of this study was to develop novel liver-targeting GC prodrugs as improved treatment for inflammatory liver diseases and sepsis.</p></div><div><h3>Methods</h3><p>A hydrophilic linker or an ultra-hydrophilic zwitterionic linker carboxylic betaine (CB) was used to bridge cholic acid (CA) and dexamethasone (DEX) to generate transporter-dependent liver-targeting GC prodrugs CA-DEX and the highly hydrophilic CA-CB-DEX. The efficacy of liver-targeting DEX prodrugs and DEX were determined in primary human hepatocytes (PHH), macrophages, human whole blood, and/or mice with sepsis induced by cecal ligation and puncture.</p></div><div><h3>Results</h3><p>CA-DEX was moderately water soluble, whereas CA-CB-DEX was highly water soluble. CA-CB-DEX and CA-DEX displayed highly transporter-dependent activities in reporter assays. Data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe alcoholic hepatitis. These key GR-target genes were similarly and rapidly (within 6 h) induced or down-regulated by CA-CB-DEX and DEX in PHH. CA-CB-DEX had much weaker inhibitory effects than DEX on endotoxin-induced cytokines in mouse macrophages and human whole blood. In contrast, CA-CB-DEX exerted more potent anti-inflammatory effects than DEX in livers of septic mice.</p></div><div><h3>Conclusions</h3><p>CA-CB-DEX demonstrated good hepatocyte-selectivity <em>in vitro</em> and better anti-inflammatory effects <em>in vivo</em>. Further test of CA-CB-DEX as a novel liver-targeting GC prodrug for inflammatory liver diseases and sepsis is warranted.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"21 ","pages":"Article 100172"},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098623000222/pdfft?md5=65e46408fee78355f7e79c5701389515&pid=1-s2.0-S2590098623000222-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138472055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}