Pub Date : 2022-10-05DOI: 10.3389/fddsv.2022.1013229
J. Menendez-Gonzalez, K. Strange, Marcella Bassetto, A. Brancale, N. Rodrigues, S. Ferla
Despite major therapeutic advances leading to improved patient outcomes for other haematological malignancies, development of new therapeutics to improve prognosis for acute myeloid leukemia (AML) patients remains an area of unmet clinical need. Overexpression of GATA2, a member of the GATA family of zinc finger transcription factors, has been implicated in AML. In settings where GATA2 is overexpressed in human AML cells, K7174, a proteasome inhibitor that inhibits GATA2, induces apoptosis and enhances the killing activity of AML chemotherapeutics in vitro yet targeting the proteasome has been associated with high toxicity in the clinic. Using an in silico approach, we embarked on a screen to identify specific GATA2 inhibitors that will target AML cells independently of the proteasome. A shape-based virtual screening of an in-house library of small molecules was performed using a low-energy conformation of K7174. The virtual hit compounds were subsequently filtered according to their potential selectivity for GATA2 over the proteasome. From 15 selected compounds evaluated for their ability to kill AML cells in vitro, one compound, an asymmetrical substituted piperazine with Hepatitis C antiviral activity, exhibited superior ability to induce apoptosis and reduce cell cycling in AML cells without proteasome inhibition. This compound was also able to promote cell death of the relapse propagating leukemic stem cell (LSC) compartment while sparing Gata2 knockout LSCs, crucially demonstrating specificity to inhibit GATA2. We have identified a GATA2 specific inhibitor with promising capability to target AML cells in vitro, including LSCs that underpin poor prognosis in AML.
{"title":"Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells","authors":"J. Menendez-Gonzalez, K. Strange, Marcella Bassetto, A. Brancale, N. Rodrigues, S. Ferla","doi":"10.3389/fddsv.2022.1013229","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1013229","url":null,"abstract":"Despite major therapeutic advances leading to improved patient outcomes for other haematological malignancies, development of new therapeutics to improve prognosis for acute myeloid leukemia (AML) patients remains an area of unmet clinical need. Overexpression of GATA2, a member of the GATA family of zinc finger transcription factors, has been implicated in AML. In settings where GATA2 is overexpressed in human AML cells, K7174, a proteasome inhibitor that inhibits GATA2, induces apoptosis and enhances the killing activity of AML chemotherapeutics in vitro yet targeting the proteasome has been associated with high toxicity in the clinic. Using an in silico approach, we embarked on a screen to identify specific GATA2 inhibitors that will target AML cells independently of the proteasome. A shape-based virtual screening of an in-house library of small molecules was performed using a low-energy conformation of K7174. The virtual hit compounds were subsequently filtered according to their potential selectivity for GATA2 over the proteasome. From 15 selected compounds evaluated for their ability to kill AML cells in vitro, one compound, an asymmetrical substituted piperazine with Hepatitis C antiviral activity, exhibited superior ability to induce apoptosis and reduce cell cycling in AML cells without proteasome inhibition. This compound was also able to promote cell death of the relapse propagating leukemic stem cell (LSC) compartment while sparing Gata2 knockout LSCs, crucially demonstrating specificity to inhibit GATA2. We have identified a GATA2 specific inhibitor with promising capability to target AML cells in vitro, including LSCs that underpin poor prognosis in AML.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45531372","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 : 2022-10-04DOI: 10.3389/fddsv.2022.1019706
M. DiNuzzo
The pharmaceutical industry suffered a significant decline of innovation in the last few decades, whose simple reason is complex biology. Artificial intelligence (AI) promises to make the entire drug discovery and development process more efficient. Here I consider the potential benefits of using AI to deepen our mechanistic understanding of disease by leveraging data and knowledge for modeling and simulation of genome-scale biological networks. I outline recent developments that are moving the field forward and I identify several overarching challenges for advancing the state of the art towards the successful integration of AI with modeling and simulation in drug discovery.
{"title":"How artificial intelligence enables modeling and simulation of biological networks to accelerate drug discovery","authors":"M. DiNuzzo","doi":"10.3389/fddsv.2022.1019706","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1019706","url":null,"abstract":"The pharmaceutical industry suffered a significant decline of innovation in the last few decades, whose simple reason is complex biology. Artificial intelligence (AI) promises to make the entire drug discovery and development process more efficient. Here I consider the potential benefits of using AI to deepen our mechanistic understanding of disease by leveraging data and knowledge for modeling and simulation of genome-scale biological networks. I outline recent developments that are moving the field forward and I identify several overarching challenges for advancing the state of the art towards the successful integration of AI with modeling and simulation in drug discovery.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42996186","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 : 2022-09-23DOI: 10.3389/fddsv.2022.969415
Miranda C. Palumbo, E. Sosa, Florencia A Castello, Gustavo Schottlender, F. Serral, A. Turjanski, M. M. Palomino, D. F. Do Porto
Listeria monocytogenes (Lm) is a Gram-positive bacillus responsible for listeriosis in humans. Listeriosis has become a major foodborne illness in recent years. This illness is mainly associated with the consumption of contaminated food and ready-to-eat products. Recently, Lm has developed resistances to a broad range of antimicrobials, including those used as the first choice of therapy. Moreover, multidrug-resistant strains have been detected in clinical isolates and settings associated with food processing. This scenario punctuates the need for novel antimicrobials against Lm. On the other hand, increasingly available omics data for diverse pathogens has created new opportunities for rational drug discovery. Identification of an appropriate molecular target is currently accepted as a critical step of this process. In this work, we generated multiple layers of omics data related to Lm, aiming to prioritize proteins that could serve as attractive targets for antimicrobials against L. monocytogenes. We generated genomic, transcriptomic, metabolic, and protein structural information, and this data compendium was integrated onto a freely available web server (Target Pathogen). Thirty targets with desirable features from a drug development point of view were shortlisted. This set of target proteins participates in key metabolic processes such as fatty acid, pentose, rhamnose, and amino acids metabolism. Collectively, our results point towards novel targets for the control of Lm and related bacteria. We invite researchers working in the field of drug discovery to follow up experimentally on our revealed targets.
{"title":"Integrating diverse layers of omic data to identify novel drug targets in Listeria monocytogenes","authors":"Miranda C. Palumbo, E. Sosa, Florencia A Castello, Gustavo Schottlender, F. Serral, A. Turjanski, M. M. Palomino, D. F. Do Porto","doi":"10.3389/fddsv.2022.969415","DOIUrl":"https://doi.org/10.3389/fddsv.2022.969415","url":null,"abstract":"Listeria monocytogenes (Lm) is a Gram-positive bacillus responsible for listeriosis in humans. Listeriosis has become a major foodborne illness in recent years. This illness is mainly associated with the consumption of contaminated food and ready-to-eat products. Recently, Lm has developed resistances to a broad range of antimicrobials, including those used as the first choice of therapy. Moreover, multidrug-resistant strains have been detected in clinical isolates and settings associated with food processing. This scenario punctuates the need for novel antimicrobials against Lm. On the other hand, increasingly available omics data for diverse pathogens has created new opportunities for rational drug discovery. Identification of an appropriate molecular target is currently accepted as a critical step of this process. In this work, we generated multiple layers of omics data related to Lm, aiming to prioritize proteins that could serve as attractive targets for antimicrobials against L. monocytogenes. We generated genomic, transcriptomic, metabolic, and protein structural information, and this data compendium was integrated onto a freely available web server (Target Pathogen). Thirty targets with desirable features from a drug development point of view were shortlisted. This set of target proteins participates in key metabolic processes such as fatty acid, pentose, rhamnose, and amino acids metabolism. Collectively, our results point towards novel targets for the control of Lm and related bacteria. We invite researchers working in the field of drug discovery to follow up experimentally on our revealed targets.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46383150","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 : 2022-09-09DOI: 10.3389/fddsv.2022.963045
Junyan Wu, H. Yao, X. Lv, Suiwen Ye, Nan Zhang
The experimental drug SHR6390 has anti-tumor activity as a cyclin dependent kinase 4/6 inhibitor and is metabolized primarily by the cytochrome P450 3A4 enzyme. Therefore, The purpose of this trial was to evaluate the safety and pharmacokinetics of SHR6390, a potent cytochrome P450 3A4 inhibitor, in healthy Chinese subjects. In this trial study, 18 subjects received a single oral dose of SHR6390 50 mg on day 1, multiple doses of 200 mg itraconazole on days 12–24 for 13 days, and a single oral dose of SHR6390 50 mg on day 15. After coadministration with itraconazole, the maximum plasma concentration (Cmax) of SHR6390 increased by 70.7% (from 14.3 ng/ml to 24.5 ng/ml), and the area under the time curve from 0 to T (AUC0-T) increased by 110.8% from 468 h∙ng/mL to 988 h∙ng/mL. The area under the concentration-time curve extrapolated to ∞(AUC0-∞) increases from 509 H∙ng/mL to 1,040 h∙ng/mL, an increase of 105.1%. Oral gap (CL/F) decreased (47.9 L/h and 98.3 L/h) and apparent volume of distribution (Vz/F) decreased (4190 L and 5890 L). According to common terminology criteria, 15 32 adverse events were reported in 18 subjects (AEs) (27 SHR6390-related AEs and 15 Itraconazole-related AEs), AEs were all Class 1 adverse events. Overall, co-administration of Itraconazole increased the plasma exposure of SHR6390 in healthy subjects. Both SHR6390 alone and co-administration of Itraconazole showed acceptable safety profiles, which warrants further investigation. The experimental drug SHR-6390 of this clinical trial has been applied for registration, which is classified as Chemical drugs Class 1. The study drug SHR6390 registration number:ClinicalTrials.gov Identifier: NCT04423601 (https://clinicaltrials.gov/)
{"title":"Effect of itraconazole on the safety and pharmacokinetics of antitumor SHR6390","authors":"Junyan Wu, H. Yao, X. Lv, Suiwen Ye, Nan Zhang","doi":"10.3389/fddsv.2022.963045","DOIUrl":"https://doi.org/10.3389/fddsv.2022.963045","url":null,"abstract":"The experimental drug SHR6390 has anti-tumor activity as a cyclin dependent kinase 4/6 inhibitor and is metabolized primarily by the cytochrome P450 3A4 enzyme. Therefore, The purpose of this trial was to evaluate the safety and pharmacokinetics of SHR6390, a potent cytochrome P450 3A4 inhibitor, in healthy Chinese subjects. In this trial study, 18 subjects received a single oral dose of SHR6390 50 mg on day 1, multiple doses of 200 mg itraconazole on days 12–24 for 13 days, and a single oral dose of SHR6390 50 mg on day 15. After coadministration with itraconazole, the maximum plasma concentration (Cmax) of SHR6390 increased by 70.7% (from 14.3 ng/ml to 24.5 ng/ml), and the area under the time curve from 0 to T (AUC0-T) increased by 110.8% from 468 h∙ng/mL to 988 h∙ng/mL. The area under the concentration-time curve extrapolated to ∞(AUC0-∞) increases from 509 H∙ng/mL to 1,040 h∙ng/mL, an increase of 105.1%. Oral gap (CL/F) decreased (47.9 L/h and 98.3 L/h) and apparent volume of distribution (Vz/F) decreased (4190 L and 5890 L). According to common terminology criteria, 15 32 adverse events were reported in 18 subjects (AEs) (27 SHR6390-related AEs and 15 Itraconazole-related AEs), AEs were all Class 1 adverse events. Overall, co-administration of Itraconazole increased the plasma exposure of SHR6390 in healthy subjects. Both SHR6390 alone and co-administration of Itraconazole showed acceptable safety profiles, which warrants further investigation. The experimental drug SHR-6390 of this clinical trial has been applied for registration, which is classified as Chemical drugs Class 1. The study drug SHR6390 registration number:ClinicalTrials.gov Identifier: NCT04423601 (https://clinicaltrials.gov/)","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43724388","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 : 2022-09-08DOI: 10.3389/fddsv.2022.1019705
B. Villoutreix, C. Cavasotto, J. Fernández-Recio
INSERM Unit 1141, Hospital Robert Debré, University of Paris, Paris, France, Computational Drug Design and Biomedical Informatics Laboratory, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral-CONICET, Pilar, Argentina, Facultad de Ciencias Biomédicasand Facultad de Ingeniería, Universidad Austral, Pilar, Argentina, Austral Institute for Applied Artificial Intelligence, Universidad Austral, Pilar, Argentina, Institute of Vine and Wine Sciences, Spanish National Research Council (CSIC), Logroño, Spain
{"title":"Editorial: Development of COVID-19 therapies: Lessons learnt and ongoing efforts","authors":"B. Villoutreix, C. Cavasotto, J. Fernández-Recio","doi":"10.3389/fddsv.2022.1019705","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1019705","url":null,"abstract":"INSERM Unit 1141, Hospital Robert Debré, University of Paris, Paris, France, Computational Drug Design and Biomedical Informatics Laboratory, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral-CONICET, Pilar, Argentina, Facultad de Ciencias Biomédicasand Facultad de Ingeniería, Universidad Austral, Pilar, Argentina, Austral Institute for Applied Artificial Intelligence, Universidad Austral, Pilar, Argentina, Institute of Vine and Wine Sciences, Spanish National Research Council (CSIC), Logroño, Spain","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48819812","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 : 2022-08-31DOI: 10.3389/fddsv.2022.962988
C. Kahlenborn, W. Severs, K. Nawab
Various literature cited suggests that bismuth may have usefulness against Covid-19 both in vitro and in vivo. During the course of caring for Covid-19 patients we administered bismuth subsalicylate to those who displayed diarrhea and/or gastric complaints. Using relatively conservative criteria, upon retrospective review, we noted marked improvement in oxygen requirements in most of the cases. This improvement was observed even when prior therapy with standard anti-Covid drugs had failed. Our overall impression is that these positive results support a detailed evaluation of bismuth as an adjunct treatment for the treatment of Covid-19.
{"title":"Bismuth subsalicylate as potential treatment for Covid-19 pneumonia: A case series report","authors":"C. Kahlenborn, W. Severs, K. Nawab","doi":"10.3389/fddsv.2022.962988","DOIUrl":"https://doi.org/10.3389/fddsv.2022.962988","url":null,"abstract":"Various literature cited suggests that bismuth may have usefulness against Covid-19 both in vitro and in vivo. During the course of caring for Covid-19 patients we administered bismuth subsalicylate to those who displayed diarrhea and/or gastric complaints. Using relatively conservative criteria, upon retrospective review, we noted marked improvement in oxygen requirements in most of the cases. This improvement was observed even when prior therapy with standard anti-Covid drugs had failed. Our overall impression is that these positive results support a detailed evaluation of bismuth as an adjunct treatment for the treatment of Covid-19.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42269330","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 : 2022-08-26DOI: 10.3389/fddsv.2022.925825
E. Ogbadoyi, Ndagi Umar
The disease which is today known as COVID-19 is caused by severe acute respiratory. Syndrome coronavirus 2 (SARS-COV-2), was first reported in Wuhan, China in December 2019. The disease has claimed well over six million lives from over 500 million cases. Vaccine hesitancy militates against successful mass vaccination. There is the rapid emergence of new SARS-COV-2 variants, constituting a challenge to the effectiveness of vaccines. Moreover, none of the available vaccines offers 100% protection and even the protection offered is of short duration necessitating booster doses to be taken. Moving forward, the development of plant-based edible vaccines will be a remarkable strategic approach to overcome vaccine hesitancy and improve vaccine uptake. So far only about nine drugs for COVID-19 treatment have approvals by either or both the European Medicines Agency and the FDA. While drug repurposing to address the emerging need in the early period of the COVID-19 pandemic has been contextually very useful, investment in it remains relatively low for commercial reasons arising from patenting issues. Embarking on new drug discovery and development strategies targeting both the virus and host factors is a very appealing option. Targeting druggable targets that are present across viruses, particularly the coronaviruses, for drug discovery and development represents an important strategy for pandemic preparedness. Natural products are an important reservoir of chemical scaffolds with huge potential for the discovery of novel chemical entities for development of novel therapeutics. Phytopharming is an available technology that can be used for mass and accelerated production of therapeutic molecules that will be required within short periods of time as is the case in pandemic outbreaks. Nanotechnology provides excellent platforms for formulating multivalent vaccines and pan-viral medicines for the treatment of COVID-19. Taken together, this review discusses the potential for the development of therapeutics by using the tools of biocomputing, nanotechnology, and phytopharming for accelerated therapeutic development to achieve effective COVID-19 treatment and associated complications, including new and emerging variants of SARS-COV-2 and other viral pandemics that may emerge or re-emerge.
{"title":"The challenges and opportunities for the development of COVID-19 therapeutics and preparing for the next pandemic","authors":"E. Ogbadoyi, Ndagi Umar","doi":"10.3389/fddsv.2022.925825","DOIUrl":"https://doi.org/10.3389/fddsv.2022.925825","url":null,"abstract":"The disease which is today known as COVID-19 is caused by severe acute respiratory. Syndrome coronavirus 2 (SARS-COV-2), was first reported in Wuhan, China in December 2019. The disease has claimed well over six million lives from over 500 million cases. Vaccine hesitancy militates against successful mass vaccination. There is the rapid emergence of new SARS-COV-2 variants, constituting a challenge to the effectiveness of vaccines. Moreover, none of the available vaccines offers 100% protection and even the protection offered is of short duration necessitating booster doses to be taken. Moving forward, the development of plant-based edible vaccines will be a remarkable strategic approach to overcome vaccine hesitancy and improve vaccine uptake. So far only about nine drugs for COVID-19 treatment have approvals by either or both the European Medicines Agency and the FDA. While drug repurposing to address the emerging need in the early period of the COVID-19 pandemic has been contextually very useful, investment in it remains relatively low for commercial reasons arising from patenting issues. Embarking on new drug discovery and development strategies targeting both the virus and host factors is a very appealing option. Targeting druggable targets that are present across viruses, particularly the coronaviruses, for drug discovery and development represents an important strategy for pandemic preparedness. Natural products are an important reservoir of chemical scaffolds with huge potential for the discovery of novel chemical entities for development of novel therapeutics. Phytopharming is an available technology that can be used for mass and accelerated production of therapeutic molecules that will be required within short periods of time as is the case in pandemic outbreaks. Nanotechnology provides excellent platforms for formulating multivalent vaccines and pan-viral medicines for the treatment of COVID-19. Taken together, this review discusses the potential for the development of therapeutics by using the tools of biocomputing, nanotechnology, and phytopharming for accelerated therapeutic development to achieve effective COVID-19 treatment and associated complications, including new and emerging variants of SARS-COV-2 and other viral pandemics that may emerge or re-emerge.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46722146","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 : 2022-08-24DOI: 10.3389/fddsv.2022.983030
Yuhai Zhao, V. Jaber, W. Lukiw
mRNA-mediated gene expression appears to be signi cantly in AD and CNS, our understanding of con fi guration and composition of circRNA is these ssRNAs are highly can in pathophysiological for extended periods, and therapeutically can be designed and synthesized to carry multiple ssRNA-mediated regulatory signals. Based on these and other very recent fi ndings this Opinion ” paper will: 1) address our current understanding of the emerging role of circRNAs in neurodegeneration with special reference to AD; and 2) discuss the intriguing possibility of using synthetic circRNAs containing multiple inserted miRNA, (AM; antagomir), anti-mRNA and/or other sequences in tandem combination with a personalized as an innovative for the and
{"title":"Current advances in our understanding of circular RNA (circRNA) in Alzheimer’s disease (AD); the potential utilization of synthetic circRNAs as a therapeutic strategy in the clinical management of AD","authors":"Yuhai Zhao, V. Jaber, W. Lukiw","doi":"10.3389/fddsv.2022.983030","DOIUrl":"https://doi.org/10.3389/fddsv.2022.983030","url":null,"abstract":"mRNA-mediated gene expression appears to be signi cantly in AD and CNS, our understanding of con fi guration and composition of circRNA is these ssRNAs are highly can in pathophysiological for extended periods, and therapeutically can be designed and synthesized to carry multiple ssRNA-mediated regulatory signals. Based on these and other very recent fi ndings this Opinion ” paper will: 1) address our current understanding of the emerging role of circRNAs in neurodegeneration with special reference to AD; and 2) discuss the intriguing possibility of using synthetic circRNAs containing multiple inserted miRNA, (AM; antagomir), anti-mRNA and/or other sequences in tandem combination with a personalized as an innovative for the and","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47640914","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 : 2022-08-11DOI: 10.3389/fddsv.2022.948407
Chun Chou, M. Chin
Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by signs and symptoms of HF in the presence of a normal left ventricular systolic function. Over the past decade, HFpEF has become increasingly prevalent, accounting for greater than 50% of all clinical HF presentations. HFpEF is a complex disease with heterogeneous clinical presentations and multiple non-cardiac comorbidities, which frequently co-exist and contribute to its pathophysiology. To date, only a handful of therapies have been proven to improve, albeit marginally, the outcomes in HFpEF. The development of effective therapeutic agents is in part hampered by the lack of animal models that adequately recapitulate human HFpEF. Although numerous pre-clinical models developed over the years have been labeled as “HFpEF” specific, there has not been a consensus on the appropriate standards for pre-clinical HFpEF models. Thus, the extent to which they truly mirror human HFpEF cannot be systematically validated. Recently, a new algorithm (H2FPEF) was developed to standardize the clinical diagnosis of HFpEF. In this review, with the aid of the clinical H2FPEF scoring system, we evaluate the clinical applicability and translational values of various murine models of HFpEF.
{"title":"Modeling heart failure with preserved ejection fraction in rodents: Where do we stand?","authors":"Chun Chou, M. Chin","doi":"10.3389/fddsv.2022.948407","DOIUrl":"https://doi.org/10.3389/fddsv.2022.948407","url":null,"abstract":"Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by signs and symptoms of HF in the presence of a normal left ventricular systolic function. Over the past decade, HFpEF has become increasingly prevalent, accounting for greater than 50% of all clinical HF presentations. HFpEF is a complex disease with heterogeneous clinical presentations and multiple non-cardiac comorbidities, which frequently co-exist and contribute to its pathophysiology. To date, only a handful of therapies have been proven to improve, albeit marginally, the outcomes in HFpEF. The development of effective therapeutic agents is in part hampered by the lack of animal models that adequately recapitulate human HFpEF. Although numerous pre-clinical models developed over the years have been labeled as “HFpEF” specific, there has not been a consensus on the appropriate standards for pre-clinical HFpEF models. Thus, the extent to which they truly mirror human HFpEF cannot be systematically validated. Recently, a new algorithm (H2FPEF) was developed to standardize the clinical diagnosis of HFpEF. In this review, with the aid of the clinical H2FPEF scoring system, we evaluate the clinical applicability and translational values of various murine models of HFpEF.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44510927","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 : 2022-08-10DOI: 10.3389/fddsv.2022.953988
Maycon Marção, S. Müller, Pedro Luiz P. Xavier, T. Malta
Stemness is a phenotype associated with cancer initiation and progression, malignancy, and therapeutic resistance, exhibiting particular molecular signatures. Targeting stemness has been proposed as a promising strategy against breast cancer stem cells that can play a key role in breast cancer progression, metastasis, and multiple drug resistance. Here, using a previously published one-class logistic regression machine learning algorithm (OCLR) built on pluripotent stem cells to predict stemness in human cancer samples, we provide the stemness index (mRNAsi) of different canine non-tumor and mammary cancer cells. Then, we confirmed that inhibition of BET proteins by (+)-JQ1 reduces stemness in a high mRNAsi canine cancer cell. Furthermore, using public data, we observed that (+)-JQ1 can also decrease stemness in human triple-negative breast cancer cells. Our work suggests that mRNAsi can be used to estimate stemness in different species and confirm epigenetic modulation by BET inhibition as a promising strategy for modulating the stemness phenotype in canine and human mammary cancer cells.
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