Ferroptosis is a recently discovered iron dependent form of programmed cell death, characterized by accumulation of lipid reactive oxygen species (ROS). It shows a strikingly different set of morphological characteristics from other forms of cell death, like reduced mitochondrial volume, increased bi-layer membrane density, and reduction of mitochondrial cristae with absence of any nuclear changes. Ferroptosis is mainly regulated by two core biochemical processes, namely iron accumulation and lipid peroxidation. Lipid peroxides exert their toxic effects by disturbing the integrity, structure and composition of bi-lipid cell membranes. However, being highly reactive compounds, they further propagate the generation of ROS, leading to cross-linking of DNA and proteins. Key regulators of ferroptosis include various genes involved in the above pathways, inhibition of the antioxidant system and upregulation of the oxidant system. Recent studies have shown the ferroptotic pathway to be involved in the patho-physiology of many diseases, including cancer. Understanding the biochemical mechanisms and key substances upregulating/inhibiting this pathway, may have an implication towards development of targeted therapies for various cancers, and, hence, has become a hotspot for biomedical research. This review article summarizes the core biochemical processes involved in ferroptosis, with a brief summary of its role in various diseases and possible therapeutic targets.
{"title":"Ferroptosis-molecular mechanisms and newer insights into some diseases","authors":"Naba Hasan, Waleem Ahmad, F. Alam, Mahboob Hasan","doi":"10.3934/molsci.2023003","DOIUrl":"https://doi.org/10.3934/molsci.2023003","url":null,"abstract":"Ferroptosis is a recently discovered iron dependent form of programmed cell death, characterized by accumulation of lipid reactive oxygen species (ROS). It shows a strikingly different set of morphological characteristics from other forms of cell death, like reduced mitochondrial volume, increased bi-layer membrane density, and reduction of mitochondrial cristae with absence of any nuclear changes. Ferroptosis is mainly regulated by two core biochemical processes, namely iron accumulation and lipid peroxidation. Lipid peroxides exert their toxic effects by disturbing the integrity, structure and composition of bi-lipid cell membranes. However, being highly reactive compounds, they further propagate the generation of ROS, leading to cross-linking of DNA and proteins. Key regulators of ferroptosis include various genes involved in the above pathways, inhibition of the antioxidant system and upregulation of the oxidant system. Recent studies have shown the ferroptotic pathway to be involved in the patho-physiology of many diseases, including cancer. Understanding the biochemical mechanisms and key substances upregulating/inhibiting this pathway, may have an implication towards development of targeted therapies for various cancers, and, hence, has become a hotspot for biomedical research. This review article summarizes the core biochemical processes involved in ferroptosis, with a brief summary of its role in various diseases and possible therapeutic targets.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70227108","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}
Tackling COVID-19 requires halting virus proliferation and reducing viral complications in humans. Papaya leaf extract (PLE) is well known for its ability to inhibit numerous viral replications in vitro and in vivo and reduce viral complications in humans such as thrombocytopenia and cytokine storm. The goal of this research is to evaluate the possible use of papaya leaf extract as a multifaceted antiviral and potential therapy for COVID-19 using an in-silico docking followed by a 100 ns molecular dynamics simulation (MDS) approach. The targeted proteins are the SARS-CoV-2's proteins such as the nucleocapsid, main protease (MPro), RNA-dependent RNA polymerase (RdRP), spike protein (Wuhan, Delta, and Omicron variants) and human TNF-alpha and alpha-thrombin protein targets. Several compounds from PLE such as protodioscin, clitorin, glycyrrhizic acid, manghaslin, kaempferol–3–(2g–glucosylrutinoside), rutin, isoquercetrin and acacic acid were found to exhibit strong binding to these targets. The free energies of binding (Autodock) with protodioscin, the best PLE compound for nucleocapsid, main protease (MPro), RdRP and spike protein were –13.83, –13.19, –11.62 and –10.77 (Omicron), kcal/mol, respectively, while the TNF-alpha and alpha-thrombin binding free energies were –13.64 and –13.50 kcal/mol, respectively. The calculated inhibition constants for protodioscin were in the nanomolar and picomolar range at 216.34, 27.07, 73.28, and 99.93 pM, respectively, whilst RdRp and spike protein (Omicron) were in the nanomolar range at 3.02 and 12.84 nM, respectively. Protodioscin interacted with key residues of all protein targets. The binding affinity poses were confirmed by molecular dynamics simulation. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) shows favorable interaction between protodioscin, and all targets based on total binding-free energies corroborating the Autodock's docking results. In conclusion, compounds from PLE, especially protodioscin have good potentials in combating COVID-19.
{"title":"Molecular docking and dynamics studies show: Phytochemicals from Papaya leaves extracts as potential inhibitors of SARS–CoV–2 proteins targets and TNF–alpha and alpha thrombin human targets for combating COVID-19","authors":"Mohd Shukri Abd Shukor, Mohd Yunus Abd Shukor","doi":"10.3934/molsci.2023015","DOIUrl":"https://doi.org/10.3934/molsci.2023015","url":null,"abstract":"<abstract> <p>Tackling COVID-19 requires halting virus proliferation and reducing viral complications in humans. Papaya leaf extract (PLE) is well known for its ability to inhibit numerous viral replications <italic>in vitro</italic> and <italic>in vivo</italic> and reduce viral complications in humans such as thrombocytopenia and cytokine storm. The goal of this research is to evaluate the possible use of papaya leaf extract as a multifaceted antiviral and potential therapy for COVID-19 using an in-silico docking followed by a 100 ns molecular dynamics simulation (MDS) approach. The targeted proteins are the SARS-CoV-2's proteins such as the nucleocapsid, main protease (MPro), RNA-dependent RNA polymerase (RdRP), spike protein (Wuhan, Delta, and Omicron variants) and human TNF-alpha and alpha-thrombin protein targets. Several compounds from PLE such as protodioscin, clitorin, glycyrrhizic acid, manghaslin, kaempferol–3–(2g–glucosylrutinoside), rutin, isoquercetrin and acacic acid were found to exhibit strong binding to these targets. The free energies of binding (Autodock) with protodioscin, the best PLE compound for nucleocapsid, main protease (MPro), RdRP and spike protein were –13.83, –13.19, –11.62 and –10.77 (Omicron), kcal/mol, respectively, while the TNF-alpha and alpha-thrombin binding free energies were –13.64 and –13.50 kcal/mol, respectively. The calculated inhibition constants for protodioscin were in the nanomolar and picomolar range at 216.34, 27.07, 73.28, and 99.93 pM, respectively, whilst RdRp and spike protein (Omicron) were in the nanomolar range at 3.02 and 12.84 nM, respectively. Protodioscin interacted with key residues of all protein targets. The binding affinity poses were confirmed by molecular dynamics simulation. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) shows favorable interaction between protodioscin, and all targets based on total binding-free energies corroborating the Autodock's docking results. In conclusion, compounds from PLE, especially protodioscin have good potentials in combating COVID-19.</p> </abstract>","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135754374","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}
Chitho P. Feliciano, S. Cammas-Marion, Y. Nagasaki
The search for potent radiation-protective drugs for clinical use continues. Studies have, so far, focused on targeting the neutralization of radiation-generated reactive oxygen species (ROS) to protect the cells against the deleterious effects of exposure to ionizing radiation. However, the development of efficacious radioprotective drugs, which are mostly low molecular weight (LMW) compounds, is mainly limited due to their inherent toxicity and rapid excretion from the body. Thus, researchers reformulated these LMW compounds into nano-based formulations. This review discusses recent advances in the use of self-assembling redox nanoparticles as a new group of radioprotective agents. The copolymer micelle (herein referred to as redox nanoparticles; RNP) contains an active part, amino-TEMPO, that effectively scavenges radiation-induced ROS in the body, as demonstrated in vivo. With the use of nanoparticle-based technologies, optimized formulations of these LMW ROS-neutralizers lead to the significant reduction of its toxicity, high bioavailability and longer blood circulation, which consequently resulted in its notable enhanced efficacy (for example, increased survival rate, reduced radiation-induced syndromes and organ damage) against the damaging effects of ionizing radiation. Consistent with the available data on the use of RNP and other nano-based radioprotective agents, it can be concluded that the inherent ROS-targeting activity of a drug intended for radiation protection is as vital as its bioavailability in the specific tissues and organs, where the short-lived ROS are produced during radiation exposure. In this review article, we summarized the current status of the development of radioprotective agents, including our self-assembling radioprotective agents.
{"title":"Recent advances in self-assembling redox nanoparticles as a radiation protective agent","authors":"Chitho P. Feliciano, S. Cammas-Marion, Y. Nagasaki","doi":"10.3934/molsci.2023005","DOIUrl":"https://doi.org/10.3934/molsci.2023005","url":null,"abstract":"The search for potent radiation-protective drugs for clinical use continues. Studies have, so far, focused on targeting the neutralization of radiation-generated reactive oxygen species (ROS) to protect the cells against the deleterious effects of exposure to ionizing radiation. However, the development of efficacious radioprotective drugs, which are mostly low molecular weight (LMW) compounds, is mainly limited due to their inherent toxicity and rapid excretion from the body. Thus, researchers reformulated these LMW compounds into nano-based formulations. This review discusses recent advances in the use of self-assembling redox nanoparticles as a new group of radioprotective agents. The copolymer micelle (herein referred to as redox nanoparticles; RNP) contains an active part, amino-TEMPO, that effectively scavenges radiation-induced ROS in the body, as demonstrated in vivo. With the use of nanoparticle-based technologies, optimized formulations of these LMW ROS-neutralizers lead to the significant reduction of its toxicity, high bioavailability and longer blood circulation, which consequently resulted in its notable enhanced efficacy (for example, increased survival rate, reduced radiation-induced syndromes and organ damage) against the damaging effects of ionizing radiation. Consistent with the available data on the use of RNP and other nano-based radioprotective agents, it can be concluded that the inherent ROS-targeting activity of a drug intended for radiation protection is as vital as its bioavailability in the specific tissues and organs, where the short-lived ROS are produced during radiation exposure. In this review article, we summarized the current status of the development of radioprotective agents, including our self-assembling radioprotective agents.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70226767","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}
Ramkrishna Ghosh, P. Singha, L. Das, D. Ghosh, Syed Benazir Firdaus
Natural compounds are a repertoire of organoleptic molecules. This indicates that although they are not a significant source of nutrients, still they exhibit a wide range of medicinal properties through their plethora of anti-inflammatory and immune-modulatory activities. Coumarins, found in a variety of plants from different biodiversity regions, also have been reported to be present in many plants of the Indo-Gangetic plain. Here, we would attempt to enumerate the natural coumarin compounds, their pharmaco-therapeutic potential and their occurrence as well as abundance in the flora of the aforesaid biodiversity region. Coumarins, derived their name from the French word “coumarou” for Tonka bean. First isolated in 1820, coumarin still finds its relevance in the study of implementation of natural compounds in treating neuro-degenerative and cancer-like fatal diseases. Naturally occurring benzopyrones, chemically classified as lactones and coumarin compounds need to be reviewed to develop new era drugs from natural resources. This promises an effective treatment regimen with minimal side effects and also paves the path for a sustainable future with efforts to manage our health problems from the plant products in our immediate environment.
{"title":"Anti-inflammatory activity of natural coumarin compounds from plants of the Indo-Gangetic plain","authors":"Ramkrishna Ghosh, P. Singha, L. Das, D. Ghosh, Syed Benazir Firdaus","doi":"10.3934/molsci.2023007","DOIUrl":"https://doi.org/10.3934/molsci.2023007","url":null,"abstract":"Natural compounds are a repertoire of organoleptic molecules. This indicates that although they are not a significant source of nutrients, still they exhibit a wide range of medicinal properties through their plethora of anti-inflammatory and immune-modulatory activities. Coumarins, found in a variety of plants from different biodiversity regions, also have been reported to be present in many plants of the Indo-Gangetic plain. Here, we would attempt to enumerate the natural coumarin compounds, their pharmaco-therapeutic potential and their occurrence as well as abundance in the flora of the aforesaid biodiversity region. Coumarins, derived their name from the French word “coumarou” for Tonka bean. First isolated in 1820, coumarin still finds its relevance in the study of implementation of natural compounds in treating neuro-degenerative and cancer-like fatal diseases. Naturally occurring benzopyrones, chemically classified as lactones and coumarin compounds need to be reviewed to develop new era drugs from natural resources. This promises an effective treatment regimen with minimal side effects and also paves the path for a sustainable future with efforts to manage our health problems from the plant products in our immediate environment.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70227061","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}
Oral biofilms are the major etiological agents of periodontal pathologies. Neutrophils are the first line of defense in fighting the pathogens in the biofilm. One of the mechanisms by which they operate is neutrophil extracellular traps (NETs), which are a novel mechanism of defense in the presence of pathogenic plaque. The present study was carried out to investigate their role in periodontal disease.
Methodology
Following institutional ethical committee approval, ten gingival (biopsy) samples from individuals with periodontitis were collected during periodontal flap surgery and processed and examined under scanning electron microscope (SEM).
Results
SEM examination revealed that the excised gingival tissues displayed an intricate meshwork of NETs.
Conclusion
NETs may be one of the means of defense against periodontal infections, although further research is necessary to understand the exact nature of their role.
{"title":"The potential role of neutrophil extracellular traps (NETS) in periodontal disease—A scanning electron microscopy (SEM) study","authors":"Shreya Shetty, Sampat Kumar Srigiri, Karunakar Shetty","doi":"10.3934/molsci.2023014","DOIUrl":"https://doi.org/10.3934/molsci.2023014","url":null,"abstract":"<abstract><sec> <title>Background</title> <p>Oral biofilms are the major etiological agents of periodontal pathologies. Neutrophils are the first line of defense in fighting the pathogens in the biofilm. One of the mechanisms by which they operate is neutrophil extracellular traps (NETs), which are a novel mechanism of defense in the presence of pathogenic plaque. The present study was carried out to investigate their role in periodontal disease.</p> </sec><sec> <title>Methodology</title> <p>Following institutional ethical committee approval, ten gingival (biopsy) samples from individuals with periodontitis were collected during periodontal flap surgery and processed and examined under scanning electron microscope (SEM).</p> </sec><sec> <title>Results</title> <p>SEM examination revealed that the excised gingival tissues displayed an intricate meshwork of NETs.</p> </sec><sec> <title>Conclusion</title> <p>NETs may be one of the means of defense against periodontal infections, although further research is necessary to understand the exact nature of their role.</p> </sec></abstract>","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135551638","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}
Kishore Kumar Meenakshi Sundaram, G. Bupesh, K. Saravanan
The cancer cells could be celled biomass without normal cellular regulation. They bypass most of the signaling pathways leading to programmed cell division. On the other hand, the embryos are highly regulated, giving rise to the whole organism based on the planned regulation. Understanding the bridge concepts between them might be an interventional art for discovering valuable cancer drugs. The present review highlighted the most similarities between them and recent literary works.
{"title":"Instrumentals behind embryo and cancer: a platform for prospective future in cancer research","authors":"Kishore Kumar Meenakshi Sundaram, G. Bupesh, K. Saravanan","doi":"10.3934/molsci.2022002","DOIUrl":"https://doi.org/10.3934/molsci.2022002","url":null,"abstract":"The cancer cells could be celled biomass without normal cellular regulation. They bypass most of the signaling pathways leading to programmed cell division. On the other hand, the embryos are highly regulated, giving rise to the whole organism based on the planned regulation. Understanding the bridge concepts between them might be an interventional art for discovering valuable cancer drugs. The present review highlighted the most similarities between them and recent literary works.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70226230","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}
Beta thalassemia is caused by a mutation in the human beta globin gene. More than 400 causative mutations have been characterized in the Hemoglobin Subunit Beta (HBB) gene. These causative mutations are present in the beta globin gene or the regulatory region. Though more than 400 causative mutations of HBB region have been described, rare and novel mutations are being reported in studies indicating the need for characterization of mutations in all regions and information regarding the same should be made available for successful implementation of prenatal diagnosis. The study aims to characterize the spectrum of beta thalassemia mutations in beta thalassemia heterozygous among residents of Chennai. A total of 5,207 cases were screened for beta thalassemia heterozygous by HPLC method. 387 beta thalassemia heterozygous identified by HPLC method were subjected to molecular DNA analysis by ARMS PCR technique and DNA Sanger sequencing for the characterization of causative beta thalassemia mutations. In the present study molecular characterization of beta thalassemia mutations revealed 30 different mutations with a high prevalence of IVS 1-5 (G-C) mutation, five new rare mutations viz., IVS II-1 (G>T), CD 37 TGG-TGA, IVS II 781 (C-G), CD114 CTG-CCG and Poly A (A-G) were diagnosed and reported first in India. One novel beta thalassemia mutation HBB.c319DelC was detected in the study. The diagnostic outcome of detecting the causative mutations for beta thalassemia imposes strong resources for developing easy and cheaper methods for prenatal diagnosis which will reduce the burden of disease.
地中海贫血是由人类-珠蛋白基因突变引起的。血红蛋白亚单位β (HBB)基因中有400多种致病突变。这些致病突变存在于-珠蛋白基因或调控区域。虽然已经描述了400多个HBB区域的致病突变，但研究中正在报道罕见和新颖的突变，这表明需要对所有区域的突变进行表征，并应提供有关这些突变的信息，以成功实施产前诊断。本研究旨在描述金奈居民β -地中海贫血杂合突变谱。采用高效液相色谱法对5207例杂合型地中海贫血进行筛查。采用HPLC法鉴定的387例β -地中海贫血杂合子，采用ARMS PCR技术进行分子DNA分析和DNA Sanger测序，鉴定β -地中海贫血致病突变。在本研究中，发现了30种不同的地中海贫血突变，其中IVS 1-5 (G- c)突变高发，IVS II-1 (G b> T)、cd37 TGG-TGA、IVS II 781 (C-G)、CD114 CTG-CCG和Poly a (a -G) 5种新的罕见突变在印度首次被诊断和报道。一种新的-地中海贫血突变HBB。研究中检测到c319DelC。检测地中海贫血致病突变的诊断结果为开发简单和廉价的产前诊断方法提供了强大的资源，这将减少疾病负担。
{"title":"Studies on molecular spectrum of beta thalassemia among residents of Chennai","authors":"Bhuvana Selvaraj, Ganesan Subramanian, Senthil Kumar Ramanathan, S. Soundararajan, Shettu Narayanasamy","doi":"10.3934/molsci.2022007","DOIUrl":"https://doi.org/10.3934/molsci.2022007","url":null,"abstract":"Beta thalassemia is caused by a mutation in the human beta globin gene. More than 400 causative mutations have been characterized in the Hemoglobin Subunit Beta (HBB) gene. These causative mutations are present in the beta globin gene or the regulatory region. Though more than 400 causative mutations of HBB region have been described, rare and novel mutations are being reported in studies indicating the need for characterization of mutations in all regions and information regarding the same should be made available for successful implementation of prenatal diagnosis. The study aims to characterize the spectrum of beta thalassemia mutations in beta thalassemia heterozygous among residents of Chennai. A total of 5,207 cases were screened for beta thalassemia heterozygous by HPLC method. 387 beta thalassemia heterozygous identified by HPLC method were subjected to molecular DNA analysis by ARMS PCR technique and DNA Sanger sequencing for the characterization of causative beta thalassemia mutations. In the present study molecular characterization of beta thalassemia mutations revealed 30 different mutations with a high prevalence of IVS 1-5 (G-C) mutation, five new rare mutations viz., IVS II-1 (G>T), CD 37 TGG-TGA, IVS II 781 (C-G), CD114 CTG-CCG and Poly A (A-G) were diagnosed and reported first in India. One novel beta thalassemia mutation HBB.c319DelC was detected in the study. The diagnostic outcome of detecting the causative mutations for beta thalassemia imposes strong resources for developing easy and cheaper methods for prenatal diagnosis which will reduce the burden of disease.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70226625","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}
Aging and senescence seem linked by fundamental, yet still ill-understood mechanisms. For this reason, this paper expands on the background of a discovery that still has to gain acknowledgement by public policies to find its place in a market hungry for a non-toxic anti-inflammatory molecule. Reversibility of the senescent cell phenotype was the starting-point of a research that turned out to identify the monoterpenes class of molecules as able to achieve this goal. Indeed, these compounds strongly inhibit the circulation of pro-inflammatory cytokines as well as the expression of cell-anchored adhesive molecules, liable to recruit activated immune cells. Starting from cell-based studies, the pre-clinical and clinical assays reported here confirmed the capacities of these compounds, both in experimental colitis, dermatitis and stress murine models, but also in-human studies addressing the latent chronic inflammation associated with age or psoriasis. Last but not least, because of an intriguing mechanism yet not totally unraveled and most probably depending on the effect of monoterpenes on gut microbiota strains–apart from assuring a constant gut barrier repair-a consistent Quality of Life amelioration, i.e. mood modulation probably due to enhanced dopamine secretion was also demonstrated. Finally, after entering in more pharmacologic considerations on toxicity and bio-availability studies as for the safety of this class of compounds, a strategic positioning of the precious role of anti-inflammatory drugs in a market that has yet to overcome common chronic diseases because of their predisposing condition not only to cancer and neuro-degenerative diseases but now also to COVID-19 is envisioned.
{"title":"d-Limonene challenging anti-inflammatory strategies","authors":"P. d'Alessio, M. Béné, C. Menut","doi":"10.3934/molsci.2022003","DOIUrl":"https://doi.org/10.3934/molsci.2022003","url":null,"abstract":"Aging and senescence seem linked by fundamental, yet still ill-understood mechanisms. For this reason, this paper expands on the background of a discovery that still has to gain acknowledgement by public policies to find its place in a market hungry for a non-toxic anti-inflammatory molecule. Reversibility of the senescent cell phenotype was the starting-point of a research that turned out to identify the monoterpenes class of molecules as able to achieve this goal. Indeed, these compounds strongly inhibit the circulation of pro-inflammatory cytokines as well as the expression of cell-anchored adhesive molecules, liable to recruit activated immune cells. Starting from cell-based studies, the pre-clinical and clinical assays reported here confirmed the capacities of these compounds, both in experimental colitis, dermatitis and stress murine models, but also in-human studies addressing the latent chronic inflammation associated with age or psoriasis. Last but not least, because of an intriguing mechanism yet not totally unraveled and most probably depending on the effect of monoterpenes on gut microbiota strains–apart from assuring a constant gut barrier repair-a consistent Quality of Life amelioration, i.e. mood modulation probably due to enhanced dopamine secretion was also demonstrated. Finally, after entering in more pharmacologic considerations on toxicity and bio-availability studies as for the safety of this class of compounds, a strategic positioning of the precious role of anti-inflammatory drugs in a market that has yet to overcome common chronic diseases because of their predisposing condition not only to cancer and neuro-degenerative diseases but now also to COVID-19 is envisioned.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70226314","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}
Oscar Cienfuegos-Jiménez, Abril Morales-Hernández, Olivia A. Robles‐Rodríguez, Sergio Bustos-Montes, Kevin A. Bañuelos-Alduncin, Aurora R. Cortés-Castillo, Hugo D. Barreto-Hurtado, Luis Carrete-Salgado, I. Marino-Martínez
The pH Low Insertion Peptide (pHLIP) has versatile applications in several diseases due to its differential behavior at slightly different pH values. pHLIP is an unstructured and peripheral membrane-associated peptide at neutral pH and an α-helical transmembrane peptide at acidic values. Similar to what happened to insulin and growth hormone, pHLIP´s expanding applications require high-yield production to further scale-up its usefulness. To date, synthesis of the pHLIP has not been reported in a prokaryotic platform, mainly relying on solid-phase synthesis. Bacterial production arises as an option for high-amount peptide generation and larger pHLIP fusion protein-synthesis; however, cell-based pH-responsive peptide production could be challenging due to intracellular peptide interactions or degradation due to unstructured conformations. An Escherichia coli (E. coli)-BL21 cell culture was induced with Isopropyl ß-D-1-thiogalactopyranoside (IPTG) in order to produce a Glutathione S-transferase-pHLIP (GST-pHLIP) fusion construct. Purification was done with Glutathione (GSH)-decorated magnetic beads using 4 ml of the induced cell culture. The production was quantified with Bradford reagent and characterized with SDS-PAGE and Western blot, contrasting Bradford results with densitometry analysis to obtain production approximate absolute values. A purified approximate total yield of ~26 µg with an apparent GSH-bead saturation and a total production of ~82 µg was obtained. Our Western Blot assay confirmed the presence of the GST-pHLIP construct in all the IPTG-induced fractions. Conclusion: A high-yield pHLIP production irrespective of its membrane affinity in acidic environments or its unstructured nature was achieved. Our study could be useful to scale up pHLIP synthesis for future applications.
{"title":"High-yield production and purification of the fusion pH-responsive peptide GST-pHLIP in Escherichia coli BL21","authors":"Oscar Cienfuegos-Jiménez, Abril Morales-Hernández, Olivia A. Robles‐Rodríguez, Sergio Bustos-Montes, Kevin A. Bañuelos-Alduncin, Aurora R. Cortés-Castillo, Hugo D. Barreto-Hurtado, Luis Carrete-Salgado, I. Marino-Martínez","doi":"10.3934/molsci.2022008","DOIUrl":"https://doi.org/10.3934/molsci.2022008","url":null,"abstract":"The pH Low Insertion Peptide (pHLIP) has versatile applications in several diseases due to its differential behavior at slightly different pH values. pHLIP is an unstructured and peripheral membrane-associated peptide at neutral pH and an α-helical transmembrane peptide at acidic values. Similar to what happened to insulin and growth hormone, pHLIP´s expanding applications require high-yield production to further scale-up its usefulness. To date, synthesis of the pHLIP has not been reported in a prokaryotic platform, mainly relying on solid-phase synthesis. Bacterial production arises as an option for high-amount peptide generation and larger pHLIP fusion protein-synthesis; however, cell-based pH-responsive peptide production could be challenging due to intracellular peptide interactions or degradation due to unstructured conformations. An Escherichia coli (E. coli)-BL21 cell culture was induced with Isopropyl ß-D-1-thiogalactopyranoside (IPTG) in order to produce a Glutathione S-transferase-pHLIP (GST-pHLIP) fusion construct. Purification was done with Glutathione (GSH)-decorated magnetic beads using 4 ml of the induced cell culture. The production was quantified with Bradford reagent and characterized with SDS-PAGE and Western blot, contrasting Bradford results with densitometry analysis to obtain production approximate absolute values. A purified approximate total yield of ~26 µg with an apparent GSH-bead saturation and a total production of ~82 µg was obtained. Our Western Blot assay confirmed the presence of the GST-pHLIP construct in all the IPTG-induced fractions. Conclusion: A high-yield pHLIP production irrespective of its membrane affinity in acidic environments or its unstructured nature was achieved. Our study could be useful to scale up pHLIP synthesis for future applications.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70226395","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}
M. Esawy, Amir Abd-elhameed, Alshimaa L. Abdallah, Maha E. Alsadik, Elsayed S. Abd elbaser, M. Shabana, Rania M. Abdullah
LncRNA HULC regulates inflammation in vascular endothelial cells resulting in their dysfunction. Endothelial dysfunction contributes to severe COVID-19. lncRNA HULC targets miRNA-9 that play roles in the pathogenesis and progression of COVID-19 through the acute inflammatory response mediated by IL-6. This study aimed to evaluate the role of lncRNA HULC, miRNA-9, and IL-6 in estimating the severity and predicting the prognosis of COVID-19. There were 38 non-severe, 38 severe COVID-19 patients, and 38 healthy controls enrolled in this study. Expression of lncRNA HULC and miRNA-9 was performed using RT-qPCR. ELISA was utilized to measure serum IL-6. Expression of lncRNA HULC and IL-6 level were increased in severe patients compared to non-severe patients and controls (p < 0.001). MiRNA-9 showed the lowest expression levels in the severe patients in comparison with non-severe patients and controls (p < 0.001) lncRNA HULC was negatively correlated with miRNA-9 (p < 0.001, r = −0.582) and positively correlated with IL-6 (p < 0.001, r = 0.567). Furthermore, miRNA-9 showed a negative correlation with IL-6 (p < 0.001, r = −0.0466). For severity prediction, lncRNA HULC expression had an adjusted OR of 52.5 (95% CI: 1.43−192.2, p = 0.031). The lncRNA HULC had an adjusted mortality hazard ratio of 1.9 (95% CI: 1.02−3.56, p = 0.043) after the adjustment of IL-6. So, in COVID-19 patients, the lncRNA HULC had a positive correlation with IL-6 and a negative correlation with miRNA-9. The COVID-19 severity and mortality appear to be predicted independently by the lncRNA HULC.
{"title":"Long noncoding RNA HULC is an independent predictor of COVID-19 severity and mortality in relation to microRNA-9 and IL-6","authors":"M. Esawy, Amir Abd-elhameed, Alshimaa L. Abdallah, Maha E. Alsadik, Elsayed S. Abd elbaser, M. Shabana, Rania M. Abdullah","doi":"10.3934/molsci.2022005","DOIUrl":"https://doi.org/10.3934/molsci.2022005","url":null,"abstract":"LncRNA HULC regulates inflammation in vascular endothelial cells resulting in their dysfunction. Endothelial dysfunction contributes to severe COVID-19. lncRNA HULC targets miRNA-9 that play roles in the pathogenesis and progression of COVID-19 through the acute inflammatory response mediated by IL-6. This study aimed to evaluate the role of lncRNA HULC, miRNA-9, and IL-6 in estimating the severity and predicting the prognosis of COVID-19. There were 38 non-severe, 38 severe COVID-19 patients, and 38 healthy controls enrolled in this study. Expression of lncRNA HULC and miRNA-9 was performed using RT-qPCR. ELISA was utilized to measure serum IL-6. Expression of lncRNA HULC and IL-6 level were increased in severe patients compared to non-severe patients and controls (p < 0.001). MiRNA-9 showed the lowest expression levels in the severe patients in comparison with non-severe patients and controls (p < 0.001) lncRNA HULC was negatively correlated with miRNA-9 (p < 0.001, r = −0.582) and positively correlated with IL-6 (p < 0.001, r = 0.567). Furthermore, miRNA-9 showed a negative correlation with IL-6 (p < 0.001, r = −0.0466). For severity prediction, lncRNA HULC expression had an adjusted OR of 52.5 (95% CI: 1.43−192.2, p = 0.031). The lncRNA HULC had an adjusted mortality hazard ratio of 1.9 (95% CI: 1.02−3.56, p = 0.043) after the adjustment of IL-6. So, in COVID-19 patients, the lncRNA HULC had a positive correlation with IL-6 and a negative correlation with miRNA-9. The COVID-19 severity and mortality appear to be predicted independently by the lncRNA HULC.","PeriodicalId":44217,"journal":{"name":"AIMS Molecular Science","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70226434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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