Oligonucleotide therapeutics (ONTs) represent a growing new class of therapeutic agents aimed at addressing chronic diseases that remain untreatable by small molecules and antibodies. Our goal was to establish a selection of several criteria to design and develop miRNA-based ONTs, focusing on improved chemistry, pharmacokinetics/pharmacodynamics (PK/PD) profiles, and safety characteristics to combat cardiometabolic pandemics. By leveraging our own experimental data obtained from experiments involving miR-22-3p antagomirs and a careful review of the literature, we established a set of seven criteria to optimize the design of miRNA ONTs. These criteria prioritize simplified drug synthesis, optimized PK/PD properties, and reduced potential toxicities. This proposed set of seven criteria represents a novel strategy for developing active cellular targeting miRNA ONTs for various therapeutic indications.
{"title":"Criteria for developing active cellular targeting miRNA oligonucleotide therapeutics with a peptide nucleic acid backbone: Combating cardiometabolic pandemics","authors":"Marc Thibonnier","doi":"10.36922/itps.3025","DOIUrl":"https://doi.org/10.36922/itps.3025","url":null,"abstract":"Oligonucleotide therapeutics (ONTs) represent a growing new class of therapeutic agents aimed at addressing chronic diseases that remain untreatable by small molecules and antibodies. Our goal was to establish a selection of several criteria to design and develop miRNA-based ONTs, focusing on improved chemistry, pharmacokinetics/pharmacodynamics (PK/PD) profiles, and safety characteristics to combat cardiometabolic pandemics. By leveraging our own experimental data obtained from experiments involving miR-22-3p antagomirs and a careful review of the literature, we established a set of seven criteria to optimize the design of miRNA ONTs. These criteria prioritize simplified drug synthesis, optimized PK/PD properties, and reduced potential toxicities. This proposed set of seven criteria represents a novel strategy for developing active cellular targeting miRNA ONTs for various therapeutic indications.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":" 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141831809","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}
CD4-expressing T-cells (CD4Ts) play a crucial role in maintaining the normal functioning of the mammalian immune system and overall systemic health. Diseased individuals, such as those infected with the human immunodeficiency virus type I (HIV-1), experience progressive and eventual depletion of CD4T leading to uncurable conditions and ultimate death if left untreated. Although much is known about the role of CD4T-mediated immunity, the understanding of CD4T-related transcriptomic patterns remains incomplete. This proof-of-concept study aims to identify a transcriptome-wide gene signature for CD4T abundance by Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling in 340 healthy peripheral blood samples. The optimized LASSO model demonstrated computational robustness (tenfold average Pearson’s r = 0.89) and biological relevance evidenced by four significant Gene Ontology terms (all odds ratio [OR] ≥ 4.5 and false discovery rate ≤0.05). Subsequently, in an independent cohort with 24 HIV-1-infected men who received anti-retroviral therapies, there is a significant, positive association between the gene signature and a strong anti-retroviral response before (OR = 13.6, P < 0.05) and after adjusting for subject age, sex, and race (OR = 14.4, P < 0.05). Taken together, the gene expression pattern associated with CD4T abundance is predictable, generalizable, and biologically relevant, shedding new light on the importance of CD4T abundance.
{"title":"Transcriptomic signature of CD4-expressing T-cell abundance developed in healthy peripheral blood predicts strong anti-retroviral therapeutic response in HIV-1: A retrospective and proof-of-concept study","authors":"Youdinghuan Chen","doi":"10.36922/itps.2761","DOIUrl":"https://doi.org/10.36922/itps.2761","url":null,"abstract":"CD4-expressing T-cells (CD4Ts) play a crucial role in maintaining the normal functioning of the mammalian immune system and overall systemic health. Diseased individuals, such as those infected with the human immunodeficiency virus type I (HIV-1), experience progressive and eventual depletion of CD4T leading to uncurable conditions and ultimate death if left untreated. Although much is known about the role of CD4T-mediated immunity, the understanding of CD4T-related transcriptomic patterns remains incomplete. This proof-of-concept study aims to identify a transcriptome-wide gene signature for CD4T abundance by Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling in 340 healthy peripheral blood samples. The optimized LASSO model demonstrated computational robustness (tenfold average Pearson’s r = 0.89) and biological relevance evidenced by four significant Gene Ontology terms (all odds ratio [OR] ≥ 4.5 and false discovery rate ≤0.05). Subsequently, in an independent cohort with 24 HIV-1-infected men who received anti-retroviral therapies, there is a significant, positive association between the gene signature and a strong anti-retroviral response before (OR = 13.6, P < 0.05) and after adjusting for subject age, sex, and race (OR = 14.4, P < 0.05). Taken together, the gene expression pattern associated with CD4T abundance is predictable, generalizable, and biologically relevant, shedding new light on the importance of CD4T abundance.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":"209 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141834157","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}
Spinal cord injury (SCI) is a kind of disease that indiscriminately affects all age groups, although the number of SCI cases in children is far lower than that in adults. In this paper, we discuss the appropriate diagnostic methods and prevention methods for SCI caused by repetitive hyperextension movement. Case study reports available in the published literature concerning SCI due to hyperextension movement, which were categorized using the American Spinal Injury Association (ASIA) grades, were gathered. Moreover, the age, gender, lesion length on magnetic resonance image (MRI), time of symptoms appearance, initial spinal cord atrophy region, neurological level of injury, and initial and final ASIA grades were analyzed. A total of 144 cases with SCI after backbend dance were included in our analysis, with some cases with an incubation period ranging between 15 min and 4 h showing no symptoms. Most of the collected cases were young girls of <11 years old. Early MRI showed that the pathological changes had extended toward cephalocaudal regions. In summation, the number of SCI cases, which are disabling for many children, is rapidly accumulating in China. Thus, SCI following repetitive hyperextension movements requires further research.
{"title":"Recommendations on the management and prevention of spinal cord injury in children following backbend dance","authors":"Jamal Alshorman, Ruba Altahla, Xu Tao","doi":"10.36922/itps.3460","DOIUrl":"https://doi.org/10.36922/itps.3460","url":null,"abstract":"Spinal cord injury (SCI) is a kind of disease that indiscriminately affects all age groups, although the number of SCI cases in children is far lower than that in adults. In this paper, we discuss the appropriate diagnostic methods and prevention methods for SCI caused by repetitive hyperextension movement. Case study reports available in the published literature concerning SCI due to hyperextension movement, which were categorized using the American Spinal Injury Association (ASIA) grades, were gathered. Moreover, the age, gender, lesion length on magnetic resonance image (MRI), time of symptoms appearance, initial spinal cord atrophy region, neurological level of injury, and initial and final ASIA grades were analyzed. A total of 144 cases with SCI after backbend dance were included in our analysis, with some cases with an incubation period ranging between 15 min and 4 h showing no symptoms. Most of the collected cases were young girls of <11 years old. Early MRI showed that the pathological changes had extended toward cephalocaudal regions. In summation, the number of SCI cases, which are disabling for many children, is rapidly accumulating in China. Thus, SCI following repetitive hyperextension movements requires further research.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":"60 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141834650","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}
Zingisia Sitobo, Liberty Tinotenda Navhaya, Xolani Henry Makhoba
Diabetes is a severe chronic illness that has impacted thousands of individuals worldwide. It is caused by the body’s failure to produce insulin or insufficient production of insulin. While diabetes is not curable, it can be managed with injectable insulin, which decreases blood glucose levels. However, this treatment has several disadvantages that can affect a patient’s health, and it is often unaffordable for some individuals. Previous studies have suggested that phytochemicals can improve insulin sensitivity. Due to the presence of therapeutic phytochemicals in natural plants, medicinal plants emerge as potential candidates for treating diabetes. In addition, compared to conventional diabetes treatments, phytochemical treatment may be affordable for all diabetics and has fewer side effects. This review primarily focuses on the symptoms and treatment options for the four known types of diabetes: type 1 diabetes mellitus, type 2 diabetes mellitus, type 3c diabetes mellitus, and neonatal diabetes. The article reviews medicinal plants that have been used to treat diabetes effectively with minimum side effects, such as Momordica charantia L., Syzygium cumini (L.) Skeels, and Ocimum tenuiflorum L., among others. In addition, some newly approved drugs, such as tirzepatide, sergliflozin, saxagliptin, and liraglutide, recommended for treating patients suffering from various forms of diabetes, are discussed.
{"title":"Medicinal plants as a source of natural remedies in the management of diabetes","authors":"Zingisia Sitobo, Liberty Tinotenda Navhaya, Xolani Henry Makhoba","doi":"10.36922/itps.1885","DOIUrl":"https://doi.org/10.36922/itps.1885","url":null,"abstract":"Diabetes is a severe chronic illness that has impacted thousands of individuals worldwide. It is caused by the body’s failure to produce insulin or insufficient production of insulin. While diabetes is not curable, it can be managed with injectable insulin, which decreases blood glucose levels. However, this treatment has several disadvantages that can affect a patient’s health, and it is often unaffordable for some individuals. Previous studies have suggested that phytochemicals can improve insulin sensitivity. Due to the presence of therapeutic phytochemicals in natural plants, medicinal plants emerge as potential candidates for treating diabetes. In addition, compared to conventional diabetes treatments, phytochemical treatment may be affordable for all diabetics and has fewer side effects. This review primarily focuses on the symptoms and treatment options for the four known types of diabetes: type 1 diabetes mellitus, type 2 diabetes mellitus, type 3c diabetes mellitus, and neonatal diabetes. The article reviews medicinal plants that have been used to treat diabetes effectively with minimum side effects, such as Momordica charantia L., Syzygium cumini (L.) Skeels, and Ocimum tenuiflorum L., among others. In addition, some newly approved drugs, such as tirzepatide, sergliflozin, saxagliptin, and liraglutide, recommended for treating patients suffering from various forms of diabetes, are discussed.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":"99 s1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141835667","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}
Henry Lowe, Amza Ali, Blair Steele, Lorenzo Gordon, Justin Grant
Terpenes form part of a huge and diverse class of naturally occurring and volatile secondary metabolites produced by many plants, fruits, animals, insects, and other organisms. They are the largest group of naturally occurring metabolites, with over 55,000 types of terpenes produced by plants alone, primarily as essential oils. In humans, they contain significant biological properties such as antifungal, antiviral, antimicrobial, anti-inflammatory, antiparasitic, antihyperglycemic, anti-cancer, and analgesic agents. In plants, terpenes also play significant roles in defensive mechanisms against herbivores and invasive plants, disease resistance, chemical signaling and communication between plants, protection against photo-oxidation, plant-environment mediation, thermo-protection, and the attraction of pollinators. In addition, terpenes are responsible for a plant’s scent, taste, flavor, and pigmentation, leading to their commercial use as fragrances and food dyes. Terpenes are also used in the production of synthetic polymers, natural rubbers (polyisoprene), organic solvents, varnishes, inks, adhesives, cleaning products, biofuels, pesticides, and food and drink products. For these reasons, terpenes have significant value in modern medicine, pharmacy, nutraceuticals, cosmetics, and other industries.
{"title":"The potential therapeutic value of terpenes","authors":"Henry Lowe, Amza Ali, Blair Steele, Lorenzo Gordon, Justin Grant","doi":"10.36922/itps.0332","DOIUrl":"https://doi.org/10.36922/itps.0332","url":null,"abstract":"Terpenes form part of a huge and diverse class of naturally occurring and volatile secondary metabolites produced by many plants, fruits, animals, insects, and other organisms. They are the largest group of naturally occurring metabolites, with over 55,000 types of terpenes produced by plants alone, primarily as essential oils. In humans, they contain significant biological properties such as antifungal, antiviral, antimicrobial, anti-inflammatory, antiparasitic, antihyperglycemic, anti-cancer, and analgesic agents. In plants, terpenes also play significant roles in defensive mechanisms against herbivores and invasive plants, disease resistance, chemical signaling and communication between plants, protection against photo-oxidation, plant-environment mediation, thermo-protection, and the attraction of pollinators. In addition, terpenes are responsible for a plant’s scent, taste, flavor, and pigmentation, leading to their commercial use as fragrances and food dyes. Terpenes are also used in the production of synthetic polymers, natural rubbers (polyisoprene), organic solvents, varnishes, inks, adhesives, cleaning products, biofuels, pesticides, and food and drink products. For these reasons, terpenes have significant value in modern medicine, pharmacy, nutraceuticals, cosmetics, and other industries.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":" 46","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141375345","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}
The random-pattern skin flap is a common method used for reconstructing skin defects. However, flap ischemia necrosis remains a significant challenge in plastic surgery. Strategies aimed at reducing persistent inflammation and promoting blood supply through angiogenesis have been identified as crucial for improving flap survival. Dapsone, a chemotherapeutic agent known for its anti-inflammatory properties through multiple pathways, is of interest in this regard. This study aims to investigate the effect of dapsone on random-pattern flap survival in rats, along with its impact on inflammation and angiogenesis. The ischemia/reperfusion (I/R) injury rat models were created using a caudal-based dorsal skin flap with delayed I/R. Twenty-four male Sprague Dawley rats were divided into control, sham, and two treatment groups receiving dapsone at doses of 12.5 mg/kg/day and 5 mg/kg/day, respectively. On the 7th post-operative day, flap survival was evaluated. Neutrophil infiltration and ulceration were measured through microscopic examination, and interleukin (IL)-8 levels through enzyme-linked immunosorbent assay. Expression levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were determined using an immunohistochemistry (IHC) array. The findings revealed an increased flap survival on day 7 post-operation following systemic administration of dapsone for 5 consecutive days. Dapsone at both dosages significantly reduced the ulcer thickness, neutrophil infiltration, and IL-8 levels. The IHC results revealed that VEGF expression was significantly higher in the treatment groups compared to the control group. Moreover, TNF-α expression was significantly lower in the treatment groups compared to the control group. In conclusion, we confirmed that treatment with dapsone promotes skin flap survival, and this effect aligned with a reduction in persistent inflammation and the enhancement of VEGF. Nonetheless, more studies are required to elucidate the precise anti-inflammatory mechanism of dapsone in I/R injuries.
{"title":"The effect of dapsone on skin flap survival depends on modulation of inflammatory response and VEGF expression","authors":"Abolfazl Badripour, Anahita Najafi, Zahra Ebrahim Soltani, Alireza Hasanzadeh, M. Behzadi, Alireza Rahbar, Armaghan Ahangarishizary, Seyed Mohsen Ahmadi-Tafti, Mohammad Ashouri, Ahmadreza Dehpour","doi":"10.36922/itps.2241","DOIUrl":"https://doi.org/10.36922/itps.2241","url":null,"abstract":"The random-pattern skin flap is a common method used for reconstructing skin defects. However, flap ischemia necrosis remains a significant challenge in plastic surgery. Strategies aimed at reducing persistent inflammation and promoting blood supply through angiogenesis have been identified as crucial for improving flap survival. Dapsone, a chemotherapeutic agent known for its anti-inflammatory properties through multiple pathways, is of interest in this regard. This study aims to investigate the effect of dapsone on random-pattern flap survival in rats, along with its impact on inflammation and angiogenesis. The ischemia/reperfusion (I/R) injury rat models were created using a caudal-based dorsal skin flap with delayed I/R. Twenty-four male Sprague Dawley rats were divided into control, sham, and two treatment groups receiving dapsone at doses of 12.5 mg/kg/day and 5 mg/kg/day, respectively. On the 7th post-operative day, flap survival was evaluated. Neutrophil infiltration and ulceration were measured through microscopic examination, and interleukin (IL)-8 levels through enzyme-linked immunosorbent assay. Expression levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were determined using an immunohistochemistry (IHC) array. The findings revealed an increased flap survival on day 7 post-operation following systemic administration of dapsone for 5 consecutive days. Dapsone at both dosages significantly reduced the ulcer thickness, neutrophil infiltration, and IL-8 levels. The IHC results revealed that VEGF expression was significantly higher in the treatment groups compared to the control group. Moreover, TNF-α expression was significantly lower in the treatment groups compared to the control group. In conclusion, we confirmed that treatment with dapsone promotes skin flap survival, and this effect aligned with a reduction in persistent inflammation and the enhancement of VEGF. Nonetheless, more studies are required to elucidate the precise anti-inflammatory mechanism of dapsone in I/R injuries.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":"28 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140696089","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}
Kevin Tochukwu Dibia, Sandra Nneka Van-Dibia, Philomena Kanwulia Igbokwe
Dysregulation or aberrant activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is commonly observed in various cancers and is associated with tumor growth, metastasis, and resistance to therapy. Targeting PI3K-α with appropriate inhibitors can disrupt this pathway, hindering cancer progression, and potentially enhancing the immune system’s ability to recognize and eliminate cancer cells. In this study, we aimed to design a novel and potent inhibitor of PI3K-α for cancer immunotherapy using rational drug design techniques, including virtual screening, molecular docking, and 3D-QSAR. We obtained the human PI3K-α protein (6PYS) complexed with (3S)-3-benzyl-3-methyl-5-[5-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-dihydro-2H-indol-2-one (PJ5) from the RCSB Protein Data Bank. Virtual screening of ligands, integrated with predictive computational molecular docking and 3D-field-based-QSAR, was implemented using appropriate Schrödinger Maestro modules. Rational drug design was also carried out, and its clinical relevance was validated across several ADMET descriptors. Docking results suggested that a hybrid of sulfonamide and pyridine-based heterocyclic compounds, functionalized with potent moieties derived from alkaloids, exhibited adequate synergistic biological effects capable of enhancing sufficient biological activity against PI3K-α. A field-based 3D-QSAR model was built on four partial least squares factors, and five statistical metrics were employed to validate the model. The newly designed ligand from this approach, named 6’-amino-5’-(2-fluoro-1,3-oxazol-5-yl)-N-{[3-(hydroxymethyl)oxetan-3-yl]methyl}-3-methyl-[2,3’-bipyridine]-6-sulfonamide or T85, exhibited a predicted bioactivity (pIC50) of 8.25. The predicted ADMET properties of T85 fell reasonably within the range of recommended standards, especially adhering to Lipinski’s rule of five and Jorgensen’s rule of three. In conclusion, the results of this study offer significant insights into in silico drug design using a rational approach, which could expedite the discovery and development of new drug molecules.
{"title":"Rational drug design from phosphatidylinositol 3-kinase-α inhibitors through molecular docking and 3D-QSAR methodologies for cancer immunotherapy","authors":"Kevin Tochukwu Dibia, Sandra Nneka Van-Dibia, Philomena Kanwulia Igbokwe","doi":"10.36922/itps.2340","DOIUrl":"https://doi.org/10.36922/itps.2340","url":null,"abstract":"Dysregulation or aberrant activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is commonly observed in various cancers and is associated with tumor growth, metastasis, and resistance to therapy. Targeting PI3K-α with appropriate inhibitors can disrupt this pathway, hindering cancer progression, and potentially enhancing the immune system’s ability to recognize and eliminate cancer cells. In this study, we aimed to design a novel and potent inhibitor of PI3K-α for cancer immunotherapy using rational drug design techniques, including virtual screening, molecular docking, and 3D-QSAR. We obtained the human PI3K-α protein (6PYS) complexed with (3S)-3-benzyl-3-methyl-5-[5-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-dihydro-2H-indol-2-one (PJ5) from the RCSB Protein Data Bank. Virtual screening of ligands, integrated with predictive computational molecular docking and 3D-field-based-QSAR, was implemented using appropriate Schrödinger Maestro modules. Rational drug design was also carried out, and its clinical relevance was validated across several ADMET descriptors. Docking results suggested that a hybrid of sulfonamide and pyridine-based heterocyclic compounds, functionalized with potent moieties derived from alkaloids, exhibited adequate synergistic biological effects capable of enhancing sufficient biological activity against PI3K-α. A field-based 3D-QSAR model was built on four partial least squares factors, and five statistical metrics were employed to validate the model. The newly designed ligand from this approach, named 6’-amino-5’-(2-fluoro-1,3-oxazol-5-yl)-N-{[3-(hydroxymethyl)oxetan-3-yl]methyl}-3-methyl-[2,3’-bipyridine]-6-sulfonamide or T85, exhibited a predicted bioactivity (pIC50) of 8.25. The predicted ADMET properties of T85 fell reasonably within the range of recommended standards, especially adhering to Lipinski’s rule of five and Jorgensen’s rule of three. In conclusion, the results of this study offer significant insights into in silico drug design using a rational approach, which could expedite the discovery and development of new drug molecules.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":"334 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140703621","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}
The intricate interplay between cardiovascular health and metabolic regulation forms a critical junction in understanding the complexities of heart-related conditions. Cardiometabolic regulation orchestrates a sophisticated network of factors governing energy utilization, substrate metabolism, and cellular processes within the cardiovascular system. Balancing these mechanisms is pivotal for optimal heart function, considering the substantial energy demands for both contractile and non-contractile activities. In a healthy heart, fatty acids (FAs) derived from FA β-oxidation contribute to approximately 70% of total energy production. However, emerging evidence sheds light on pathological changes in the heart that lead to profound metabolic alterations. These alterations involve a shift from predominant FA utilization to alternative substrates such as glucose and ketone bodies, accompanied by an increased reliance on FAs. This metabolic remodeling extends beyond substrate metabolism, encompassing changes in transporter expression, the activity of metabolic-related proteins, hormonal functions, and cardiac mitochondrial energetics. This comprehensive review article delves into the intricate web of cardiometabolic regulation, elucidating the multifaceted factors influencing cardiac metabolism across diverse states encompassing health, metabolic disorders, and heart diseases. Unraveling the molecular intricacies and interconnected pathways shaping cardiac metabolism in various physiological and pathological conditions provides critical insights into the adaptive mechanisms and dysregulations associated with heart-related conditions. Furthermore, the exploration of these regulatory mechanisms offers promising avenues for targeted therapeutic interventions and diagnostic strategies in cardiovascular medicine. Integrating multidisciplinary approaches and leveraging advanced technologies will facilitate a deeper understanding of cardiac metabolism, paving the way for innovative interventions to mitigate metabolic dysregulation and optimize cardiac health.
心血管健康与新陈代谢调节之间错综复杂的相互作用，是了解心脏相关疾病复杂性的关键所在。心血管代谢调节是一个复杂的网络，其中的各种因素对心血管系统内的能量利用、底物代谢和细胞过程起着调节作用。考虑到收缩和非收缩活动都需要大量能量，平衡这些机制对于优化心脏功能至关重要。在健康的心脏中，FA β-氧化产生的脂肪酸（FAs）约占总能量产生的 70%。然而，新出现的证据揭示了心脏的病理变化，这些病理变化导致了新陈代谢的深刻改变。这些变化涉及从主要利用 FA 到葡萄糖和酮体等替代底物的转变，同时对 FA 的依赖性增加。这种代谢重塑超出了底物代谢的范围，包括转运体表达、代谢相关蛋白的活性、激素功能和心脏线粒体能量的变化。这篇综合性综述文章深入探讨了错综复杂的心脏代谢调控网络，阐明了在包括健康、代谢紊乱和心脏病在内的不同状态下影响心脏代谢的多方面因素。揭示各种生理和病理状态下影响心脏代谢的错综复杂的分子机制和相互关联的途径，有助于深入了解与心脏相关疾病有关的适应机制和失调。此外，对这些调控机制的探索为心血管医学中的靶向治疗干预和诊断策略提供了前景广阔的途径。整合多学科方法和利用先进技术将有助于加深对心脏代谢的理解，为减轻代谢失调和优化心脏健康的创新干预措施铺平道路。
{"title":"Navigating the complex landscape of cardiac metabolism in health and disease states","authors":"Pongpan Tanajak, Tipthida Pasachan","doi":"10.36922/itps.2302","DOIUrl":"https://doi.org/10.36922/itps.2302","url":null,"abstract":"The intricate interplay between cardiovascular health and metabolic regulation forms a critical junction in understanding the complexities of heart-related conditions. Cardiometabolic regulation orchestrates a sophisticated network of factors governing energy utilization, substrate metabolism, and cellular processes within the cardiovascular system. Balancing these mechanisms is pivotal for optimal heart function, considering the substantial energy demands for both contractile and non-contractile activities. In a healthy heart, fatty acids (FAs) derived from FA β-oxidation contribute to approximately 70% of total energy production. However, emerging evidence sheds light on pathological changes in the heart that lead to profound metabolic alterations. These alterations involve a shift from predominant FA utilization to alternative substrates such as glucose and ketone bodies, accompanied by an increased reliance on FAs. This metabolic remodeling extends beyond substrate metabolism, encompassing changes in transporter expression, the activity of metabolic-related proteins, hormonal functions, and cardiac mitochondrial energetics. This comprehensive review article delves into the intricate web of cardiometabolic regulation, elucidating the multifaceted factors influencing cardiac metabolism across diverse states encompassing health, metabolic disorders, and heart diseases. Unraveling the molecular intricacies and interconnected pathways shaping cardiac metabolism in various physiological and pathological conditions provides critical insights into the adaptive mechanisms and dysregulations associated with heart-related conditions. Furthermore, the exploration of these regulatory mechanisms offers promising avenues for targeted therapeutic interventions and diagnostic strategies in cardiovascular medicine. Integrating multidisciplinary approaches and leveraging advanced technologies will facilitate a deeper understanding of cardiac metabolism, paving the way for innovative interventions to mitigate metabolic dysregulation and optimize cardiac health.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":"612 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140750070","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}
Brandon H. Adame-Velasco, Pablo Octavio-Aguilar, Luis H. Mendoza-Huizar, Liliana M. Aguilar-Castro
The SARS-CoV-2 virus gains entry into host cells by binding its spike glycoprotein (S-glycoprotein) to the angiotensin 2 receptor. This viral protein contains several conserved regions, such as the receptor binding domain region, making it an ideal target for treating COVID-19. Notably, the majority of existing vaccines elicit antigenic reaction by targeting this protein epitope. This study evaluated the binding affinities of 44 different drugs against the SARS-CoV-2 S-glycoprotein, considering their toxicity profiles and previous clinical studies at different testing stages. Our results revealed that maraviroc and estradiol benzoate exhibited high affinities (−7.7 and −7.6 kcal mol−1, respectively), while other ligands, such as indinavir and ritonavir, showed affinity at lower levels. Among the drugs with high affinity, toxicity levels ranged from harmful if swallowed (300 mg/kg < LD50 < 2000 mg/kg) to non-toxic (LD50 > 5000 mg/kg), with only three having undergone clinical testing, yielding promising or controversial results. Furthermore, emtricitabine and docosanol, previously explored as COVID-19 treatments, exhibited the lowest affinities (−4.7 and −3.9 kcal mol−1, respectively), with associated harmful effects if swallowed. These results provide essential information about drug interaction against the SARS-CoV-2 S-glycoprotein and potential treatment pathways for COVID-19.
{"title":"Evaluating the SARS-CoV-2 spike glycoprotein as a molecular target for therapeutic development","authors":"Brandon H. Adame-Velasco, Pablo Octavio-Aguilar, Luis H. Mendoza-Huizar, Liliana M. Aguilar-Castro","doi":"10.36922/itps.1651","DOIUrl":"https://doi.org/10.36922/itps.1651","url":null,"abstract":"The SARS-CoV-2 virus gains entry into host cells by binding its spike glycoprotein (S-glycoprotein) to the angiotensin 2 receptor. This viral protein contains several conserved regions, such as the receptor binding domain region, making it an ideal target for treating COVID-19. Notably, the majority of existing vaccines elicit antigenic reaction by targeting this protein epitope. This study evaluated the binding affinities of 44 different drugs against the SARS-CoV-2 S-glycoprotein, considering their toxicity profiles and previous clinical studies at different testing stages. Our results revealed that maraviroc and estradiol benzoate exhibited high affinities (−7.7 and −7.6 kcal mol−1, respectively), while other ligands, such as indinavir and ritonavir, showed affinity at lower levels. Among the drugs with high affinity, toxicity levels ranged from harmful if swallowed (300 mg/kg < LD50 < 2000 mg/kg) to non-toxic (LD50 > 5000 mg/kg), with only three having undergone clinical testing, yielding promising or controversial results. Furthermore, emtricitabine and docosanol, previously explored as COVID-19 treatments, exhibited the lowest affinities (−4.7 and −3.9 kcal mol−1, respectively), with associated harmful effects if swallowed. These results provide essential information about drug interaction against the SARS-CoV-2 S-glycoprotein and potential treatment pathways for COVID-19.","PeriodicalId":13673,"journal":{"name":"INNOSC Theranostics and Pharmacological Sciences","volume":"101 41","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140379695","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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