Aspects of molecular medicine最新文献

Prevalence of pathogenic genetic variants associated with familial hypercholesterolemia in Ghanaian children

Aspects of molecular medicine

Pub Date : 2025-02-20 DOI: 10.1016/j.amolm.2025.100067

Philip Opoku-Agyeman , Prince Ameyaw , Selassie Bruku , Gideon Ofori Addo , Gideon Tetteh , Esther Baafi , Sandra Korkor Asare , Abigail Foriwaah Frimpong , Samuel Adu-Poku , Sena Adzoa Matrevi , Nancy Odurowah Duah-Quashie , Kwesi Z. Tandoh

Familial hypercholesterolemia (FH) is an important contributor to atherosclerotic cardiovascular disease (ASCVD) burden globally. FH disrupts cholesterol metabolism and causes lifelong elevation in low-density lipoprotein cholesterol (LDL-C). In sub-Saharan Africa (SSA), the increasing burden of ASCVD may be partly driven by genetic dyslipidemias of which FH is the commonest. However, there is absence of data on FH prevalence in SSA which delineates an important gap in the management of ASCVD. This study is the first to investigate the prevalence of pathogenic variants associated with FH in Ghana. We used 96 deidentified archived dried blood spot samples collected from a Ghanaian cohort, to determine the prevalence of pathogenic genetic variants associated with FH. These samples were collected from children under 9 years old as part of surveillance for antimalarial drug resistance in 2021. We searched the NCBI's ClinVar database and used in silico tools to identify 500–800 nucleotide base pair regions of interest in 3 genes known to harbor the commonest genetic variants associated with FH. We selected these regions of interest from the LDLR gene exons 4, 9 and 10, APOB exon 26 and PCSK9 exon 2 loci. Next, we amplified these regions of interest using conventional polymerase chain reaction. Finally, we sequenced the amplicons using paired-end Sanger sequencing and called variants from the chromatogram files using an in-house custom built bash script utilizing the open access program Tracy. Subsequently, we did quality checks on all reported pathogenic variant calls manually using Benchling's sequence alignment tool. We identified one pathogenic variant V523 M in the LDLR exon 10 region and report an FH prevalence of 1% (1/96), 95% CI: [0%,3.07%], in our Ghanaian cohort. Our finding underscores the importance of FH in driving ASCVD burden in Ghana and advocates the need for implementation science-driven programs to manage this genetic dyslipidemia in Ghana and SSA.

{"title":"Prevalence of pathogenic genetic variants associated with familial hypercholesterolemia in Ghanaian children","authors":"Philip Opoku-Agyeman , Prince Ameyaw , Selassie Bruku , Gideon Ofori Addo , Gideon Tetteh , Esther Baafi , Sandra Korkor Asare , Abigail Foriwaah Frimpong , Samuel Adu-Poku , Sena Adzoa Matrevi , Nancy Odurowah Duah-Quashie , Kwesi Z. Tandoh","doi":"10.1016/j.amolm.2025.100067","DOIUrl":"10.1016/j.amolm.2025.100067","url":null,"abstract":"<div><div>Familial hypercholesterolemia (FH) is an important contributor to atherosclerotic cardiovascular disease (ASCVD) burden globally. FH disrupts cholesterol metabolism and causes lifelong elevation in low-density lipoprotein cholesterol (LDL-C). In sub-Saharan Africa (SSA), the increasing burden of ASCVD may be partly driven by genetic dyslipidemias of which FH is the commonest. However, there is absence of data on FH prevalence in SSA which delineates an important gap in the management of ASCVD. This study is the first to investigate the prevalence of pathogenic variants associated with FH in Ghana. We used 96 deidentified archived dried blood spot samples collected from a Ghanaian cohort, to determine the prevalence of pathogenic genetic variants associated with FH. These samples were collected from children under 9 years old as part of surveillance for antimalarial drug resistance in 2021. We searched the NCBI's ClinVar database and used <em>in silico</em> tools to identify 500–800 nucleotide base pair regions of interest in 3 genes known to harbor the commonest genetic variants associated with FH. We selected these regions of interest from the <em>LDLR</em> gene exons 4, 9 and 10, <em>APOB</em> exon 26 and <em>PCSK9</em> exon 2 loci. Next, we amplified these regions of interest using conventional polymerase chain reaction. Finally, we sequenced the amplicons using paired-end Sanger sequencing and called variants from the chromatogram files using an in-house custom built bash script utilizing the open access program Tracy. Subsequently, we did quality checks on all reported pathogenic variant calls manually using Benchling's sequence alignment tool. We identified one pathogenic variant V523 M in the <em>LDLR</em> exon 10 region and report an FH prevalence of 1% (1/96), 95% CI: [0%,3.07%], in our Ghanaian cohort. Our finding underscores the importance of FH in driving ASCVD burden in Ghana and advocates the need for implementation science-driven programs to manage this genetic dyslipidemia in Ghana and SSA.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"5 ","pages":"Article 100067"},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chalcone-related small molecules as potent antibacterial and antifungal agents: Design, synthesis, In vitro, and computational approaches

Aspects of molecular medicine

Pub Date : 2025-02-15 DOI: 10.1016/j.amolm.2025.100066

Narmin Hamaamin Hussen , Larin Barzan Hussein , Aso Hameed Hasan , Shokhan Jamal Hamid , Chawan Othman Abdl , Bakhcha Sarkar , Kozhin Muhammed , Daroon Muhamad

Infectious diseases caused by bacteria and fungi are a global health concern due to resistance to traditional antimicrobial medications. A variety of chalcone-related small molecules have been designed, synthesized, and characterized small molecules using FTIR, NMR, and MS to find antimicrobial agents for treating these infections. These designed compounds (9, 11, 13) were evaluated for their potential inhibitory activity against five bacterial strains and one fungal strain using disc diffusion and MIC assays utilizing ampicillin and fluconazole as reference drugs. The MIC values ranged from 2.5 to 160 μg/mL, which can be attributed to improved membrane penetration and increased ligand-protein binding capability. Among them, molecule 9 exhibited a broad spectrum of antibacterial activity against gram-negative bacteria, with an MICs of 40 μg/mL against P. aeruginosa and 80 μg/mL against E. coli. Compound 11 showed potent activity against gram-positive bacteria and fungi, with a MICs of 40 μg/mL against S. aureus and 80 μg/mL against C. albicans. Furthermore, similar to in vitro study results, molecular docking demonstrated that compounds 9 and 11 had a better binding affinity against gram-positive and gram-negative bacteria and fungal species than reference drugs. Finally, physicochemical and drug-likeness results showed that all the compounds can pass Lipinski's rule of five, are absorbed through the GIT, and are suitable for oral administration.

{"title":"Chalcone-related small molecules as potent antibacterial and antifungal agents: Design, synthesis, In vitro, and computational approaches","authors":"Narmin Hamaamin Hussen , Larin Barzan Hussein , Aso Hameed Hasan , Shokhan Jamal Hamid , Chawan Othman Abdl , Bakhcha Sarkar , Kozhin Muhammed , Daroon Muhamad","doi":"10.1016/j.amolm.2025.100066","DOIUrl":"10.1016/j.amolm.2025.100066","url":null,"abstract":"<div><div>Infectious diseases caused by bacteria and fungi are a global health concern due to resistance to traditional antimicrobial medications. A variety of chalcone-related small molecules have been designed, synthesized, and characterized small molecules using FTIR, NMR, and MS to find antimicrobial agents for treating these infections. These designed compounds (<strong>9, 11, 13</strong>) were evaluated for their potential inhibitory activity against five bacterial strains and one fungal strain using disc diffusion and MIC assays utilizing ampicillin and fluconazole as reference drugs. The MIC values ranged from 2.5 to 160 μg/mL, which can be attributed to improved membrane penetration and increased ligand-protein binding capability. Among them, molecule 9 exhibited a broad spectrum of antibacterial activity against gram-negative bacteria, with an MICs of 40 μg/mL against <em>P. aeruginosa</em> and 80 μg/mL against <em>E. coli</em>. Compound <strong>11</strong> showed potent activity against gram-positive bacteria and fungi, with a MICs of 40 μg/mL against <em>S. aureus</em> and 80 μg/mL against <em>C. albicans</em>. Furthermore, similar to <em>in vitro</em> study results, molecular docking demonstrated that compounds <strong>9</strong> and <strong>11</strong> had a better binding affinity against gram-positive and gram-negative bacteria and fungal species than reference drugs. Finally, physicochemical and drug-likeness results showed that all the compounds can pass Lipinski's rule of five, are absorbed through the GIT, and are suitable for oral administration.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"5 ","pages":"Article 100066"},"PeriodicalIF":0.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vitro and in silico Anti-diabetes mechanism of phytochemicals from Curculigo pilosa and its pharmacokinetic profiling via α-amylase inhibition

Aspects of molecular medicine

Pub Date : 2025-01-31 DOI: 10.1016/j.amolm.2025.100064

Damilola A. Omoboyowa , Temitope C. Aribigbola , Simbo T. Akinsulure , Damilola S. Bodun , Ezekiel A. Olugbogi , Ebenezer A. Oni

Diabetes mellitus is characterized by elevated blood glucose resulting from carbohydrate metabolism via glucose metabolizing enzymes such as α-amylase. Curculigo pilosa is traditionally used as herbal medication as anti-diabetes therapy but its mechanism of action is yet to be explored. This study investigates α-amylase inhibitory potential of C. pilosa using in vitro and in silico approaches. The ethylacetate, n-butanol and methanol extracts of C. pilosa were subjected to in vitro α-amylase inhibitory assay, followed by identification of the bioactive compounds from the most potent extract using HPLC. Integrated computational analyses were performed on ten (10) active compounds against α-amylase using Maestro Schrodinger (v2). The results of the in vitro α–amylase assay revealed n-butanol extract as the potent extract with IC₅₀ of 132.70 μg/mL, although the standard drug (acarbose IC₅₀ = 128.70 μg/mL) inhibits α-amylase better than the extracts. The HPLC result revealed the presence of ten (10) active compounds. Acarbose was observed to possess better binding affinity (−11.502 kcal/mol) than all the compounds but curculigoside was the hit compound with binding affinity of −8.797 kcal/mol. Some of the compounds showed appreciable inhibitory pIC₅₀ and fitness scores comparable to the standard drug. The pharmacokinetic profile revealed that none of the compounds violated more than one Lipinski's rule of five while the standard drug (acarbose) violated three (3) of the rules. The root mean square deviation shows reasonable level of stability within the simulation period for both curculigoside and acarbose. The result of in silico study showed significant inhibitory potential of the active compounds against α-amylase which was consistent with the in vitro inhibition of α amylase by the plant extract suggesting this as the possible mechanism of antidiabetes action of C. pilosa.

{"title":"In vitro and in silico Anti-diabetes mechanism of phytochemicals from Curculigo pilosa and its pharmacokinetic profiling via α-amylase inhibition","authors":"Damilola A. Omoboyowa , Temitope C. Aribigbola , Simbo T. Akinsulure , Damilola S. Bodun , Ezekiel A. Olugbogi , Ebenezer A. Oni","doi":"10.1016/j.amolm.2025.100064","DOIUrl":"10.1016/j.amolm.2025.100064","url":null,"abstract":"<div><div>Diabetes mellitus is characterized by elevated blood glucose resulting from carbohydrate metabolism via glucose metabolizing enzymes such as α-amylase. <em>Curculigo pilosa</em> is traditionally used as herbal medication as anti-diabetes therapy but its mechanism of action is yet to be explored. This study investigates α-amylase inhibitory potential of <em>C. pilosa</em> using in vitro and in silico approaches. The ethylacetate, n-butanol and methanol extracts of <em>C. pilosa</em> were subjected to in vitro α-amylase inhibitory assay, followed by identification of the bioactive compounds from the most potent extract using HPLC. Integrated computational analyses were performed on ten (10) active compounds against α-amylase using Maestro Schrodinger (v2). The results of the in vitro α–amylase assay revealed n-butanol extract as the potent extract with IC<sub>50</sub> of 132.70 μg/mL, although the standard drug (acarbose IC<sub>50</sub> = 128.70 μg/mL) inhibits α-amylase better than the extracts. The HPLC result revealed the presence of ten (10) active compounds. Acarbose was observed to possess better binding affinity (−11.502 kcal/mol) than all the compounds but curculigoside was the hit compound with binding affinity of −8.797 kcal/mol. Some of the compounds showed appreciable inhibitory pIC<sub>50</sub> and fitness scores comparable to the standard drug. The pharmacokinetic profile revealed that none of the compounds violated more than one Lipinski's rule of five while the standard drug (acarbose) violated three (3) of the rules. The root mean square deviation shows reasonable level of stability within the simulation period for both curculigoside and acarbose. The result of in silico study showed significant inhibitory potential of the active compounds against α-amylase which was consistent with the in vitro inhibition of α amylase by the plant extract suggesting this as the possible mechanism of antidiabetes action of <em>C. pilosa</em>.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"5 ","pages":"Article 100064"},"PeriodicalIF":0.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143146624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Stimuli-responsive supramolecular hydrogels for paclitaxel delivery: Progress and prospects

Aspects of molecular medicine

Pub Date : 2025-01-04 DOI: 10.1016/j.amolm.2024.100062

Mohammad Qutub , Amol Tatode , Jayshree Taksande , Tanvi Premchandani , Milind Umekar , Ujban Md Hussain , Dinesh Biyani , Dadaso Mane

Cancer remains a leading cause of death worldwide, while chemotherapy playing a pivotal role in its management. However, traditional chemotherapy often encounters challenges such as non-specific drug delivery, systemic toxicity, and rapid clearance. Thermosensitive supramolecular hydrogels have emerged as an innovative platform for localized and sustained drug delivery, particularly for paclitaxel (PTX), a potent chemotherapeutic agent. These hydrogels exhibit unique sol-gel phase transitions at physiological temperatures, enabling minimally invasive administration and prolonged retention at tumor sites. Advances in hydrogel formulations, including dual stimuli-responsive systems and nanocrystal-loaded designs, enhance drug stability, controlled release, and therapeutic efficacy. Additionally, these hydrogels can incorporate multimodal therapeutic agents, such as immunomodulators and photosensitizers, achieving synergistic anticancer effects. Despite significant progress, challenges remain in optimizing tumor penetration, scaling production, and addressing tumor heterogeneity. Ongoing research into hydrogel composition, biocompatibility, and targeted delivery mechanisms aims to overcome these limitations, paving the way for their clinical translation. This review highlights recent advancements and future prospects of thermosensitive hydrogels for PTX delivery, emphasizing their potential to revolutionize cancer treatment by reducing systemic toxicity and improving localized therapeutic outcomes.

{"title":"Stimuli-responsive supramolecular hydrogels for paclitaxel delivery: Progress and prospects","authors":"Mohammad Qutub , Amol Tatode , Jayshree Taksande , Tanvi Premchandani , Milind Umekar , Ujban Md Hussain , Dinesh Biyani , Dadaso Mane","doi":"10.1016/j.amolm.2024.100062","DOIUrl":"10.1016/j.amolm.2024.100062","url":null,"abstract":"<div><div>Cancer remains a leading cause of death worldwide, while chemotherapy playing a pivotal role in its management. However, traditional chemotherapy often encounters challenges such as non-specific drug delivery, systemic toxicity, and rapid clearance. Thermosensitive supramolecular hydrogels have emerged as an innovative platform for localized and sustained drug delivery, particularly for paclitaxel (PTX), a potent chemotherapeutic agent. These hydrogels exhibit unique sol-gel phase transitions at physiological temperatures, enabling minimally invasive administration and prolonged retention at tumor sites. Advances in hydrogel formulations, including dual stimuli-responsive systems and nanocrystal-loaded designs, enhance drug stability, controlled release, and therapeutic efficacy. Additionally, these hydrogels can incorporate multimodal therapeutic agents, such as immunomodulators and photosensitizers, achieving synergistic anticancer effects. Despite significant progress, challenges remain in optimizing tumor penetration, scaling production, and addressing tumor heterogeneity. Ongoing research into hydrogel composition, biocompatibility, and targeted delivery mechanisms aims to overcome these limitations, paving the way for their clinical translation. This review highlights recent advancements and future prospects of thermosensitive hydrogels for PTX delivery, emphasizing their potential to revolutionize cancer treatment by reducing systemic toxicity and improving localized therapeutic outcomes.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"5 ","pages":"Article 100062"},"PeriodicalIF":0.0,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143146631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of antioxidants in skin aging and the molecular mechanism of ROS: A comprehensive review

Aspects of molecular medicine

Pub Date : 2025-01-04 DOI: 10.1016/j.amolm.2025.100063

Narmin Hama amin Hussen , Sakar Karem Abdulla , Naza Mohammed Ali , Van Abdulqader Ahmed , Aso Hameed Hasan , Eman Erfan Qadir

Skin aging is a multifaceted and gradual process influenced by both internal and external factors, including environmental stressors. These two mechanisms contribute to oxidative stress, triggered by ROS, which accelerates the aging of the skin. UV exposure increases the production of ROS in cells, which collectively contribute to the various skin changes linked to aging. However, the skin has a sophisticated antioxidant defense system that shields it from oxidative damage caused by both internal and external factors. The use of topical antioxidants have been shown to shield the skin from harmful free radicals generated intrinsically by regular cellular metabolism or as a result of UV light exposure. This review focuses on the assessment of the injury environmental factors cause to the skin, molecular mechanism of ROS in the skin aging, and the use of antioxidants to prevent that damaging and producing a protection against UV radiation from environmental factors. The systematic search was done for eligible articles which including in vivo and in vitro studies from studies between (1997 until 2024).

{"title":"Role of antioxidants in skin aging and the molecular mechanism of ROS: A comprehensive review","authors":"Narmin Hama amin Hussen , Sakar Karem Abdulla , Naza Mohammed Ali , Van Abdulqader Ahmed , Aso Hameed Hasan , Eman Erfan Qadir","doi":"10.1016/j.amolm.2025.100063","DOIUrl":"10.1016/j.amolm.2025.100063","url":null,"abstract":"<div><div>Skin aging is a multifaceted and gradual process influenced by both internal and external factors, including environmental stressors. These two mechanisms contribute to oxidative stress, triggered by ROS, which accelerates the aging of the skin. UV exposure increases the production of ROS in cells, which collectively contribute to the various skin changes linked to aging. However, the skin has a sophisticated antioxidant defense system that shields it from oxidative damage caused by both internal and external factors. The use of topical antioxidants have been shown to shield the skin from harmful free radicals generated intrinsically by regular cellular metabolism or as a result of UV light exposure. This review focuses on the assessment of the injury environmental factors cause to the skin, molecular mechanism of ROS in the skin aging, and the use of antioxidants to prevent that damaging and producing a protection against UV radiation from environmental factors. The systematic search was done for eligible articles which including in vivo and in vitro studies from studies between (1997 until 2024).</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"5 ","pages":"Article 100063"},"PeriodicalIF":0.0,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143146629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular vesicles in thalassemia: Mechanisms, implications, and therapeutic potential

Aspects of molecular medicine

Pub Date : 2024-12-30 DOI: 10.1016/j.amolm.2024.100061

Shahzad Ali Jiskani

Thalassemia is one of the most common inherited disorders of erythrocytes, caused by abnormalities in the production of globin chains. The clinical spectrum of thalassemia is broad, ranging from severe and persistent anemia that necessitates consistent blood transfusions to mild, asymptomatic conditions. Key contributors to thalassemia complications, particularly, in patients with β-thalassemia major, are ineffective erythropoiesis and iron overload. These complications can lead to a variety of severe health issues, including chronic inflammation, organ dysfunction, thrombosis, vascular abnormalities, and systemic iron overload. Extracellular vesicles (EVs) are tiny membrane-bound particles secreted from the plasma membranes of various cells during activation and cell death. Research has indicated that EVs are involved in numerous physiological and pathological processes, including inflammatory responses, clot formation, and vascular injury. Recently, the role of EVs has garnered interest of their potential as biomarkers, providing diagnostic and prognostic value of various disorders. In the context of thalassemia, elevated levels of EVs have been observed, highlighting their significance in the disease's cellular activities. The current review aims to examine the role of EVs in the pathogenesis of thalassemia, their implications, and their potential clinical applications. By exploring the involvement of EVs in the inflammatory and vascular complications associated with thalassemia, this review provides insights into their potential as therapeutic targets and diagnostic tools, offering a new perspective on managing this complex and multifaceted disorder.

{"title":"Extracellular vesicles in thalassemia: Mechanisms, implications, and therapeutic potential","authors":"Shahzad Ali Jiskani","doi":"10.1016/j.amolm.2024.100061","DOIUrl":"10.1016/j.amolm.2024.100061","url":null,"abstract":"<div><div>Thalassemia is one of the most common inherited disorders of erythrocytes, caused by abnormalities in the production of globin chains. The clinical spectrum of thalassemia is broad, ranging from severe and persistent anemia that necessitates consistent blood transfusions to mild, asymptomatic conditions. Key contributors to thalassemia complications, particularly, in patients with β-thalassemia major, are ineffective erythropoiesis and iron overload. These complications can lead to a variety of severe health issues, including chronic inflammation, organ dysfunction, thrombosis, vascular abnormalities, and systemic iron overload. Extracellular vesicles (EVs) are tiny membrane-bound particles secreted from the plasma membranes of various cells during activation and cell death. Research has indicated that EVs are involved in numerous physiological and pathological processes, including inflammatory responses, clot formation, and vascular injury. Recently, the role of EVs has garnered interest of their potential as biomarkers, providing diagnostic and prognostic value of various disorders. In the context of thalassemia, elevated levels of EVs have been observed, highlighting their significance in the disease's cellular activities. The current review aims to examine the role of EVs in the pathogenesis of thalassemia, their implications, and their potential clinical applications. By exploring the involvement of EVs in the inflammatory and vascular complications associated with thalassemia, this review provides insights into their potential as therapeutic targets and diagnostic tools, offering a new perspective on managing this complex and multifaceted disorder.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"5 ","pages":"Article 100061"},"PeriodicalIF":0.0,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143146630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the molecular mechanisms and clinical implications of maslinic acid in diabetes mellitus: Insights from network pharmacology

Aspects of molecular medicine

Pub Date : 2024-12-10 DOI: 10.1016/j.amolm.2024.100060

Sarvesh Sabarathinam , Sanjana Satheesh

Maslinic acid(MA), a natural pentacyclic triterpene, has potent anti-tumor activity and exerts effects by various mechanisms, including apoptosis, cell cycle arrest, autophagy regulation, and angiogenesis alteration. We investigated the Network pharmacology and Molecular docking analysis of Maslinic Acid The network pharmacology report shows that 23 overlapping targets were identified with Maslinic Acid. Followed by the binding scores were found to be similar to the reference standard Rosiglitazone & Pioglitazone. Maslinic Acid exerts its effect on insulin resistance via inhibition of peroxisome proliferator-activated receptor, α-amylase, and α-glucosidase inhibition, glycogen phosphorylase inhibition, reduction in ghrelin concentration, downregulation of SGLT1 and GLUT2 genes, NF-κB suppression, Nrf2 activation, and AMPK/SIRT 1 pathway activation. The Network analysis and docking score confirm the diabetic activity of Maslinic Acid. This study aims to study various targets of Maslinic Acid in correlation to Diabetes mellitus and analyze their mechanism in detail. Our investigation of MA as a potential treatment target for insulin resistance or diabetes mellitus using network pharmacology revealed that it has significant roles in producing glucose-lowering activity by regulating glucose homeostasis via several insulin signaling pathways discussed above.

{"title":"Unveiling the molecular mechanisms and clinical implications of maslinic acid in diabetes mellitus: Insights from network pharmacology","authors":"Sarvesh Sabarathinam , Sanjana Satheesh","doi":"10.1016/j.amolm.2024.100060","DOIUrl":"10.1016/j.amolm.2024.100060","url":null,"abstract":"<div><div>Maslinic acid(MA), a natural pentacyclic triterpene, has potent anti-tumor activity and exerts effects by various mechanisms, including apoptosis, cell cycle arrest, autophagy regulation, and angiogenesis alteration. We investigated the Network pharmacology and Molecular docking analysis of Maslinic Acid The network pharmacology report shows that 23 overlapping targets were identified with Maslinic Acid. Followed by the binding scores were found to be similar to the reference standard Rosiglitazone & Pioglitazone. Maslinic Acid exerts its effect on insulin resistance via inhibition of peroxisome proliferator-activated receptor, α-amylase, and α-glucosidase inhibition, glycogen phosphorylase inhibition, reduction in ghrelin concentration, downregulation of SGLT1 and GLUT2 genes, NF-κB suppression, Nrf2 activation, and AMPK/SIRT 1 pathway activation. The Network analysis and docking score confirm the diabetic activity of Maslinic Acid. This study aims to study various targets of Maslinic Acid in correlation to Diabetes mellitus and analyze their mechanism in detail. Our investigation of MA as a potential treatment target for insulin resistance or diabetes mellitus using network pharmacology revealed that it has significant roles in producing glucose-lowering activity by regulating glucose homeostasis via several insulin signaling pathways discussed above.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"5 ","pages":"Article 100060"},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143146628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of natural compounds as novel FMS-like tyrosine kinase-3 (FLT3) therapeutic inhibitors for the treatment of acute myeloid leukemia: An in-silico approach

Aspects of molecular medicine

Pub Date : 2024-11-30 DOI: 10.1016/j.amolm.2024.100058

Uddalak Das , Lavanya Chandramouli , Akshay Uttarkar , Jitendra Kumar , Vidya Niranjan

FLT3 mutations, observed in approximately 30–35% of Acute Myeloid Leukemia (AML) cases, drive leukemic proliferation and survival pathways, presenting a significant challenge in clinical management. To address this therapeutic need, we employed a comprehensive computational approach integrating pharmacophore screening, molecular docking, ADMET analysis, and molecular dynamics simulations to identify potent inhibitors targeting FLT3. Utilizing ligand-based pharmacophore models generated from experimentally proven FLT3 inhibitors from BindingDB, we screened over 400,000 natural compounds from the COCONUT database. Hits identified through pharmacophore screening underwent further evaluation via Lipinski and Golden triangle criteria to ensure drug-like properties. Molecular docking against the FLT3 receptor, combined with ADMET analyses, facilitated the prioritization of lead compounds. Subsequently, three promising candidates were subjected to molecular dynamics simulations to assess binding stability. Our findings reveal three top-performing compounds, demonstrating robust and stable binding affinity and favorable ADMET characteristics. These compounds hold promise as potential scaffolds or leads for developing novel FLT3 inhibitors in AML therapy.

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引用次数: 0

BCL-2 and BAX expression and germ cell apoptosis following the intervention of 1-isothiocyanato-4-methylsulfinylbutane in cisplatin-induced testicular toxicity and sperm DNA fragmentation in Sprague-Dawley rat 1-isothiocyanato-4-methylsulfinylbutane 干预顺铂诱导的 Sprague-Dawley 大鼠睾丸毒性和精子 DNA 断裂后的 BCL-2 和 BAX 表达及生殖细胞凋亡

Aspects of molecular medicine

Pub Date : 2024-10-16 DOI: 10.1016/j.amolm.2024.100055

Sunday Aderemi Adelakun , Olalekan Wasiu Akintunde , Babatunde Ogunlade , Akwu Bala Peter , Jacob Adewale Siyanbade

Cisplatin (CP) has been used in clinical oncology but causes spermatogenesis damage. Isothiocyanato-4-methylsulfonylbutane (SFN) is a potent dietary bioactive agent that has been extensively studied for its effects on disease prevention. This study focused on the intervention of SFN on Germ cell apoptosis in CP-induced testicular toxicity and sperm DNA fragmentation (SDF). A total of ninety (90) male and ninety (90) female rats (weighing, 150–200 g, 12–14 weeks old) were assigned randomly into nine groups of ten (n = 10) rats each. Group A received normal saline, group B received a single dose of 10 mg/kg CP (i.p.), group C received 50 mg/kg bwt of SFN, group D received 100 mg/kg bwt of SFN, group E received 10 mg/kg bwt CP and 50 mg/kg bwt of SFN, group F received 10 mg/kg bwt CP and 100 mg/kg bwt of SFN, group G received 10 mg/kg bwt CP and 50 mg/kg bwt vitamin C, group H received 50 mg/kg bwt of SFN and 10 mg/kg bwt CP, Group I received 100 mg/kg bwt of SFN and 10 mg/kg bwt CP. The procedure lasted for 56 days. At the end of each treatment, the 90 male rats were introduced to the 90 female rats on the proestrus at a ratio of 1:1 for fertility tests. Testicular histopathological, apoptotic marker, immunoreactivity, sperm parameters, and SDF were investigated.

Cisplatin significantly decreases chromatin condensation/de-condensation levels, haploid germ cells, the number of fetuses, and BCL-2 expression. Also, CP increases SDF and BAX expression relative to control. Treatment with SFN increased BCL-2 expression, haploid germ cells, protected sperm chromatin condensation, improved microarchitecture of testes, and decreased SDF and BAX expression.

Therefore, SFN protects against CP-induced apoptosis by controlling BCL-2 and BAX expression and ameliorates SDF.

顺铂（CP）已被用于临床肿瘤学，但会对精子发生造成损害。异硫氰基-4-甲基磺酰基丁烷（SFN）是一种有效的膳食生物活性剂，其预防疾病的作用已被广泛研究。本研究的重点是 SFN 对 CP 诱导的睾丸毒性和精子 DNA 断裂（SDF）中生殖细胞凋亡的干预。将九十（90）只雄性大鼠和九十（90）只雌性大鼠（体重 150-200 克，12-14 周大）随机分为九组，每组十只（n = 10）。A 组接受生理盐水，B 组接受单剂量 10 毫克/千克 CP（i.p.体重），C 组接受 50 毫克/公斤体重的 SFN，D 组接受 100 毫克/公斤体重的 SFN，E 组接受 10 毫克/公斤体重的 CP 和 50 毫克/公斤体重的 SFN，F 组接受 10 毫克/公斤体重的 CP 和 100 毫克/公斤体重的 SFN、G 组接受 10 毫克/千克体重的氯化石蜡和 50 毫克/千克体重的维生素 C，H 组接受 50 毫克/千克体重的 SFN 和 10 毫克/千克体重的氯化石蜡，I 组接受 100 毫克/千克体重的 SFN 和 10 毫克/千克体重的氯化石蜡。该过程持续了 56 天。每次治疗结束后，将 90 只雄性大鼠与 90 只处于发情期的雌性大鼠按 1:1 的比例进行繁殖力测试。顺铂能显著降低染色质凝集/解凝水平、单倍体生殖细胞、胎儿数量和BCL-2的表达。与对照组相比，顺铂还能增加 SDF 和 BAX 的表达。因此，SFN可通过控制BCL-2和BAX的表达以及改善SDF来防止CP诱导的细胞凋亡。

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引用次数: 0

The role of gut microbiota, immune system, and autophagy in the pathogenesis of inflammatory bowel disease: Molecular mechanisms and therapeutic approaches 肠道微生物群、免疫系统和自噬在炎症性肠病发病机制中的作用：分子机制和治疗方法

Aspects of molecular medicine

Pub Date : 2024-10-16 DOI: 10.1016/j.amolm.2024.100056

Beatrice Garavaglia , Letizia Vallino , Angela Amoruso , Marco Pane , Alessandra Ferraresi , Ciro Isidoro

The crosstalk between gut microbiota, intestinal epithelial cells, and innate and adaptive immune system governs the maintenance of the intestinal homeostasis. Any interference in this tight dialogue and in the processes preserving cellular homeostasis (e.g., autophagy) may dysregulate the immune response and impair the clearance of harmful bacteria favoring the dysbiotic alteration of the microbial flora that leads to chronic inflammation. Gut dysbiosis is strongly associated with gastrointestinal inflammatory disorders, among them the inflammatory bowel disease (IBD). This review discusses the current knowledge on IBD, from the genetic background of high-risk patients to the molecular mechanisms underlying the disease, the contribution of the microbial flora, and the role of autophagy in intestinal epithelia homeostasis. Further, we illustrate the state of art regarding the targeted-nutritional approaches aimed to restore the beneficial crosstalk between an “anti-inflammatory” microbiota and the host. Analysis of the molecular pathogenesis of IBD will help identify genetic and diet-associated risk factors and thus suggest personalized strategies to prevent and manage the disease to improve quality of life with long-term maintenance of the remission phase.

肠道微生物群、肠道上皮细胞、先天性免疫系统和适应性免疫系统之间的相互协作决定着肠道平衡的维持。对这种紧密对话和维持细胞平衡过程（如自噬）的任何干扰都可能导致免疫反应失调，影响有害细菌的清除，从而导致微生物菌群失调，引发慢性炎症。肠道菌群失调与胃肠道炎症性疾病密切相关，其中包括炎症性肠病（IBD）。本综述讨论了有关 IBD 的现有知识，从高危患者的遗传背景到该疾病的分子机制、微生物菌群的贡献以及自噬在肠上皮稳态中的作用。此外，我们还说明了旨在恢复 "抗炎 "微生物群与宿主之间有益串联的靶向营养方法的最新进展。对 IBD 分子发病机制的分析将有助于确定遗传和饮食相关的风险因素，从而提出预防和控制疾病的个性化策略，在长期维持缓解阶段的情况下提高生活质量。

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引用次数: 0