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Biomolecules, Volume 14, Issue 6 (June 2024) – 113 articles

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25 pages, 501 KiB  
Review
The Role of Zinc in Developed Countries in Pediatric Patients: A 360-Degree View
by Flavia Padoan, Elena Piccoli, Angelo Pietrobelli, Luis A. Moreno, Giorgio Piacentini and Luca Pecoraro
Biomolecules 2024, 14(6), 718; https://doi.org/10.3390/biom14060718 - 17 Jun 2024
Abstract
Zinc is an important trace element for growth and health at pediatric ages. Zinc is fundamental in inflammatory pathways, oxidative balance, and immune function. Zinc exhibits anti-inflammatory properties by modulating Nuclear Factor-kappa (NF-κB) activity and reducing histamine release from basophils, leukocytes, and mast [...] Read more.
Zinc is an important trace element for growth and health at pediatric ages. Zinc is fundamental in inflammatory pathways, oxidative balance, and immune function. Zinc exhibits anti-inflammatory properties by modulating Nuclear Factor-kappa (NF-κB) activity and reducing histamine release from basophils, leukocytes, and mast cells. Furthermore, its antioxidant activity protects against oxidative damage and chronic diseases. Finally, zinc improves the ability to trigger effective immune responses against pathogens by contributing to the maturation of lymphocytes, the production of cytokines, and the regulation of apoptosis. Given these properties, zinc can be considered an adjunctive therapy in treating and preventing respiratory, nephrological, and gastrointestinal diseases, both acute and chronic. This review aims to deepen the role and metabolism of zinc, focusing on the role of supplementation in developed countries in pediatric diseases. Full article
(This article belongs to the Special Issue Zinc in Health and Disease Conditions II)
13 pages, 816 KiB  
Article
The Role of Intestinal Cytochrome P450s in Vitamin D Metabolism
by Minori Uga, Ichiro Kaneko, Yuji Shiozaki, Megumi Koike, Naoko Tsugawa, Peter W. Jurutka, Ken-Ichi Miyamoto and Hiroko Segawa
Biomolecules 2024, 14(6), 717; https://doi.org/10.3390/biom14060717 - 17 Jun 2024
Abstract
Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. [...] Read more.
Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys. Interestingly, a recently identified mutation in another CYP enzyme, CYP3A4 (gain-of-function), caused type III vitamin D-dependent rickets. CYP3A are also expressed in the intestine, but their hydroxylation activities towards vitamin D substrates are unknown. We evaluated CYP3A or CYP24A1 activities on vitamin D action in cultured cells. In addition, we examined the expression level and regulation of CYP enzymes in intestines from mice. The expression of CYP3A or CYP24A1 significantly reduced 1,25(OH)2D3-VDRE activity. Moreover, in mice, Cyp24a1 mRNA was significantly induced by 1,25(OH)2D3 in the intestine, but a mature form (approximately 55 kDa protein) was also expressed in mitochondria and induced by 1,25(OH)2D3, and this mitochondrial enzyme appears to hydroxylate 25OHD3 to 24,25(OH)2D3. Thus, CYP3A or CYP24A1 could locally attenuate 25OHD3 or 1,25(OH)2D3 action, and we suggest the small intestine is both a vitamin D target tissue, as well as a newly recognized vitamin D-metabolizing tissue. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog II)
14 pages, 16651 KiB  
Article
Accurate Early Detection and EGFR Mutation Status Prediction of Lung Cancer Using Plasma cfDNA Coverage Patterns: A Proof-of-Concept Study
by Zhixin Bie, Yi Ping, Xiaoguang Li, Xun Lan and Lihui Wang
Biomolecules 2024, 14(6), 716; https://doi.org/10.3390/biom14060716 - 17 Jun 2024
Abstract
Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer detection and monitoring, utilizing various features of circulating cell-free DNA (cfDNA). In this study, we established two [...] Read more.
Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer detection and monitoring, utilizing various features of circulating cell-free DNA (cfDNA). In this study, we established two models based on cfDNA coverage patterns at the transcription start sites (TSSs) from 6X whole-genome sequencing: an Early Cancer Screening Model and an EGFR mutation status prediction model. The Early Cancer Screening Model showed encouraging prediction ability, especially for early-stage lung cancer. The EGFR mutation status prediction model exhibited high accuracy in distinguishing between EGFR-positive and wild-type cases. Additionally, cfDNA coverage patterns at TSSs also reflect gene expression patterns at the pathway level in lung cancer patients. These findings demonstrate the potential applications of cfDNA coverage patterns at TSSs in early cancer screening and in cancer subtyping. Full article
(This article belongs to the Special Issue Recent Developments in the Biology of Extracellular or Cell-Free DNA)
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15 pages, 4319 KiB  
Article
Functional Validation of the Cytochrome P450 Family PgCYP309 Gene in Panax ginseng
by Yang Jiang, Gaohui He, Ruiqi Li, Kangyu Wang, Yi Wang, Mingzhu Zhao and Meiping Zhang
Biomolecules 2024, 14(6), 715; https://doi.org/10.3390/biom14060715 - 17 Jun 2024
Abstract
Ginseng (Panax ginseng C. A. Meyer) is an ancient and valuable Chinese herbal medicine, and ginsenoside, as the main active ingredient of ginseng, has received wide attention because of its various pharmacological active effects. Cytochrome P450 is the largest family of enzymes [...] Read more.
Ginseng (Panax ginseng C. A. Meyer) is an ancient and valuable Chinese herbal medicine, and ginsenoside, as the main active ingredient of ginseng, has received wide attention because of its various pharmacological active effects. Cytochrome P450 is the largest family of enzymes in plant metabolism and is involved in the biosynthesis of terpenoids, alkaloids, lipids, and other primary and secondary plant metabolites. It is significant to explore more PgCYP450 genes with unknown functions and reveal their roles in ginsenoside synthesis. In this study, based on the five PgCYP450 genes screened in the pre-laboratory, through the correlation analysis with the content of ginsenosides and the analysis of the interactions network of the key enzyme genes for ginsenoside synthesis, we screened out those highly correlated with ginsenosides, PgCYP309, as the target gene from among the five PgCYP450 genes. Methyl jasmonate-induced treatment of ginseng adventitious roots showed that the PgCYP309 gene responded to methyl jasmonate induction and was involved in the synthesis of ginsenosides. The PgCYP309 gene was cloned and the overexpression vector pBI121-PgCYP309 and the interference vector pART27-PgCYP309 were constructed. Transformation of ginseng adventitious roots by the Agrobacterium fermentum-mediated method and successful induction of transgenic ginseng hairy roots were achieved. The transformation rate of ginseng hairy roots with overexpression of the PgCYP309 gene was 22.7%, and the transformation rate of ginseng hairy roots with interference of the PgCYP309 gene was 40%. Analysis of ginseng saponin content and relative gene expression levels in positive ginseng hairy root asexual lines revealed a significant increase in PPD, PPT, and PPT-type monomeric saponins Re and Rg2. The relative expression levels of PgCYP309 and PgCYP716A53v2 genes were also significantly increased. PgCYP309 gene promotes the synthesis of ginsenosides, and it was preliminarily verified that PgCYP309 gene can promote the synthesis of dammarane-type ginsenosides. Full article
(This article belongs to the Section Molecular Biology)
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23 pages, 3471 KiB  
Review
Advances in Platelet-Dysfunction Diagnostic Technologies
by Inkwon Yoon, Jong Hyeok Han and Hee-Jae Jeon
Biomolecules 2024, 14(6), 714; https://doi.org/10.3390/biom14060714 - 17 Jun 2024
Viewed by 114
Abstract
The crucial role of platelets in hemostasis and their broad implications under various physiological conditions underscore the importance of accurate platelet-function testing. Platelets are key to clotting blood and healing wounds. Therefore, accurate diagnosis and management of platelet disorders are vital for patient [...] Read more.
The crucial role of platelets in hemostasis and their broad implications under various physiological conditions underscore the importance of accurate platelet-function testing. Platelets are key to clotting blood and healing wounds. Therefore, accurate diagnosis and management of platelet disorders are vital for patient care. This review outlines the significant advancements in platelet-function testing technologies, focusing on their working principles and the shift from traditional diagnostic methods to more innovative approaches. These improvements have deepened our understanding of platelet-related disorders and ushered in personalized treatment options. Despite challenges such as interpretation of complex data and the costs of new technologies, the potential for artificial-intelligence integration and the creation of wearable monitoring devices offers exciting future possibilities. This review underscores how these technological advances have enhanced the landscape of precision medicine and provided better diagnostic and treatment options for platelet-function disorders. Full article
(This article belongs to the Special Issue New Discoveries in Biological Functions of Platelet)
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15 pages, 3824 KiB  
Article
The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors
by Kuo-Hao Lee, Gisela Andrea Camacho-Hernandez, Amy Hauck Newman and Lei Shi
Biomolecules 2024, 14(6), 713; https://doi.org/10.3390/biom14060713 - 17 Jun 2024
Viewed by 115
Abstract
Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is [...] Read more.
Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT. Full article
(This article belongs to the Collection Molecular Biology: Feature Papers)
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13 pages, 2925 KiB  
Article
De Novo Synthesis of Resveratrol from Sucrose by Metabolically Engineered Yarrowia lipolytica
by Gehad G. Ibrahim, Madhavi Perera, Saadiah A. Abdulmalek, Jinyong Yan and Yunjun Yan
Biomolecules 2024, 14(6), 712; https://doi.org/10.3390/biom14060712 - 16 Jun 2024
Viewed by 241
Abstract
Resveratrol, a phenylpropanoid compound, exhibits diverse pharmacological properties, making it a valuable candidate for health and disease management. However, the demand for resveratrol exceeds the capacity of plant extraction methods, necessitating alternative production strategies. Microbial synthesis offers several advantages over plant-based approaches and [...] Read more.
Resveratrol, a phenylpropanoid compound, exhibits diverse pharmacological properties, making it a valuable candidate for health and disease management. However, the demand for resveratrol exceeds the capacity of plant extraction methods, necessitating alternative production strategies. Microbial synthesis offers several advantages over plant-based approaches and presents a promising alternative. Yarrowia lipolytica stands out among microbial hosts due to its safe nature, abundant acetyl-CoA and malonyl-CoA availability, and robust pentose phosphate pathway. This study aimed to engineer Y. lipolytica for resveratrol production. The resveratrol biosynthetic pathway was integrated into Y. lipolytica by adding genes encoding tyrosine ammonia lyase from Rhodotorula glutinis, 4-coumarate CoA ligase from Nicotiana tabacum, and stilbene synthase from Vitis vinifera. This resulted in the production of 14.3 mg/L resveratrol. A combination of endogenous and exogenous malonyl-CoA biosynthetic modules was introduced to enhance malonyl-CoA availability. This included genes encoding acetyl-CoA carboxylase 2 from Arabidopsis thaliana, malonyl-CoA synthase, and a malonate transporter protein from Bradyrhizobium diazoefficiens. These strategies increased resveratrol production to 51.8 mg/L. The further optimization of fermentation conditions and the utilization of sucrose as an effective carbon source in YP media enhanced the resveratrol concentration to 141 mg/L in flask fermentation. By combining these strategies, we achieved a titer of 400 mg/L resveratrol in a controlled fed-batch bioreactor. These findings demonstrate the efficacy of Y. lipolytica as a platform for the de novo production of resveratrol and highlight the importance of metabolic engineering, enhancing malonyl-CoA availability, and media optimization for improved resveratrol production. Full article
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24 pages, 5396 KiB  
Article
Insights into the Effects of Ligand Binding on Leucyl-tRNA Synthetase Inhibitors for Tuberculosis: In Silico Analysis and Isothermal Titration Calorimetry Validation
by Zia Ur Rehman, Asim Najmi and Khalid Zoghebi
Biomolecules 2024, 14(6), 711; https://doi.org/10.3390/biom14060711 - 16 Jun 2024
Viewed by 302
Abstract
Incidences of drug-resistant tuberculosis have become common and are rising at an alarming rate. Aminoacyl t-RNA synthetase has been validated as a newer target against Mycobacterium tuberculosis. Leucyl t-RNA synthetase (LeuRS) is ubiquitously found in all organisms and regulates transcription, protein synthesis, [...] Read more.
Incidences of drug-resistant tuberculosis have become common and are rising at an alarming rate. Aminoacyl t-RNA synthetase has been validated as a newer target against Mycobacterium tuberculosis. Leucyl t-RNA synthetase (LeuRS) is ubiquitously found in all organisms and regulates transcription, protein synthesis, mitochondrial RNA cleavage, and proofreading of matured t-RNA. Leucyl t-RNA synthetase promotes growth and development and is the key enzyme needed for biofilm formation in Mycobacterium. Inhibition of this enzyme could restrict the growth and development of the mycobacterial population. A database consisting of 2734 drug-like molecules was screened against leucyl t-RNA synthetase enzymes through virtual screening. Based on the docking scores and MMGBSA energy values, the top three compounds were selected for molecular dynamics simulation. The druggable nature of the top three hits was confirmed by predicting their pharmacokinetic parameters. The top three hits—compounds 1035 (ZINC000001543916), 1054 (ZINC000001554197), and 2077 (ZINC000008214483)—were evaluated for their binding affinity toward leucyl t-RNA synthetase by an isothermal titration calorimetry study. The inhibitory activity of these compounds was tested against antimycobacterial activity, biofilm formation, and LeuRS gene expression potential. Compound 1054 (Macimorelin) was found to be the most potent molecule, with better antimycobacterial activity, enzyme binding affinity, and significant inhibition of biofilm formation, as well as inhibition of the LeuRS gene expression. Compound 1054, the top hit compound, has the potential to be used as a lead to develop successful leucyl t-RNA synthetase inhibitors. Full article
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18 pages, 2574 KiB  
Article
Aromatic Characterisation of Moscato Giallo by GC-MS/MS and Validation of Stable Isotopic Ratio Analysis of the Major Volatile Compounds
by Mauro Paolini, Alberto Roncone, Lorenzo Cucinotta, Danilo Sciarrone, Luigi Mondello, Federica Camin, Sergio Moser, Roberto Larcher and Luana Bontempo
Biomolecules 2024, 14(6), 710; https://doi.org/10.3390/biom14060710 - 16 Jun 2024
Viewed by 346
Abstract
Among the Moscato grapes, Moscato Giallo is a winegrape variety characterised by a high content of free and glycosylated monoterpenoids, which gives wines very intense notes of ripe fruit and flowers. The aromatic bouquet of Moscato Giallo is strongly influenced by the high [...] Read more.
Among the Moscato grapes, Moscato Giallo is a winegrape variety characterised by a high content of free and glycosylated monoterpenoids, which gives wines very intense notes of ripe fruit and flowers. The aromatic bouquet of Moscato Giallo is strongly influenced by the high concentration of linalool, geraniol, linalool oxides, limonene, α-terpineol, citronellol, hotrienol, diendiols, trans/cis-8-hydroxy linalool, geranic acid and myrcene, that give citrus, rose, and peach notes. Except for quali-quantitative analysis, no investigations regarding the isotopic values of the target volatile compounds in grapes and wines are documented in the literature. Nevertheless, the analysis of the stable isotope ratio represents a modern and powerful tool used by the laboratories responsible for official consumer protection, for food quality and genuineness assessment. To this aim, the aromatic compounds extracted from grapes and wine were analysed both by GC-MS/MS, to define the aroma profiles, and by GC-C/Py-IRMS, for a preliminary isotope compound-specific investigation. Seventeen samples of Moscato Giallo grapes were collected during the harvest season in 2021 from two Italian regions renowned for the cultivation of this aromatic variety, Trentino Alto Adige and Veneto, and the corresponding wines were produced at micro-winery scale. The GC-MS/MS analysis confirmed the presence of the typical terpenoids both in glycosylated and free forms, responsible for the characteristic aroma of the Moscato Giallo variety, while the compound-specific isotope ratio analysis allowed us to determine the carbon (δ13C) and hydrogen (δ2H) isotopic signatures of the major volatile compounds for the first time. Full article
(This article belongs to the Special Issue 2nd Edition: Biochemistry of Wine and Beer)
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12 pages, 2032 KiB  
Article
Myogenic Anti-Nucleolin Aptamer iSN04 Inhibits Proliferation and Promotes Differentiation of Vascular Smooth Muscle Cells
by Mana Miyoshi, Takeshi Shimosato and Tomohide Takaya
Biomolecules 2024, 14(6), 709; https://doi.org/10.3390/biom14060709 - 15 Jun 2024
Viewed by 263
Abstract
De-differentiation and subsequent increased proliferation and inflammation of vascular smooth muscle cells (VSMCs) is one of the mechanisms of atherogenesis. Maintaining VSMCs in a contractile differentiated state is therefore a promising therapeutic strategy for atherosclerosis. We have reported the 18-base myogenetic oligodeoxynucleotide, iSN04, [...] Read more.
De-differentiation and subsequent increased proliferation and inflammation of vascular smooth muscle cells (VSMCs) is one of the mechanisms of atherogenesis. Maintaining VSMCs in a contractile differentiated state is therefore a promising therapeutic strategy for atherosclerosis. We have reported the 18-base myogenetic oligodeoxynucleotide, iSN04, which serves as an anti-nucleolin aptamer and promotes skeletal and myocardial differentiation. The present study investigated the effect of iSN04 on VSMCs because nucleolin has been reported to contribute to VSMC de-differentiation under pathophysiological conditions. Nucleolin is localized in the nucleoplasm and nucleoli of both rat and human VSMCs. iSN04 without a carrier was spontaneously incorporated into VSMCs, indicating that iSN04 would serve as an anti-nucleolin aptamer. iSN04 treatment decreased the ratio of 5-ethynyl-2′-deoxyuridine (EdU)-positive proliferating VSMCs and increased the expression of α-smooth muscle actin, a contractile marker of VSMCs. iSN04 also suppressed angiogenesis of mouse aortic rings ex vivo, which is a model of pathological angiogenesis involved in plaque formation, growth, and rupture. These results demonstrate that antagonizing nucleolin with iSN04 preserves VSMC differentiation, providing a nucleic acid drug candidate for the treatment of vascular disease. Full article
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17 pages, 7664 KiB  
Opinion
Can We Explain Thousands of Molecularly Identified Mouse Neuronal Types? From Knowing to Understanding
by Luis Puelles and Rudolf Nieuwenhuys
Biomolecules 2024, 14(6), 708; https://doi.org/10.3390/biom14060708 - 15 Jun 2024
Viewed by 285
Abstract
At the end of 2023, the Whole Mouse Brain Atlas was announced, revealing that there are about 5300 molecularly defined neuronal types in the mouse brain. We ask whether brain models exist that contemplate how this is possible. The conventional columnar model, implicitly [...] Read more.
At the end of 2023, the Whole Mouse Brain Atlas was announced, revealing that there are about 5300 molecularly defined neuronal types in the mouse brain. We ask whether brain models exist that contemplate how this is possible. The conventional columnar model, implicitly used by the authors of the Atlas, is incapable of doing so with only 20 brain columns (5 brain vesicles with 4 columns each). We argue that the definition of some 1250 distinct progenitor microzones, each producing at least 4–5 neuronal types over time, may be sufficient. Presently, this is nearly achieved by the prosomeric model amplified by the secondary dorsoventral and anteroposterior microzonation of progenitor areas, plus the clonal variation in cell types produced, on average, by each of them. Full article
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18 pages, 2068 KiB  
Article
Rapid Movement of Palmitoleic Acid from Phosphatidylcholine to Phosphatidylinositol in Activated Human Monocytes
by Miguel A. Bermúdez, Alvaro Garrido, Laura Pereira, Teresa Garrido, María A. Balboa and Jesús Balsinde
Biomolecules 2024, 14(6), 707; https://doi.org/10.3390/biom14060707 - 15 Jun 2024
Viewed by 174
Abstract
This work describes a novel route for phospholipid fatty acid remodeling involving the monounsaturated fatty acid palmitoleic acid. When administered to human monocytes, palmitoleic acid rapidly incorporates into membrane phospholipids, notably into phosphatidylcholine (PC). In resting cells, palmitoleic acid remains within the phospholipid [...] Read more.
This work describes a novel route for phospholipid fatty acid remodeling involving the monounsaturated fatty acid palmitoleic acid. When administered to human monocytes, palmitoleic acid rapidly incorporates into membrane phospholipids, notably into phosphatidylcholine (PC). In resting cells, palmitoleic acid remains within the phospholipid pools where it was initially incorporated, showing no further movement. However, stimulation of the human monocytes with either receptor-directed (opsonized zymosan) or soluble (calcium ionophore A23187) agonists results in the rapid transfer of palmitoleic acid moieties from PC to phosphatidylinositol (PI). This is due to the activation of a coenzyme A-dependent remodeling route involving two different phospholipase A2 enzymes that act on different substrates to generate free palmitoleic acid and lysoPI acceptors. The stimulated enrichment of specific PI molecular species with palmitoleic acid unveils a hitherto-unrecognized pathway for lipid turnover in human monocytes which may play a role in regulating lipid signaling during innate immune activation. Full article
(This article belongs to the Collection Feature Papers in Biomacromolecules: Lipids)
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14 pages, 2784 KiB  
Article
2α-Substituted Vitamin D Derivatives Effectively Enhance the Osteoblast Differentiation of Dedifferentiated Fat Cells
by Michiyasu Ishizawa, Masashi Takano, Atsushi Kittaka, Taro Matsumoto and Makoto Makishima
Biomolecules 2024, 14(6), 706; https://doi.org/10.3390/biom14060706 - 15 Jun 2024
Viewed by 199
Abstract
The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a principal regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). Previous studies have shown that 2α-(3-hydroxypropyl)-1,25D3 (O1C3) and 2α-(3-hydroxypropoxy)-1,25D3 (O2C3), [...] Read more.
The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a principal regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). Previous studies have shown that 2α-(3-hydroxypropyl)-1,25D3 (O1C3) and 2α-(3-hydroxypropoxy)-1,25D3 (O2C3), vitamin D derivatives resistant to inactivation enzymes, can activate VDR, induce leukemic cell differentiation, and increase blood calcium levels in rats more effectively than 1,25(OH)2D3. In this study, to further investigate the usefulness of 2α-substituted vitamin D derivatives, we examined the effects of O2C3, O1C3, and their derivatives on VDR activity in cells and mouse tissues and on osteoblast differentiation of dedifferentiated fat (DFAT) cells, a cell type with potential therapeutic application in regenerative medicine. In cell culture experiments using kidney-derived HEK293 cells, intestinal mucosa-derived CaCO2 cells, and osteoblast-derived MG63 cells, and in mouse experiments, O2C2, O2C3, O1C3, and O1C4 had a weaker effect than or equivalent effect to 1,25(OH)2D3 in VDR transactivation and induction of the VDR target gene CYP24A1, but they enhanced osteoblast differentiation in DFAT cells equally to or more effectively than 1,25(OH)2D3. In long-term treatment with the compound without the medium change (7 days), the derivatives enhanced osteoblast differentiation more effectively than 1,25(OH)2D3. O2C3 and O1C3 were more stable than 1,25(OH)2D3 in DFAT cell culture. These results indicate that 2α-substituted vitamin D derivatives, such as inactivation-resistant O2C3 and O1C3, are more effective than 1,25(OH)2D3 in osteoblast differentiation of DFAT cells, suggesting potential roles in regenerative medicine with DFAT cells and other multipotent cells. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog II)
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20 pages, 4271 KiB  
Article
3,5-DCQA as a Major Molecule in MeJA-Treated Dendropanax morbifera Adventitious Root to Promote Anti-Lung Cancer and Anti-Inflammatory Activities
by Fengjiao Xu, Anjali Kariyarath Valappil, Shaojian Zheng, Bingsong Zheng, Deokchun Yang and Qiang Wang
Biomolecules 2024, 14(6), 705; https://doi.org/10.3390/biom14060705 - 15 Jun 2024
Viewed by 285
Abstract
(1) Background: Phytochemicals are crucial antioxidants that play a significant role in preventing cancer. (2) Methods: We explored the use of methyl jasmonate (MeJA) in the in vitro cultivation of D. morbifera adventitious roots (DMAR) and evaluated its impact on secondary metabolite production [...] Read more.
(1) Background: Phytochemicals are crucial antioxidants that play a significant role in preventing cancer. (2) Methods: We explored the use of methyl jasmonate (MeJA) in the in vitro cultivation of D. morbifera adventitious roots (DMAR) and evaluated its impact on secondary metabolite production in DMAR, optimizing concentration and exposure time for cost-effectiveness. We also assessed its anti-inflammatory and anti-lung cancer activities and related gene expression levels. (3) Results: MeJA treatment significantly increased the production of the phenolic compound 3,5-Di-caffeoylquinic acid (3,5-DCQA). The maximum 3,5-DCQA production was achieved with a MeJA treatment at 40 µM for 36 h. MeJA-DMARE displayed exceptional anti-inflammatory activity by inhibiting the production of nitric oxide (NO) and reactive oxygen species (ROS) in LPS-induced RAW 264.7 cells. Moreover, it downregulated the mRNA expression of key inflammation-related cytokines. Additionally, MeJA-DMARE exhibited anti-lung cancer activity by promoting ROS production in A549 lung cancer cells and inhibiting its migration. It also modulated apoptosis in lung cancer cells via the Bcl-2 and p38 MAPK pathways. (4) Conclusions: MeJA-treated DMARE with increased 3,5-DCQA production holds significant promise as a sustainable and novel material for pharmaceutical applications thanks to its potent antioxidant, anti-inflammatory, and anti-lung cancer properties. Full article
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14 pages, 704 KiB  
Article
Lack of Mitochondrial DNA Provides Metabolic Advantage in Yeast Osmoadaptation
by Maria Antonietta Di Noia, Ohiemi Benjamin Ocheja, Pasquale Scarcia, Isabella Pisano, Eugenia Messina, Gennaro Agrimi, Luigi Palmieri and Nicoletta Guaragnella
Biomolecules 2024, 14(6), 704; https://doi.org/10.3390/biom14060704 - 14 Jun 2024
Viewed by 117
Abstract
Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and tumorigenesis. However, adaptation to mitochondrial dysfunction can occur through the activation of survival pathways, whose mechanisms are still poorly understood. The yeast [...] Read more.
Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and tumorigenesis. However, adaptation to mitochondrial dysfunction can occur through the activation of survival pathways, whose mechanisms are still poorly understood. The yeast Saccharomyces cerevisiae is an invaluable model organism for studying how mitochondrial dysfunction can affect stress response and adaptation processes. In this study, we analyzed and compared in the absence and in the presence of osmostress wild-type cells with two models of cells lacking mitochondrial DNA: ethidium bromide-treated cells (ρ0) and cells lacking the mitochondrial pyrimidine nucleotide transporter RIM2 (ΔRIM2). Our results revealed that the lack of mitochondrial DNA provides an advantage in the kinetics of stress response. Additionally, wild-type cells exhibited higher osmosensitivity in the presence of respiratory metabolism. Mitochondrial mutants showed increased glycerol levels, required in the short-term response of yeast osmoadaptation, and prolonged oxidative stress. The involvement of the mitochondrial retrograde signaling in osmoadaptation has been previously demonstrated. The expression of CIT2, encoding the peroxisomal isoform of citrate synthase and whose up-regulation is prototypical of RTG pathway activation, appeared to be increased in the mutants. Interestingly, selected TCA cycle genes, CIT1 and ACO1, whose expression depends on RTG signaling upon stress, showed a different regulation in ρ0 and ΔRIM2 cells. These data suggest that osmoadaptation can occur through different mechanisms in the presence of mitochondrial defects and will allow us to gain insight into the relationships among metabolism, mitochondria-mediated stress response, and cell adaptation. Full article
15 pages, 988 KiB  
Article
When Chromatin Decondensation Affects Nuclear γH2AX Foci Pattern and Kinetics and Biases the Assessment of DNA Double-Strand Breaks by Immunofluorescence
by Adeline Granzotto, Laura El Nachef, Juliette Restier-Verlet, Laurène Sonzogni, Joëlle Al-Choboq, Michel Bourguignon and Nicolas Foray
Biomolecules 2024, 14(6), 703; https://doi.org/10.3390/biom14060703 - 14 Jun 2024
Viewed by 158
Abstract
Immunofluorescence with antibodies against phosphorylated forms of H2AX (γH2AX) is revolutionizing our understanding of repair and signaling of DNA double-strand breaks (DSBs). Unfortunately, the pattern of γH2AX foci depends upon a number of parameters (nature of stress, number of foci, radiation dose, repair [...] Read more.
Immunofluorescence with antibodies against phosphorylated forms of H2AX (γH2AX) is revolutionizing our understanding of repair and signaling of DNA double-strand breaks (DSBs). Unfortunately, the pattern of γH2AX foci depends upon a number of parameters (nature of stress, number of foci, radiation dose, repair time, cell cycle phase, gene mutations, etc…) whose one of the common points is chromatin condensation/decondensation. Here, we endeavored to demonstrate how chromatin conformation affects γH2AX foci pattern and influences immunofluorescence signal. DSBs induced in non-transformed human fibroblasts were analyzed by γH2AX immunofluorescence with sodium butyrate treatment of chromatin applied after the irradiation that decondenses chromatin but does not induce DNA breaks. Our data showed that the pattern of γH2AX foci may drastically change with the experimental protocols in terms of size and brightness. Notably, some γH2AX minifoci resulting from the dispersion of the main signal due to chromatin decondensation may bias the quantification of the number of DSBs. We proposed a model called “Christmas light models” to tentatively explain this diversity of γH2AX foci pattern that may also be considered for any DNA damage marker that relocalizes as nuclear foci. Full article
(This article belongs to the Section Molecular Biophysics)
14 pages, 580 KiB  
Systematic Review
Clinical Insights in RNA-Binding Protein Motif 20 Cardiomyopathy: A Systematic Review
by Marika Martini, Maria Bueno Marinas, Ilaria Rigato, Kalliopi Pilichou and Barbara Bauce
Biomolecules 2024, 14(6), 702; https://doi.org/10.3390/biom14060702 - 14 Jun 2024
Viewed by 159
Abstract
Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and heart transplantation (HTx), with genetic factors playing a significant role. In recent years, the RNA-binding protein motif 20 (RBM20), which affects the gene splicing of various proteins with different [...] Read more.
Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and heart transplantation (HTx), with genetic factors playing a significant role. In recent years, the RNA-binding protein motif 20 (RBM20), which affects the gene splicing of various proteins with different cellular functions, was identified as the first DCM gene with regulatory properties. Variants of RBM20 have been associated with severe forms of DCM. The aim of this critical systematic review was to analyse RBM20 cardiomyopathy clinical features and outcomes. According to PRISMA guidelines, a search was run in the PubMed, Scopus and Web of Science electronic databases using the following keywords: “RBM20”; “cardiomyopathy”; “arrhythmias”; “heart failure”. A total of 181 records were screened, of which 27 studies were potentially relevant to the topic. Through the application of inclusion and exclusion criteria, eight papers reporting 398 patients with RBM20 pathogenic variants were analysed. The mean age at presentation was 41 years. Familiarity with cardiomyopathy was available in 59% of cases, with 55% of probands reporting a positive family history. Imaging data indicated a mild reduction of left ventricular ejection fraction (mean LVEF 40%), while tissue characterization was reported in 24.3% of cases, showing late gadolinium enhancement in 33% of patients. Composite outcomes of sustained monomorphic ventricular tachycardia or ventricular fibrillation occurred in 19.4% of patients, with 12% undergoing HTx. There were no gender differences in arrhythmic outcomes, while 96.4% of patients who underwent HTx were male. In conclusion, RBM20 cardiomyopathy exhibits a severe phenotypic expression, both in terms of arrhythmic burden and HF progression. Full article
(This article belongs to the Section Molecular Genetics)
15 pages, 379 KiB  
Review
Chemo-Enzymatic Generation of Highly Fluorescent Nucleoside Analogs Using Purine-Nucleoside Phosphorylase
by Alicja Stachelska-Wierzchowska and Jacek Wierzchowski
Biomolecules 2024, 14(6), 701; https://doi.org/10.3390/biom14060701 - 14 Jun 2024
Viewed by 231
Abstract
Chemo-enzymatic syntheses of strongly fluorescent nucleoside analogs, potentially applicable in analytical biochemistry and cell biology are reviewed. The syntheses and properties of fluorescent ribofuranosides of several purine, 8-azapurine, and etheno-purine derivatives, obtained using various types of purine nucleoside phosphorylase (PNP) as catalysts, as [...] Read more.
Chemo-enzymatic syntheses of strongly fluorescent nucleoside analogs, potentially applicable in analytical biochemistry and cell biology are reviewed. The syntheses and properties of fluorescent ribofuranosides of several purine, 8-azapurine, and etheno-purine derivatives, obtained using various types of purine nucleoside phosphorylase (PNP) as catalysts, as well as α-ribose-1-phosphate (r1P) as a second substrate, are described. In several instances, the ribosylation sites are different to the canonical purine N9. Some of the obtained ribosides show fluorescence yields close to 100%. Possible applications of the new analogs include assays of PNP, nucleoside hydrolases, and other enzyme activities both in vitro and within living cells using fluorescence microscopy. Full article
30 pages, 2551 KiB  
Review
Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy
by Zibing Qian, Wanyuan Xiong, Xiaorong Mao and Junfeng Li
Biomolecules 2024, 14(6), 700; https://doi.org/10.3390/biom14060700 - 14 Jun 2024
Viewed by 382
Abstract
Macrophages, as important immune cells of the organism, are involved in maintaining intrahepatic microenvironmental homeostasis and can undergo rapid phenotypic changes in the injured or recovering liver. In recent years, the crucial role of macrophage-programmed cell death in the development and regression of [...] Read more.
Macrophages, as important immune cells of the organism, are involved in maintaining intrahepatic microenvironmental homeostasis and can undergo rapid phenotypic changes in the injured or recovering liver. In recent years, the crucial role of macrophage-programmed cell death in the development and regression of liver diseases has become a research hotspot. Moreover, macrophage-targeted therapeutic strategies are emerging in both preclinical and clinical studies. Given the macrophages’ vital role in complex organismal environments, there is tremendous academic interest in developing novel therapeutic strategies that target these cells. This review provides an overview of the characteristics and interactions between macrophage polarization, programmed cell death, related biomarkers, and macrophage-targeted therapies. It aims to deepen the understanding of macrophage immunomodulation and molecular mechanisms and to provide a basis for the treatment of macrophage-associated liver diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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13 pages, 1846 KiB  
Article
Enhancing Selective Antimicrobial and Antibiofilm Activities of Melittin through 6-Aminohexanoic Acid Substitution
by Naveenkumar Radhakrishnan, Sukumar Dinesh Kumar, Song-Yub Shin and Sungtae Yang
Biomolecules 2024, 14(6), 699; https://doi.org/10.3390/biom14060699 - 14 Jun 2024
Viewed by 227
Abstract
Leucine residues are commonly found in the hydrophobic face of antimicrobial peptides (AMPs) and are crucial for membrane permeabilization, leading to the cell death of invading pathogens. Melittin, which contains four leucine residues, demonstrates broad-spectrum antimicrobial properties but also significant cytotoxicity against mammalian [...] Read more.
Leucine residues are commonly found in the hydrophobic face of antimicrobial peptides (AMPs) and are crucial for membrane permeabilization, leading to the cell death of invading pathogens. Melittin, which contains four leucine residues, demonstrates broad-spectrum antimicrobial properties but also significant cytotoxicity against mammalian cells. To enhance the cell selectivity of melittin, this study synthesized five analogs by replacing leucine with its structural isomer, 6-aminohexanoic acid. Among these analogs, Mel-LX3 exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Importantly, Mel-LX3 displayed significantly reduced hemolytic and cytotoxic effects compared to melittin. Mechanistic studies, including membrane depolarization, SYTOX green uptake, FACScan analysis, and inner/outer membrane permeation assays, demonstrated that Mel-LX3 effectively permeabilized bacterial membranes similar to melittin. Notably, Mel-LX3 showed robust antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Furthermore, Mel-LX3 effectively inhibited biofilm formation and eradicated existing biofilms of MDRPA. With its improved selective antimicrobial and antibiofilm activities, Mel-LX3 emerges as a promising candidate for the development of novel antimicrobial agents. We propose that the substitution of leucine with 6-aminohexanoic acid in AMPs represents a significant strategy for combating resistant bacteria. Full article
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10 pages, 3056 KiB  
Communication
Strain-Modulated Flexible Bio-Organic/Graphene/PET Sensors Based on DNA-Curcumin Biopolymer
by Siva Pratap Reddy Mallem, Peddathimula Puneetha, Dong Yeon Lee and Sung Jin An
Biomolecules 2024, 14(6), 698; https://doi.org/10.3390/biom14060698 - 14 Jun 2024
Viewed by 246
Abstract
In recent years, there has been growing interest in the development of metal-free, environmentally friendly, and cost-effective biopolymer-based piezoelectric strain sensors (bio-PSSs) for flexible applications. In this study, we have developed a bio-PSS based on pure deoxyribonucleic acid (DNA) and curcumin materials in [...] Read more.
In recent years, there has been growing interest in the development of metal-free, environmentally friendly, and cost-effective biopolymer-based piezoelectric strain sensors (bio-PSSs) for flexible applications. In this study, we have developed a bio-PSS based on pure deoxyribonucleic acid (DNA) and curcumin materials in a thin-film form and studied its strain-induced current-voltage characteristics based on piezoelectric phenomena. The bio-PSS exhibited flexibility under varying compressive and tensile loads. Notably, the sensor achieved a strain gauge factor of 407 at an applied compressive strain of −0.027%, which is 8.67 times greater than that of traditional metal strain gauges. Furthermore, the flexible bio-PSS demonstrated a rapid response under a compressive strain of −0.08%. Our findings suggest that the proposed flexible bio-PSS holds significant promise as a motion sensor, addressing the demand for environmentally safe, wearable, and flexible strain sensor applications. Full article
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31 pages, 3154 KiB  
Review
Exploring Therapeutic Potential of Catalase: Strategies in Disease Prevention and Management
by Shehwaz Anwar, Faris Alrumaihi, Tarique Sarwar, Ali Yousif Babiker, Amjad Ali Khan, Sitrarasu Vijaya Prabhu and Arshad Husain Rahmani
Biomolecules 2024, 14(6), 697; https://doi.org/10.3390/biom14060697 - 14 Jun 2024
Viewed by 252
Abstract
The antioxidant defense mechanisms play a critical role in mitigating the deleterious effects of reactive oxygen species (ROS). Catalase stands out as a paramount enzymatic antioxidant. It efficiently catalyzes the decomposition of hydrogen peroxide (H2O2) into water and oxygen, [...] Read more.
The antioxidant defense mechanisms play a critical role in mitigating the deleterious effects of reactive oxygen species (ROS). Catalase stands out as a paramount enzymatic antioxidant. It efficiently catalyzes the decomposition of hydrogen peroxide (H2O2) into water and oxygen, a potentially harmful byproduct of cellular metabolism. This reaction detoxifies H2O2 and prevents oxidative damage. Catalase has been extensively studied as a therapeutic antioxidant. Its applications range from direct supplementation in conditions characterized by oxidative stress to gene therapy approaches to enhance endogenous catalase activity. The enzyme’s stability, bioavailability, and the specificity of its delivery to target tissues are significant hurdles. Furthermore, studies employing conventional catalase formulations often face issues related to enzyme purity, activity, and longevity in the biological milieu. Addressing these challenges necessitates rigorous scientific inquiry and well-designed clinical trials. Such trials must be underpinned by sound experimental designs, incorporating advanced catalase formulations or novel delivery systems that can overcome existing limitations. Enhancing catalase’s stability, specificity, and longevity in vivo could unlock its full therapeutic potential. It is necessary to understand the role of catalase in disease-specific contexts, paving the way for precision antioxidant therapy that could significantly impact the treatment of diseases associated with oxidative stress. Full article
(This article belongs to the Topic Enzymes and Enzyme Inhibitors in Drug Research)
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22 pages, 7674 KiB  
Article
Quercetin Protects Blood–Brain Barrier Integrity via the PI3K/Akt/Erk Signaling Pathway in a Mouse Model of Meningitis Induced by Glaesserella parasuis
by Peiyan Sun, Yaqiong Yang, Linrong Yang, Yuanzhuo Qian, Mingxia Liang, Hongbo Chen, Jing Zhang, Yinsheng Qiu, Ling Guo and Shulin Fu
Biomolecules 2024, 14(6), 696; https://doi.org/10.3390/biom14060696 - 14 Jun 2024
Viewed by 326
Abstract
Glaesserella parasuis (G. parasuis) causes serious inflammation and meningitis in piglets. Quercetin has anti-inflammatory and anti-bacterial activities; however, whether quercetin can alleviate brain inflammation and provide protective effects during G. parasuis infection has not been studied. Here, we established a mouse [...] Read more.
Glaesserella parasuis (G. parasuis) causes serious inflammation and meningitis in piglets. Quercetin has anti-inflammatory and anti-bacterial activities; however, whether quercetin can alleviate brain inflammation and provide protective effects during G. parasuis infection has not been studied. Here, we established a mouse model of G. parasuis infection in vivo and in vitro to investigate transcriptome changes in the mouse cerebrum and determine the protective effects of quercetin on brain inflammation and blood–brain barrier (BBB) integrity during G. parasuis infection. The results showed that G. parasuis induced brain inflammation, destroyed BBB integrity, and suppressed PI3K/Akt/Erk signaling-pathway activation in mice. Quercetin decreased the expression of inflammatory cytokines (Il-18, Il-6, Il-8, and Tnf-α) and BBB-permeability marker genes (Mmp9, Vegf, Ang-2, and Et-1), increased the expression of angiogenetic genes (Sema4D and PlexinB1), reduced G. parasuis-induced tight junction disruption, and reactivated G. parasuis-induced suppression of the PI3K/Akt/Erk signaling pathway in vitro. Thus, we concluded that quercetin may protect BBB integrity via the PI3K/Akt/Erk signaling pathway during G. parasuis infection. This was the first attempt to explore the protective effects of quercetin on brain inflammation and BBB integrity in a G. parasuis-infected mouse model. Our findings indicated that quercetin is a promising natural agent for the prevention and treatment of G. parasuis infection. Full article
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13 pages, 3146 KiB  
Article
Prostate Cancer-Specific Lysine 53 Acetylation of Cytochrome c Drives Metabolic Reprogramming and Protects from Apoptosis in Intact Cells
by Paul T. Morse, Junmei Wan, Tasnim Arroum, Mackenzie K. Herroon, Hasini A. Kalpage, Viktoriia Bazylianska, Icksoo Lee, Elisabeth I. Heath, Izabela Podgorski and Maik Hüttemann
Biomolecules 2024, 14(6), 695; https://doi.org/10.3390/biom14060695 - 14 Jun 2024
Viewed by 246
Abstract
Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated [...] Read more.
Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated in prostate cancer. K53 is conserved in mammals that is known to be essential for binding to cytochrome c oxidase and apoptosis protease activating factor-1 (Apaf-1). Here we report the effects of this acetylation on the main functions of cytochrome c by expressing acetylmimetic K53Q in cytochrome c double knockout cells. Other cytochrome c variants analyzed were wild-type, K53R as a control that maintains the positive charge, and K53I, which is present in some non-mammalian species. Intact cells expressing K53Q cytochrome c showed 49% decreased mitochondrial respiration and a concomitant increase in glycolytic activity (Warburg effect). Furthermore, mitochondrial membrane potential was decreased, correlating with notably reduced basal mitochondrial superoxide levels and decreased cell death upon challenge with H2O2 or staurosporine. To test for markers of cancer aggressiveness and invasiveness, cells were grown in 3D spheroid culture. K53Q cytochrome c-expressing cells showed profoundly increased protrusions compared to WT, suggesting increased invasiveness. We propose that K53 acetylation of cytochrome c is an adaptive response that mediates prostate cancer metabolic reprogramming and evasion of apoptosis, which are two hallmarks of cancer, to better promote tumor survival and metastasis. Full article
(This article belongs to the Special Issue Advances in the Pathology of Prostate Cancer)
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14 pages, 2675 KiB  
Article
Downregulation of miR-1388 Regulates the Expression of Antiviral Genes via Tumor Necrosis Factor Receptor (TNFR)-Associated Factor 3 Targeting Following poly(I:C) Stimulation in Silver Carp (Hypophthalmichthys molitrix)
by Kun Gao, Meng Liu, Huan Tang, Zhenhua Ma, Hanyu Pan, Xiqing Zhang, Muhammad Inam, Xiaofeng Shan, Yunhang Gao and Guiqin Wang
Biomolecules 2024, 14(6), 694; https://doi.org/10.3390/biom14060694 - 14 Jun 2024
Viewed by 213
Abstract
MicroRNAs (miRNAs) are highly conserved endogenous single-stranded non-coding RNA molecules that play a crucial role in regulating gene expression to maintain normal physiological functions in fish. Nevertheless, the specific physiological role of miRNAs in lower vertebrates, particularly in comparison to mammals, remains elusive. [...] Read more.
MicroRNAs (miRNAs) are highly conserved endogenous single-stranded non-coding RNA molecules that play a crucial role in regulating gene expression to maintain normal physiological functions in fish. Nevertheless, the specific physiological role of miRNAs in lower vertebrates, particularly in comparison to mammals, remains elusive. Additionally, the mechanisms underlying the control of antiviral responses triggered by viral stimulation in fish are still not fully understood. In this study, we investigated the regulatory impact of miR-1388 on the signaling pathway mediated by IFN regulatory factor 3 (IRF3). Our findings revealed that following stimulation with the viral analog poly(I:C), the expression of miR-1388 was significantly upregulated in primary immune tissues and macrophages. Through a dual luciferase reporter assay, we corroborated a direct targeting relationship between miR-1388 and tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3). Furthermore, our study demonstrated a distinct negative post-transcriptional correlation between miR-1388 and TRAF3. We observed a significant negative post-transcriptional regulatory association between miR-1388 and the levels of antiviral genes following poly(I:C) stimulation. Utilizing reporter plasmids, we elucidated the role of miR-1388 in the antiviral signaling pathway activated by TRAF3. By intervening with siRNA-TRAF3, we validated that miR-1388 regulates the expression of antiviral genes and the production of type I interferons (IFN-Is) through its interaction with TRAF3. Collectively, our experiments highlight the regulatory influence of miR-1388 on the IRF3-mediated signaling pathway by targeting TRAF3 post poly(I:C) stimulation. These findings provide compelling evidence for enhancing our understanding of the mechanisms through which fish miRNAs participate in immune responses. Full article
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25 pages, 9936 KiB  
Article
Exploring the Molecular Mechanism of Comorbidity of Type 2 Diabetes Mellitus and Colorectal Cancer: Insights from Bulk Omics and Single-Cell Sequencing Validation
by Yongge Luo, Lei Yang, Han Wu, Hui Xu, Jin Peng, You Wang and Fuxiang Zhou
Biomolecules 2024, 14(6), 693; https://doi.org/10.3390/biom14060693 - 14 Jun 2024
Viewed by 236
Abstract
The relationship between type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) has long been extensively recognized, but their crosstalk mechanisms based on gene regulation remain elusive. In our study, for the first time, bulk RNA-seq and single-cell RNA-seq data were used to [...] Read more.
The relationship between type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) has long been extensively recognized, but their crosstalk mechanisms based on gene regulation remain elusive. In our study, for the first time, bulk RNA-seq and single-cell RNA-seq data were used to explore the shared molecular mechanisms between T2DM and CRC. Moreover, Connectivity Map and molecular docking were employed to determine potential drugs targeting the candidate targets. Eight genes (EVPL, TACSTD2, SOX4, ETV4, LY6E, MLXIPL, ENTPD3, UGP2) were identified as characteristic comorbidity genes for T2DM and CRC, with EVPL and ENTPD3 further identified as core comorbidity genes. Our results demonstrated that upregulation of EVPL and downregulation of ENTPD3 were intrinsic molecular features throughout T2DM and CRC and were significantly associated with immune responses, immune processes, and abnormal immune landscapes in both diseases. Single-cell analysis highlighted a cancer-associated fibroblast (CAF) subset that specifically expressed ENTPD3 in CRC, which exhibited high heterogeneity and unique tumor-suppressive features that were completely different from classical cancer-promoting CAFs. Furthermore, ENTPD3+ CAFs could notably predict immunotherapy response in CRC, holding promise to be an immunotherapy biomarker at the single-cell level. Finally, we identified that droperidol may be a novel drug simultaneously targeting EVPL and ENTPD3. In conclusion, previous studies have often focused solely on metabolic alterations common to T2DM and CRC. Our study establishes EVPL and ENTPD3 as characteristic molecules and immune biomarkers of comorbidity in T2DM and CRC patients, and emphasizes the importance of considering immunological mechanisms in the co-development of T2DM and CRC. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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25 pages, 2300 KiB  
Review
Advances in Integrated Multi-omics Analysis for Drug-Target Identification
by Peiling Du, Rui Fan, Nana Zhang, Chenyuan Wu and Yingqian Zhang
Biomolecules 2024, 14(6), 692; https://doi.org/10.3390/biom14060692 - 14 Jun 2024
Viewed by 293
Abstract
As an essential component of modern drug discovery, the role of drug-target identification is growing increasingly prominent. Additionally, single-omics technologies have been widely utilized in the process of discovering drug targets. However, it is difficult for any single-omics level to clearly expound the [...] Read more.
As an essential component of modern drug discovery, the role of drug-target identification is growing increasingly prominent. Additionally, single-omics technologies have been widely utilized in the process of discovering drug targets. However, it is difficult for any single-omics level to clearly expound the causal connection between drugs and how they give rise to the emergence of complex phenotypes. With the progress of large-scale sequencing and the development of high-throughput technologies, the tendency in drug-target identification has shifted towards integrated multi-omics techniques, gradually replacing traditional single-omics techniques. Herein, this review centers on the recent advancements in the domain of integrated multi-omics techniques for target identification, highlights the common multi-omics analysis strategies, briefly summarizes the selection of multi-omics analysis tools, and explores the challenges of existing multi-omics analyses, as well as the applications of multi-omics technology in drug-target identification. Full article
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27 pages, 1990 KiB  
Review
Paradoxes: Cholesterol and Hypoxia in Preeclampsia
by Nancy R. Hart
Biomolecules 2024, 14(6), 691; https://doi.org/10.3390/biom14060691 - 13 Jun 2024
Viewed by 188
Abstract
Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular disease (CVD) not only due to multiple shared pathologic elements but also because changes that develop over decades in CVD appear and resolve within days in [...] Read more.
Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular disease (CVD) not only due to multiple shared pathologic elements but also because changes that develop over decades in CVD appear and resolve within days in preeclampsia. Those affected by preeclampsia and their offspring experience increased lifetime risks of CVD. At the systemic level, preeclampsia is characterized by increased cellular, membrane, and blood levels of cholesterol; however, cholesterol-dependent signaling, such as canonical Wnt/βcatenin, Hedgehog, and endothelial nitric oxide synthase, is downregulated indicating a cholesterol deficit with the upregulation of cholesterol synthesis and efflux. Hypoxia-related signaling in preeclampsia also appears to be paradoxical with increased Hypoxia-Inducible Factors in the placenta but measurably increased oxygen in maternal blood in placental villous spaces. This review addresses the molecular mechanisms by which excessive systemic cholesterol and deficient cholesterol-dependent signaling may arise from the effects of dietary lipid variance and environmental membrane modifiers causing the cellular hypoxia that characterizes preeclampsia. Full article
(This article belongs to the Special Issue Lipids Metabolism in Cardiovascular Disease)
15 pages, 1288 KiB  
Article
Effects of A1 Milk, A2 Milk and the Opioid-like Peptide β-Casomorphin-7 on the Proliferation of Human Peripheral Blood Mononuclear Cells
by Felix Gard, Lili M. Flad, Tanja Weißer, Hermann Ammer and Cornelia A. Deeg
Biomolecules 2024, 14(6), 690; https://doi.org/10.3390/biom14060690 - 13 Jun 2024
Viewed by 290
Abstract
Special attention is given to cow’s milk and its variants, with ongoing discussions about health-related impacts primarily focusing on the A1 variant in contrast to the A2 variant. The difference between these variants lies in a single amino acid alteration at position 67 [...] Read more.
Special attention is given to cow’s milk and its variants, with ongoing discussions about health-related impacts primarily focusing on the A1 variant in contrast to the A2 variant. The difference between these variants lies in a single amino acid alteration at position 67 of β-casein. This alteration is presumed to make the A1 variant more susceptible to enzymatic breakdown during milk digestion, leading to an increased release of the peptide β-casomorphin-7 (BCM-7). BCM-7 is hypothesized to interact with µ-opioid receptors on immune cells in humans. Although BCM-7 has demonstrated both immunosuppressive and inflammatory effects, its direct impact on the immune system remains unclear. Thus, we examined the influence of A1 and A2 milk on Concanavalin A (ConA)-stimulated human peripheral blood mononuclear cells (PBMCs), as well as the effect of experimentally digested A1 and A2 milk, containing different amounts of free BCM-7 from β-casein cleavage. Additionally, we evaluated the effects of pure BCM-7 on the proliferation of ConA-stimulated PBMCs and purified CD4+ T cells. Milk fundamentally inhibited PBMC proliferation, independent of the β-casein variant. In contrast, experimentally digested milk of both variants and pure BCM-7 showed no influence on the proliferation of PBMCs or isolated CD4+ T cells. Our results indicate that milk exerts an anti-inflammatory effect on PBMCs, regardless of the A1 or A2 β-casein variant, which is nullified after in vitro digestion. Consequently, we deem BCM-7 unsuitable as a biomarker for food-induced inflammation. Full article
(This article belongs to the Special Issue Immune-Related Biomarkers II)
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31 pages, 2230 KiB  
Review
Insights into the Role of Glutathione Peroxidase 3 in Non-Neoplastic Diseases
by Nan Zhang, Haihan Liao, Zheng Lin and Qizhu Tang
Biomolecules 2024, 14(6), 689; https://doi.org/10.3390/biom14060689 - 13 Jun 2024
Viewed by 251
Abstract
Reactive oxygen species (ROSs) are byproducts of normal cellular metabolism and play pivotal roles in various physiological processes. Disruptions in the balance between ROS levels and the body’s antioxidant defenses can lead to the development of numerous diseases. Glutathione peroxidase 3 (GPX3), a [...] Read more.
Reactive oxygen species (ROSs) are byproducts of normal cellular metabolism and play pivotal roles in various physiological processes. Disruptions in the balance between ROS levels and the body’s antioxidant defenses can lead to the development of numerous diseases. Glutathione peroxidase 3 (GPX3), a key component of the body’s antioxidant system, is an oxidoreductase enzyme. GPX3 mitigates oxidative damage by catalyzing the conversion of hydrogen peroxide into water. Beyond its antioxidant function, GPX3 is vital in regulating metabolism, modulating cell growth, inducing apoptosis and facilitating signal transduction. It also serves as a significant tumor suppressor in various cancers. Recent studies have revealed aberrant expression of GPX3 in several non-neoplastic diseases, associating it with multiple pathological processes. This review synthesizes the current understanding of GPX3 expression and regulation, highlighting its extensive roles in noncancerous diseases. Additionally, this paper evaluates the potential of GPX3 as a diagnostic biomarker and explores emerging therapeutic strategies targeting this enzyme, offering potential avenues for future clinical treatment of non-neoplastic conditions. Full article
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