Biomolecules

17 pages, 1616 KiB

Open AccessReview

Roles of Mitochondrial Dysfunction in Diabetic Kidney Disease: New Perspectives from Mechanism to Therapy

by Yichen Yang, Jiahui Liu, Qiling Shi, Buyu Guo, Hanbing Jia, Yuxuan Yang and Songbo Fu

Biomolecules 2024, 14(6), 733; https://doi.org/10.3390/biom14060733 - 20 Jun 2024

Viewed by 292

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and the main cause of end-stage renal disease around the world. Mitochondria are the main organelles responsible for producing energy in cells and are closely involved in maintaining normal organ function. Studies [...] Read more.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and the main cause of end-stage renal disease around the world. Mitochondria are the main organelles responsible for producing energy in cells and are closely involved in maintaining normal organ function. Studies have found that a high-sugar environment can damage glomeruli and tubules and trigger mitochondrial dysfunction. Meanwhile, animal experiments have shown that DKD symptoms are alleviated when mitochondrial damage is targeted, suggesting that mitochondrial dysfunction is inextricably linked to the development of DKD. This article describes the mechanisms of mitochondrial dysfunction and the progression and onset of DKD. The relationship between DKD and mitochondrial dysfunction is discussed. At the same time, the progress of DKD treatment targeting mitochondrial dysfunction is summarized. We hope to provide new insights into the progress and treatment of DKD. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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18 pages, 8312 KiB

Open AccessArticle

The Rhododendron Chrysanthum Pall.s’ Acetylation Modification of Rubisco Enzymes Controls Carbon Cycling to Withstand UV−B Stress

by Meiqi Liu, Fushuai Gong, Wang Yu, Kun Cao, Hongwei Xu and Xiaofu Zhou

Biomolecules 2024, 14(6), 732; https://doi.org/10.3390/biom14060732 - 20 Jun 2024

Viewed by 252

Abstract

Lysine acetylation of proteins plays a critical regulatory function in plants. A few advances have been made in the study of plant acetylproteome. However, until now, there have been few data on Rhododendron chrysanthum Pall. (R. chrysanthum). We analyzed the molecular [...] Read more.

Lysine acetylation of proteins plays a critical regulatory function in plants. A few advances have been made in the study of plant acetylproteome. However, until now, there have been few data on Rhododendron chrysanthum Pall. (R. chrysanthum). We analyzed the molecular mechanisms of photosynthesis and stress resistance in R. chrysanthum under UV−B stress. We measured chlorophyll fluorescence parameters of R. chrysanthum under UV−B stress and performed a multi−omics analysis. Based on the determination of chlorophyll fluorescence parameters, R. chrysanthum Y(NO) (Quantum yield of non−photochemical quenching) increased under UV−B stress, indicating that the plant was damaged and photosynthesis decreased. In the analysis of acetylated proteomics data, acetylated proteins were found to be involved in a variety of biological processes. Notably, acetylated proteins were significantly enriched in the pathways of photosynthesis and carbon fixation, suggesting that lysine acetylation modifications have an important role in these activities. Our findings suggest that R. chrysanthum has decreased photosynthesis and impaired photosystems under UV−B stress, but NPQ shows that plants are resistant to UV−B. Acetylation proteomics revealed that up- or down-regulation of acetylation modification levels alters protein expression. Acetylation modification of key enzymes of the Calvin cycle (Rubisco, GAPDH) regulates protein expression, making Rubisco and GAPDH proteins expressed as significantly different proteins, which in turn affects the carbon fixation capacity of R. chrysanthum. Thus, Rubisco and GAPDH are significantly differentially expressed after acetylation modification, which affects the carbon fixation capacity and thus makes the plant resistant to UV−B stress. Lysine acetylation modification affects biological processes by regulating the expression of key enzymes in photosynthesis and carbon fixation, making plants resistant to UV−B stress. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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19 pages, 4708 KiB

Open AccessSystematic Review

Unravelling the Gut Microbiome Role in Cardiovascular Disease: A Systematic Review and a Meta-Analysis

by Diana Martins, Cláudia Silva, António Carlos Ferreira, Sara Dourado, Ana Albuquerque, Francisca Saraiva, Ana Beatriz Batista, Pedro Castro, Adelino Leite-Moreira, António S. Barros and Isabel M. Miranda

Biomolecules 2024, 14(6), 731; https://doi.org/10.3390/biom14060731 - 20 Jun 2024

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Abstract

A notable shift in understanding the human microbiome’s influence on cardiovascular disease (CVD) is underway, although the causal association remains elusive. A systematic review and meta-analysis were conducted to synthesise current knowledge on microbial taxonomy and metabolite variations between healthy controls (HCs) and [...] Read more.

A notable shift in understanding the human microbiome’s influence on cardiovascular disease (CVD) is underway, although the causal association remains elusive. A systematic review and meta-analysis were conducted to synthesise current knowledge on microbial taxonomy and metabolite variations between healthy controls (HCs) and those with CVD. An extensive search encompassing three databases identified 67 relevant studies (2012–2023) covering CVD pathologies from 4707 reports. Metagenomic and metabolomic data, both qualitative and quantitative, were obtained. Analysis revealed substantial variability in microbial alpha and beta diversities. Moreover, specific changes in bacterial populations were shown, including increased Streptococcus and Proteobacteria and decreased Faecalibacterium in patients with CVD compared with HC. Additionally, elevated trimethylamine N-oxide levels were reported in CVD cases. Biochemical parameter analysis indicated increased fasting glucose and triglycerides and decreased total cholesterol and low- and high-density lipoprotein cholesterol levels in diseased individuals. This study revealed a significant relationship between certain bacterial species and CVD. Additionally, it has become clear that there are substantial inconsistencies in the methodologies employed and the reporting standards adhered to in various studies. Undoubtedly, standardising research methodologies and developing extensive guidelines for microbiome studies are crucial for advancing the field. Full article

(This article belongs to the Special Issue Biomarkers of Cardiovascular and Cerebrovascular Diseases)

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Graphical abstract

14 pages, 2237 KiB

Open AccessArticle

Exogenous Iron Induces Mitochondrial Lipid Peroxidation, Lipofuscin Accumulation, and Ferroptosis in H9c2 Cardiomyocytes

by Konstantin G. Lyamzaev, He Huan, Alisa A. Panteleeva, Ruben A. Simonyan, Armine V. Avetisyan and Boris V. Chernyak

Biomolecules 2024, 14(6), 730; https://doi.org/10.3390/biom14060730 - 19 Jun 2024

Viewed by 358

Abstract

Lipid peroxidation plays an important role in various pathologies and aging, at least partially mediated by ferroptosis. The role of mitochondrial lipid peroxidation during ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate at [...] Read more.

Lipid peroxidation plays an important role in various pathologies and aging, at least partially mediated by ferroptosis. The role of mitochondrial lipid peroxidation during ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate at submillimolar doses induces production of reactive oxygen species (ROS) and lipid peroxidation in mitochondria that precede ferroptosis in H9c2 cardiomyocytes. The mitochondria-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of ROS in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis. SkQ1 and methylene blue also prevented accumulation of lipofuscin observed after 24 h incubation of cardiomyocytes with ferric ammonium citrate. Using isolated cardiac mitochondria as an in vitro ferroptosis model, it was shown that rotenone (complex I inhibitor) in the presence of ferrous iron stimulates lipid peroxidation and lipofuscin accumulation. Our data indicate that ROS generated in complex I stimulate mitochondrial lipid peroxidation, lipofuscin accumulation, and ferroptosis induced by exogenous iron. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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11 pages, 1151 KiB

Open AccessArticle

Novel Semi-Nested Real-Time PCR Assay Leveraging Extendable Blocking Probes for Improved SHOX2 Methylation Analysis in Lung Cancer

by Ngoc Anh Phuong, Trang Thuy Dao, Phuong Bich Pham, Ung Dinh Nguyen, Ba Van Nguyen and Tho Huu Ho

Biomolecules 2024, 14(6), 729; https://doi.org/10.3390/biom14060729 - 19 Jun 2024

Viewed by 311

Abstract

Lung cancer is the leading cause of cancer deaths globally, necessitating effective early detection methods. Traditional diagnostics like low-dose computed tomography (LDCT) often yield high false positive rates. SHOX2 gene methylation has emerged as a promising biomarker. This study aimed to develop and [...] Read more.

Lung cancer is the leading cause of cancer deaths globally, necessitating effective early detection methods. Traditional diagnostics like low-dose computed tomography (LDCT) often yield high false positive rates. SHOX2 gene methylation has emerged as a promising biomarker. This study aimed to develop and validate a novel semi-nested real-time PCR assay enhancing sensitivity and specificity for detecting SHOX2 methylation using extendable blocking probes (ExBPs). The assay integrates a semi-nested PCR approach with ExBPs, enhancing the detection of low-abundance methylated SHOX2 DNA amidst unmethylated sequences. It was tested on spiked samples with varied methylation levels and on clinical samples from lung cancer patients and individuals with benign lung conditions. The assay detected methylated SHOX2 DNA down to 0.01%. Clinical evaluations confirmed its ability to effectively differentiate between lung cancer patients and those with benign conditions, demonstrating enhanced sensitivity and specificity. The use of ExBPs minimized non-target sequence amplification, crucial for reducing false positives. The novel semi-nested real-time PCR assay offers a cost-effective, highly sensitive, and specific method for detecting SHOX2 methylation, enhancing early lung cancer detection and monitoring, particularly valuable in resource-limited settings. Full article

(This article belongs to the Special Issue Genetic and Genomic Biomarkers of Cancer)

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25 pages, 2521 KiB

Open AccessReview

New Insights into the Role of PPARγ in Skin Physiopathology

by Stefania Briganti, Sarah Mosca, Anna Di Nardo, Enrica Flori and Monica Ottaviani

Biomolecules 2024, 14(6), 728; https://doi.org/10.3390/biom14060728 - 19 Jun 2024

Viewed by 276

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for [...] Read more.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for skin homeostasis. Over the past 20 years, with increasing interest in the role of PPARs in skin physiopathology, considerable effort has been devoted to the development of PPARγ ligands as a therapeutic option for skin inflammatory disorders. In addition, PPARγ also regulates sebocyte differentiation and lipid production, making it a potential target for inflammatory sebaceous disorders such as acne. A large number of studies suggest that PPARγ also acts as a skin tumor suppressor in both melanoma and non-melanoma skin cancers, but its role in tumorigenesis remains controversial. In this review, we have summarized the current state of research into the role of PPARγ in skin health and disease and how this may provide a starting point for the development of more potent and selective PPARγ ligands with a low toxicity profile, thereby reducing unwanted side effects. Full article

(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)

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18 pages, 3067 KiB

Open AccessArticle

Shotgun Proteomics Links Proteoglycan-4⁺ Extracellular Vesicles to Cognitive Protection in Amyotrophic Lateral Sclerosis

by Beatrice Vilardo, Fabiola De Marchi, Davide Raineri, Marcello Manfredi, Veronica De Giorgis, Alen Bebeti, Lorenza Scotti, Natasa Kustrimovic, Giuseppe Cappellano, Letizia Mazzini and Annalisa Chiocchetti

Biomolecules 2024, 14(6), 727; https://doi.org/10.3390/biom14060727 - 19 Jun 2024

Viewed by 416

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder lacking reliable biomarkers for early diagnosis and disease progression monitoring. This study aimed to identify the novel biomarkers in plasmatic extracellular vesicles (EVs) isolated from ALS patients and healthy controls (HCs). A total of [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder lacking reliable biomarkers for early diagnosis and disease progression monitoring. This study aimed to identify the novel biomarkers in plasmatic extracellular vesicles (EVs) isolated from ALS patients and healthy controls (HCs). A total of 61 ALS patients and 30 age-matched HCs were enrolled in the study and the protein content of circulating EVs was analyzed by shotgun proteomics. The study was divided into a discovery phase (involving 12 ALS and 12 HC patients) and a validation one (involving 49 ALS and 20 HC patients). In the discovery phase, more than 300 proteins were identified, with 32 proteins showing differential regulation in ALS patients compared to HCs. In the validation phase, over 400 proteins were identified, with 20 demonstrating differential regulation in ALS patients compared to HCs. Notably, seven proteins were found to be common to both phases, all of which were significantly upregulated in EVs from ALS patients. Most of them have previously been linked to ALS since they have been detected in the serum or cerebrospinal fluid of ALS patients. Among them, proteoglycan (PRG)-4, also known as lubricin, was of particular interest since it was significantly increased in ALS patients with normal cognitive and motor functions. This study highlights the significance of EVs as a promising avenue for biomarker discovery in ALS. Moreover, it sheds light on the unexpected role of PRG-4 in relation to cognitive status in ALS patients. Full article

(This article belongs to the Special Issue New Insights into Diagnostic and Prognostic Biomarkers of Amyotrophic Lateral Sclerosis: Must Innovative Findings Come from New Targets?)

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16 pages, 4506 KiB

Open AccessArticle

Gasdermin D Inhibitor Necrosulfonamide Alleviates Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice

by Jia Guo, Qing Zhang, Zhidong Li, Min Qin, Jinyun Shi, Yan Wang, Wenjia Ai, Junjie Ju, Makoto Samura, Philip S Tsao and Baohui Xu

Biomolecules 2024, 14(6), 726; https://doi.org/10.3390/biom14060726 - 19 Jun 2024

Viewed by 432

Abstract

Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous [...] Read more.

Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4⁺ T cells, CD8⁺ T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease. Full article

(This article belongs to the Section Molecular Medicine)

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14 pages, 3283 KiB

Open AccessArticle

Preclinical Evaluation of a Novel Series of Polyfluorinated Thalidomide Analogs in Drug-Resistant Multiple Myeloma

by Blaire E. Barton, Matthew K. Collins, Cindy H. Chau, Hyoyoung Choo-Wosoba, David J. Venzon, Christian Steinebach, Kathleen M. Garchitorena, Bhruga Shah, Eric L. Sarin, Michael Gütschow and William D. Figg

Biomolecules 2024, 14(6), 725; https://doi.org/10.3390/biom14060725 - 19 Jun 2024

Viewed by 428

Abstract

Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It [...] Read more.

Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma. Full article

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17 pages, 4243 KiB

Open AccessArticle

GmMYB183, a R2R3-MYB Transcription Factor in Tamba Black Soybean (Glycine max. cv. Tamba), Conferred Aluminum Tolerance in Arabidopsis and Soybean

by Yunmin Wei, Rongrong Han and Yongxiong Yu

Biomolecules 2024, 14(6), 724; https://doi.org/10.3390/biom14060724 - 19 Jun 2024

Viewed by 307

Abstract

Aluminum (Al) toxicity is one of the environmental stress factors that affects crop growth, development, and productivity. MYB transcription factors play crucial roles in responding to biotic or abiotic stresses. However, the roles of MYB transcription factors in Al tolerance have not been [...] Read more.

Aluminum (Al) toxicity is one of the environmental stress factors that affects crop growth, development, and productivity. MYB transcription factors play crucial roles in responding to biotic or abiotic stresses. However, the roles of MYB transcription factors in Al tolerance have not been clearly elucidated. Here, we found that GmMYB183, a gene encoding a R2R3 MYB transcription factor, is involved in Al tolerance. Subcellular localization studies revealed that GmMYB183 protein is located in the nucleus, cytoplasm and cell membrane. Overexpression of GmMYB183 in Arabidopsis and soybean hairy roots enhanced plant tolerance towards Al stress compared to the wild type, with higher citrate secretion and less Al accumulation. Furthermore, we showed that GmMYB183 binds the GmMATE75 gene promoter encoding for a plasma-membrane-localized citrate transporter. Through a dual-luciferase reporter system and yeast one hybrid, the GmMYB183 protein was shown to directly activate the transcription of GmMATE75. Furthermore, the expression of GmMATE75 may depend on phosphorylation of Ser36 residues in GmMYB183 and two MYB sites in P3 segment of the GmMATE75 promoter. In conclusion, GmMYB183 conferred Al tolerance by promoting the secretion of citrate, which provides a scientific basis for further elucidating the mechanism of plant Al resistance. Full article

(This article belongs to the Section Natural and Bio-inspired Molecules)

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22 pages, 1357 KiB

Open AccessReview

Silk Sericin and Its Composite Materials with Antibacterial Properties to Enhance Wound Healing: A Review

by Sheng-Lan Wang, Jia-Jun Zhuo, Shou-Min Fang, Wei Xu and Quan-You Yu

Biomolecules 2024, 14(6), 723; https://doi.org/10.3390/biom14060723 - 18 Jun 2024

Viewed by 312

Abstract

Wound infections may disrupt the normal wound-healing process. Large amounts of antibiotics are frequently used to prevent pathogenic infections; however, this can lead to resistance development. Biomaterials possessing antimicrobial properties have promising applications for reducing antibiotic usage and promoting wound healing. Silk sericin [...] Read more.

Wound infections may disrupt the normal wound-healing process. Large amounts of antibiotics are frequently used to prevent pathogenic infections; however, this can lead to resistance development. Biomaterials possessing antimicrobial properties have promising applications for reducing antibiotic usage and promoting wound healing. Silk sericin (SS) has been increasingly explored for skin wound healing applications owing to its excellent biocompatibility and antioxidant, antimicrobial, and ultraviolet-resistant properties. In recent years, SS-based composite biomaterials with a broader antimicrobial spectrum have been extensively investigated and demonstrated favorable efficacy in promoting wound healing. This review summarizes various antimicrobial agents, including metal nanoparticles, natural extracts, and antibiotics, that have been incorporated into SS composites for wound healing and elucidates their mechanisms of action. It has been revealed that SS-based biomaterials can achieve sustained antimicrobial activity by slow-release-loaded antimicrobial agents. The antimicrobial-loaded SS composites may promote wound healing through anti-infection, anti-inflammation, hemostasis, angiogenesis, and collagen deposition. The manufacturing methods, benefits, and limitations of antimicrobial-loaded SS materials are briefly discussed. This review aims to enhance the understanding of new advances and directions in SS-based antimicrobial composites and guide future biomedical research. Full article

(This article belongs to the Section Biological and Bio- Materials)

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34 pages, 2926 KiB

Open AccessReview

Comprehensive Review of Olea europaea: A Holistic Exploration into Its Botanical Marvels, Phytochemical Riches, Therapeutic Potentials, and Safety Profile

by Hamza Elhrech, Oumayma Aguerd, Chaimae El Kourchi, Monica Gallo, Daniele Naviglio, Imane Chamkhi and Abdelhakim Bouyahya

Biomolecules 2024, 14(6), 722; https://doi.org/10.3390/biom14060722 - 18 Jun 2024

Viewed by 494

Abstract

Human health is now inextricably linked to lifestyle choices, which can either protect or predispose people to serious illnesses. The Mediterranean diet, characterized by the consumption of various medicinal plants and their byproducts, plays a significant role in protecting against ailments such as [...] Read more.

Human health is now inextricably linked to lifestyle choices, which can either protect or predispose people to serious illnesses. The Mediterranean diet, characterized by the consumption of various medicinal plants and their byproducts, plays a significant role in protecting against ailments such as oxidative stress, cancer, and diabetes. To uncover the secrets of this natural treasure, this review seeks to consolidate diverse data concerning the pharmacology, toxicology, phytochemistry, and botany of Olea europaea L. (O. europaea). Its aim is to explore the potential therapeutic applications and propose avenues for future research. Through web literature searches (using Google Scholar, PubMed, Web of Science, and Scopus), all information currently available on O. europaea was acquired. Worldwide, ethnomedical usage of O. europaea has been reported, indicating its effectiveness in treating a range of illnesses. Phytochemical studies have identified a range of compounds, including flavanones, iridoids, secoiridoids, flavonoids, triterpenes, biophenols, benzoic acid derivatives, among others. These components exhibit diverse pharmacological activities both in vitro and in vivo, such as antidiabetic, antibacterial, antifungal, antioxidant, anticancer, and wound-healing properties. O. europaea serves as a valuable source of conventional medicine for treating various conditions. The findings from pharmacological and phytochemical investigations presented in this review enhance our understanding of its therapeutic potential and support its potential future use in modern medicine. Full article

(This article belongs to the Section Natural and Bio-inspired Molecules)

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9 pages, 267 KiB

Open AccessArticle

Endothelial Dysfunction and Pre-Existing Cognitive Disorders in Stroke Patients

by Anne-Marie Mendyk-Bordet, Thavarak Ouk, Anne Muhr-Tailleux, Maud Pétrault, Emmanuelle Vallez, Patrick Gelé, Thibaut Dondaine, Julien Labreuche, Dominique Deplanque and Régis Bordet

Biomolecules 2024, 14(6), 721; https://doi.org/10.3390/biom14060721 - 18 Jun 2024

Viewed by 310

Abstract

Background: The origin of pre-existing cognitive impairment in stroke patients remains controversial, with a vascular or a degenerative hypothesis. Objective: To determine whether endothelial dysfunction is associated with pre-existing cognitive problems, lesion load and biological anomalies in stroke patients. Methods: Patients originated from [...] Read more.

Background: The origin of pre-existing cognitive impairment in stroke patients remains controversial, with a vascular or a degenerative hypothesis. Objective: To determine whether endothelial dysfunction is associated with pre-existing cognitive problems, lesion load and biological anomalies in stroke patients. Methods: Patients originated from the prospective STROKDEM study. The baseline cognitive state, assessed using the IQ-CODE, and risk factors for stroke were recorded at inclusion. Patients with an IQ-CODE score >64 were excluded. Endothelial function was determined 72 h after stroke symptom onset by non-invasive digital measurement of endothelium-dependent flow-mediated dilation and calculation of the reactive hyperemia index (RHI). RHI ≤ 1.67 indicated endothelial dysfunction. Different biomarkers of endothelial dysfunction were analysed in blood or plasma. All patients underwent MRI 72 h after stroke symptom onset. Results: A total of 86 patients were included (52 males; mean age 63.5 ± 11.5 years). Patients with abnormal RHI have hypertension or antihypertensive treatment more often. The baseline IQ-CODE was abnormal in 33 (38.4%) patients, indicating a pre-existing cognitive problem. Baseline IQ-CODE > 48 was observed in 15 patients (28.3%) with normal RHI and in 18 patients (54.6%) with abnormal RHI (p = 0.016). The RHI median was significantly lower in patients with abnormal IQ-CODE. Abnormal RHI was associated with a significantly higher median FAZEKAS score (2.5 vs. 2; p = 0.008), a significantly higher frequency of periventricular lesions (p = 0.015), more white matter lesions (p = 0.007) and a significantly higher cerebral atrophy score (p < 0.001) on MRI. Vascular biomarkers significantly associated with abnormal RHI were MCP-1 (p = 0.009), MIP_1a (p = 0.042), and homocysteinemia (p < 0.05). Conclusions: A vascular mechanism may be responsible for cognitive problems pre-existing stroke. The measurement of endothelial dysfunction after stroke could become an important element of follow-up, providing an indication of the functional and cognitive prognosis of stroke patients. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment (2nd Edition))

13 pages, 1000 KiB

Open AccessReview

Pioneer Transcription Factors: The First Domino in Zygotic Genome Activation

by Bo Fu, Hong Ma and Di Liu

Biomolecules 2024, 14(6), 720; https://doi.org/10.3390/biom14060720 - 18 Jun 2024

Viewed by 425

Abstract

Zygotic genome activation (ZGA) is a pivotal event in mammalian embryogenesis, marking the transition from maternal to zygotic control of development. During the ZGA process that is characterized by the intricate cascade of gene expression, who tipped the first domino in a meticulously [...] Read more.

Zygotic genome activation (ZGA) is a pivotal event in mammalian embryogenesis, marking the transition from maternal to zygotic control of development. During the ZGA process that is characterized by the intricate cascade of gene expression, who tipped the first domino in a meticulously arranged sequence is a subject of paramount interest. Recently, Dux, Obox and Nr5a2 were identified as pioneer transcription factors that reside at the top of transcriptional hierarchy. Through co-option of retrotransposon elements as hubs for transcriptional activation, these pioneer transcription factors rewire the gene regulatory network, thus initiating ZGA. In this review, we provide a snapshot of the mechanisms underlying the functions of these pioneer transcription factors. We propose that ZGA is the starting point where the embryo’s own genome begins to influence development trajectory, therefore in-depth dissecting the functions of pioneer transcription factors during ZGA will form a cornerstone of our understanding for early embryonic development, which will pave the way for advancing our grasp of mammalian developmental biology and optimizing in vitro production (IVP) techniques. Full article

(This article belongs to the Section Molecular Reproduction)

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14 pages, 1928 KiB

Open AccessArticle

Comparative Analysis of Osteoblastic Responses to Titanium and Alumina-Toughened Zirconia Implants: An In Vitro Study

by Elham Saberian, Andrej Jenča, Rahman Seyfaddini, Andrej Jenča, Hadi Zare-Zardini, Adriána Petrášová and Janka Jenčová

Biomolecules 2024, 14(6), 719; https://doi.org/10.3390/biom14060719 - 18 Jun 2024

Viewed by 394

Abstract

Introduction: Osteoblastic responses play a crucial role in the success of oral implants. Enhanced proliferation of osteoblast cells is associated with reduced cell mortality and an increase in bone regeneration. This study aims to evaluate the osteoblastic responses following oral implantation. Materials and [...] Read more.

Introduction: Osteoblastic responses play a crucial role in the success of oral implants. Enhanced proliferation of osteoblast cells is associated with reduced cell mortality and an increase in bone regeneration. This study aims to evaluate the osteoblastic responses following oral implantation. Materials and Methods: Osteoblast stem cells were harvested and subsequently cultivated using cell culture techniques. The osteoblastic phenotype of the extracted cells was confirmed by examining the extracellular matrix. Cell morphogenesis on functionalized biomaterial surfaces was assessed through indirect immunofluorescence staining. The cellular response was investigated in the presence of two types of implant materials: titanium (Ti) and alumina-toughened zirconia (ATZ). Cell viability and apoptosis were quantitatively assessed using MTT assays and flow cytometry, respectively. Results: The survival of osteoblastic lineage cells was moderately reduced post-implantation. Viability in the Ti implant group remained at approximately 86%, while in the ATZ group, it was observed at 75%, which is considered acceptable. Moreover, there was a significant disparity in cell survival between the two implant groups (p < 0.05). Analysis of apoptosis levels at various concentrations revealed that the rate of apoptosis was 3.6% in the control group and 18.5% in the ATZ group, indicating that apoptosis or programmed cell death in the ATZ-treated group had increased nearly four-fold (p < 0.05). Conclusions: The findings of this study indicate a reduction in osteoblastic cell line survival following implant treatment, with titanium implants exhibiting superior performance in terms of cell survival. However, it was also noted that the incidence of apoptosis in osteoblast cells was significantly higher in the presence of zirconium-based implants. Full article

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25 pages, 501 KiB

Open AccessReview

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

Viewed by 539

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, 2084 KiB

Open AccessArticle

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

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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)

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14 pages, 16651 KiB

Open AccessArticle

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

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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

Open AccessArticle

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

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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, 3473 KiB

Open AccessFeature PaperReview

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

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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

Open AccessArticle

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

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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

Open AccessArticle

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 527

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

Open AccessArticle

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 568

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

(This article belongs to the Special Issue In Silico Drug Design and Discovery: Big Data for Small Molecule Design 2nd Edition)

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18 pages, 2574 KiB

Open AccessArticle

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 574

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

Open AccessArticle

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 407

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

Open AccessOpinion

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

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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

(This article belongs to the Special Issue Neuroanatomy as an Implement for the Study of CNS Function and Dysfunction)

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18 pages, 2068 KiB

Open AccessArticle

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

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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

Open AccessArticle

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 318

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

Open AccessArticle

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 442

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

(This article belongs to the Topic Antitumor Activity of Natural Products and Related Compounds—2nd Edition)

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14 pages, 1766 KiB

Open AccessArticle

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

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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

(This article belongs to the Special Issue Defects in the Transport Mechanism of Membrane Proteins and Related Diseases)

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