Biomolecules

33 pages, 4414 KiB

Open AccessArticle

Effects of Pressure, Hypoxia, and Hyperoxia on Neutrophil Granulocytes

by Richard F. Kraus, Daniel Panter, Michael A. Gruber, Stephanie Arndt, Petra Unger, Michael T. Pawlik and Diane Bitzinger

Biomolecules 2024, 14(10), 1242; https://doi.org/10.3390/biom14101242 (registering DOI) - 30 Sep 2024

Abstract

Background: The application of normo- and hyperbaric O₂ is a common therapy option in various disease patterns. Thereby, the applied O₂ affects the whole body, including the blood and its components. This study investigates influences of pressure and oxygen fraction on [...] Read more.

Background: The application of normo- and hyperbaric O₂ is a common therapy option in various disease patterns. Thereby, the applied O₂ affects the whole body, including the blood and its components. This study investigates influences of pressure and oxygen fraction on human blood plasma, nutrient media, and the functions of neutrophil granulocytes (PMNs). Methods: Neutrophil migration, reactive oxygen species (ROS) production, and NETosis were examined by live cell imaging. The treatment of various matrices (Roswell Park Memorial Institute 1640 medium, Dulbecco’s Modified Eagle’s Medium, H₂O, human plasma, and isolated PMNs) with hyperbaric oxygen (HBO) was performed. In addition, the expression of different neutrophil surface epitopes (CD11b, CD62L, CD66b) and the oxidative burst were investigated by flow cytometry (FACS). The application of cold atmospheric plasma (CAP) to normoxic and normobaric culture media served as a positive control. Soluble reaction products such as H₂O₂, reactive nitrogen species (RNS: NO₂⁻ and NO₃⁻), and ROS-dependent dihydrorhodamine oxidation were quantified by fluoro- and colorimetric assay kits. Results: Under normobaric normoxia, PMNs migrate slower and shorter in comparison with normobaric hyper- or hypoxic conditions and hyperbaric hyperoxia. The pressure component has less effect on the migration behavior of PMNs than the O₂ concentration. Individual PMN cells produce prolonged ROS at normoxic conditions. PMNs showed increased expression of CD11b in normobaric normoxia, lower expression of CD62L in normobaric normoxia, and lower expression of CD66b after HBO and CAP treatment. Treatment with CAP increased the amount of ROS and RNS in common culture media. Conclusions: Hyperbaric and normobaric O₂ influences neutrophil functionality and surface epitopes in a measurable way, which may have an impact on disorders with neutrophil involvement. In the context of hyperbaric experiments, especially high amounts of H₂O₂ in RPMI after hyperbaric oxygen should be taken into account. Therefore, our data support a critical indication for the use of normobaric and hyperbaric oxygen and conscientious and careful handling of oxygen in everyday clinical practice. Full article

(This article belongs to the Special Issue Innate Immunomodulation and Inflammation: From Molecular Mechanisms to Pre-clinical Insights)

51 pages, 3229 KiB

Open AccessReview

Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review

by Alexandra K. Mitchell, Rebecca R. Bliss and Frank C. Church

Biomolecules 2024, 14(10), 1241; https://doi.org/10.3390/biom14101241 (registering DOI) - 30 Sep 2024

Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative disease in which treatment often includes an exercise regimen. Exercise is neuroprotective in animal models of PD, and, more recently, human clinical studies have verified exercise’s disease-modifying effect. Aerobic exercise and resistance training improve many of [...] Read more.

Parkinson’s disease (PD) is a prevalent neurodegenerative disease in which treatment often includes an exercise regimen. Exercise is neuroprotective in animal models of PD, and, more recently, human clinical studies have verified exercise’s disease-modifying effect. Aerobic exercise and resistance training improve many of PD’s motor and non-motor symptoms, while neuromotor therapy and stretching/flexibility exercises positively contribute to the quality of life in people with PD. Therefore, understanding the role of exercise in managing this complex disorder is crucial. Exerkines are bioactive substances that are synthesized and released during exercise and have been implicated in several positive health outcomes, including neuroprotection. Exerkines protect neuronal cells in vitro and rodent PD models in vivo. Aerobic exercise and resistance training both increase exerkine levels in the blood, suggesting a role for exerkines in the neuroprotective theory. Many exerkines demonstrate the potential for protecting the brain against pathological missteps caused by PD. Every person (people) with Parkinson’s (PwP) needs a comprehensive exercise plan tailored to their unique needs and abilities. Here, we provide an exercise template to help PwP understand the importance of exercise for treating PD, describe barriers confronting many PwP in their attempt to exercise, provide suggestions for overcoming these barriers, and explore the role of exerkines in managing PD. In conclusion, exercise and exerkines together create a powerful neuroprotective system that should contribute to slowing the chronic progression of PD. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

14 pages, 975 KiB

Open AccessArticle

Tropomyosin Isoforms Segregate into Distinct Clusters on Single Actin Filaments

by Peyman Obeidy, Thomas Sobey, Philip R. Nicovich, Adelle C. F. Coster and Elvis Pandzic

Biomolecules 2024, 14(10), 1240; https://doi.org/10.3390/biom14101240 - 30 Sep 2024

Abstract

Tropomyosins (Tpms) are rod-shaped proteins that interact head-to-tail to form a continuous polymer along both sides of most cellular actin filaments. Head-to-tail interaction between adjacent Tpm molecules and the formation of an overlap complex between them leads to the assembly of actin filaments [...] Read more.

Tropomyosins (Tpms) are rod-shaped proteins that interact head-to-tail to form a continuous polymer along both sides of most cellular actin filaments. Head-to-tail interaction between adjacent Tpm molecules and the formation of an overlap complex between them leads to the assembly of actin filaments with one type of Tpm isoform in time and space. Variations in the affinity of tropomyosin isoforms for different actin structures are proposed as a potential sorting mechanism. However, the detailed mechanisms of the spatio-temporal sorting of Tpms remain elusive. In this study, we investigated the early intermediates during actin–tropomyosin filament assembly, using a skeletal/cardiac Tpm isoform (Tpm1.1) and a cytoskeletal isoform (Tpm1.6) that differ only in the last 27 amino acids. We investigated how the muscle isoform Tpm1.1 and the cytoskeletal isoform Tpm1.6 nucleate domains on the actin filament, and tested whether (1) recruitment is affected by the actin isoform (muscle vs. cytoskeletal) and (2) whether there is specificity in recruiting the same isoform to a domain at these early stages. To address these questions, actin filaments were exposed to low concentrations of fluorescent tropomyosins in solution. The filaments were immobilized onto glass coverslips and the pattern of decoration was visualized by TIRF microscopy. We show that at the early assembly stage, tropomyosins formed multiple distinct fluorescent domains (here termed “cluster”) on the actin filaments. An automated image analysis algorithm was developed and validated to identify clusters and estimate the number of tropomyosins in each cluster. The analysis showed that tropomyosin isoform sorting onto an actin filament is unlikely to be driven by a preference for nucleating on the corresponding muscle or cytoskeletal actin isoforms, but rather is facilitated by a higher probability of incorporating the same tropomyosin isoforms into an early assembly intermediate. We showed that the 27 amino acids at the end of each tropomyosin seem to provide enough molecular information for the attachment of the same tropomyosin isoforms adjacent to each other on an actin filament. This results in the formation of homogeneous clusters composed of the same isoform rather than clusters with mixed isoforms. Full article

(This article belongs to the Section Molecular Biophysics)

20 pages, 7161 KiB

Open AccessArticle

A Moderate Water Deficit Induces Profound Changes in the Proteome of Developing Maize Ovaries

by Thierry Balliau, Mariamawit Ashenafi, Mélisande Blein-Nicolas, Olivier Turc, Michel Zivy and Elodie Marchadier

Biomolecules 2024, 14(10), 1239; https://doi.org/10.3390/biom14101239 (registering DOI) - 30 Sep 2024

Abstract

Water deficit is a major cause of yield loss for maize (Zea mays), leading to ovary abortion when applied at flowering time. To help understand the mechanisms involved in this phenomenon, the proteome response to water deficit has been analysed in [...] Read more.

Water deficit is a major cause of yield loss for maize (Zea mays), leading to ovary abortion when applied at flowering time. To help understand the mechanisms involved in this phenomenon, the proteome response to water deficit has been analysed in developing ovaries at the silk emergence stage and five days later. Differential analysis, abundance pattern clustering and co-expression networks were performed in order to draw a general picture of the proteome changes all along ovary development and under the effect of water deficit. The results show that even mild water deficit has a major impact on ovary proteome, but this impact is very different from a response to stress. A part of the changes can be related to a slowdown of ovary development, while another part cannot. In particular, ovaries submitted to water deficit show an increase in proteins involved in protein biosynthesis and in vesicle transport together with a decrease in proteins involved in amino acid metabolism and proteolysis. According to the functions of increased proteins, the changes may be linked to auxin, brassinosteroids and jasmonate signalling but not abscisic acid. Full article

(This article belongs to the Section Molecular Biology)

20 pages, 877 KiB

Open AccessArticle

Lipidomics Analysis of Human HMC3 Microglial Cells in an In Vitro Model of Metabolic Syndrome

by Mateusz Chmielarz, Mariusz Aleksander Bromke, Mateusz Olbromski, Kamila Środa-Pomianek, Magdalena Frej-Mądrzak, Piotr Dzięgiel and Beata Sobieszczańska

Biomolecules 2024, 14(10), 1238; https://doi.org/10.3390/biom14101238 - 30 Sep 2024

Abstract

Metabolic endotoxemia (ME) is associated with bacterial lipopolysaccharide (LPS, endotoxin) and increased levels of saturated fatty acids (SFAs) in the bloodstream, causing systemic inflammation. ME usually accompanies obesity and a diet rich in fats, especially SFAs. Numerous studies confirm the effect of ME-related [...] Read more.

Metabolic endotoxemia (ME) is associated with bacterial lipopolysaccharide (LPS, endotoxin) and increased levels of saturated fatty acids (SFAs) in the bloodstream, causing systemic inflammation. ME usually accompanies obesity and a diet rich in fats, especially SFAs. Numerous studies confirm the effect of ME-related endotoxin on microglial activation. Our study aimed to assess lipid metabolism and immune response in microglia pre-stimulated with TNFα (Tumor Necrosis Factor α) and then with endotoxin and palmitic acid (PA). Using ELISA, we determined cytokines IL-1β, IL-10, IL-13 (interleukin-1β, -10, -13, and TGFβ (Transforming Growth Factor β) in the culture medium from microglial cells stimulated for 24 h with TNFα and then treated with LPS (10 ng/mL) and PA (200 µM) for 24 h. HMC3 (Human Microglial Cells clone 3) cells produced negligible amounts of IL-1β, IL-10, and IL-13 after stimulation but secreted moderate levels of TGFβ. Changes in lipid metabolism accompanied changes in TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) expression. HMC3 stimulation with endotoxin increased TREM2 expression, while PA treatment decreased it. Endotoxin increased ceramide levels, while PA increased triglyceride levels. These results indicated that pre-stimulation of microglia with TNFα significantly affects its interactions with LPS and PA and modulates lipid metabolism, which may lead to microglial activation silencing and neurodegeneration. Full article

(This article belongs to the Special Issue The Role of Microglia in Aging and Neurodegenerative Disease)

24 pages, 2424 KiB

Open AccessArticle

Placental Tissue Calcification and Its Molecular Pathways in Female Patients with Late-Onset Preeclampsia

by Miguel A. Ortega, Tatiana Pekarek, Diego De Leon-Oliva, Diego Liviu Boaru, Oscar Fraile-Martinez, Cielo García-Montero, Julia Bujan, Leonel Pekarek, Silvestra Barrena-Blázquez, Raquel Gragera, Patrocinio Rodríguez-Benitez, Mauricio Hernández-Fernández, Laura López-González, Raul Díaz-Pedrero, Ángel Asúnsolo, Melchor Álvarez-Mon, Natalio García-Honduvilla, Miguel A. Saez, Juan A. De León-Luis and Coral Bravo

Biomolecules 2024, 14(10), 1237; https://doi.org/10.3390/biom14101237 - 30 Sep 2024

Abstract

Preeclampsia (PE) is a complex multisystem disease characterized by hypertension of sudden onset (>20 weeks’ gestation) coupled with the presence of at least one additional complication, such as proteinuria, maternal organ dysfunction, or uteroplacental dysfunction. Hypertensive states during pregnancy carry life-threatening risks for [...] Read more.

Preeclampsia (PE) is a complex multisystem disease characterized by hypertension of sudden onset (>20 weeks’ gestation) coupled with the presence of at least one additional complication, such as proteinuria, maternal organ dysfunction, or uteroplacental dysfunction. Hypertensive states during pregnancy carry life-threatening risks for both mother and baby. The pathogenesis of PE develops due to a dysfunctional placenta with aberrant architecture that releases factors contributing to endothelial dysfunction, an antiangiogenic state, increased oxidative stress, and maternal inflammatory responses. Previous studies have shown a correlation between grade 3 placental calcifications and an elevated risk of developing PE at term. However, little is known about the molecular pathways leading to placental calcification. In this work, we studied the gene and protein expression of c-Jun N-terminal kinase (JNK), Runt-related transcription factor 2 (RUNX2), osteocalcin (OSC), osteopontin (OSP), pigment epithelium-derived factor (PEDF), MSX-2/HOX8, SOX-9, WNT-1, and β-catenin in placental tissue from women with late-onset PE (LO-PE). In addition, we employed von Kossa staining to detect mineral deposits in placental tissues. Our results show a significant increase of all these components in placentas from women with LO-PE. Therefore, our study suggests that LO-PE may be associated with the activation of molecular pathways of placental calcification. These results could be the starting point for future research to describe the molecular mechanisms that promote placental calcification in PE and the development of therapeutic strategies directed against it. Full article

(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)

15 pages, 3103 KiB

Open AccessArticle

Repurposing Nitazoxanide for Potential Treatment of Rare Disease Lymphangioleiomyomatosis

by Stella Bähr, Ryan W. Rue, Carly J. Smith, Jillian F. Evans, Hubert Köster, Vera P. Krymskaya and Dirk Pleimes

Biomolecules 2024, 14(10), 1236; https://doi.org/10.3390/biom14101236 - 30 Sep 2024

Abstract

Lymphangioleiomyomatosis (LAM) is a rare genetic lung disease. Unfortunately, treatment with the mTORC1 inhibitor Rapamycin only slows disease progression, and incomplete responses are common. Thus, there remains an urgent need to identify new targets for the development of curative LAM treatments. Nitazoxanide (NTZ) [...] Read more.

Lymphangioleiomyomatosis (LAM) is a rare genetic lung disease. Unfortunately, treatment with the mTORC1 inhibitor Rapamycin only slows disease progression, and incomplete responses are common. Thus, there remains an urgent need to identify new targets for the development of curative LAM treatments. Nitazoxanide (NTZ) is an orally bioavailable antiprotozoal small molecule drug approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in children and adults, with a demonstrated mTORC1 inhibitory effect in several human cell lines. NTZ’s excellent safety profile characterized by its more than 20 years of clinical use makes it a promising candidate for repurposing. Our rationale for this study was to further investigate NTZ’s effect using in vitro and in vivo LAM models and to elucidate the underlying molecular mechanism beyond mTORC1 inhibition. For this purpose, we investigated cell proliferation, cell viability, and changes in protein phosphorylation and expression in primary human cell cultures derived from LAM lung samples before translating our results into a syngeneic mouse model utilizing Tsc2-null cells. NTZ reduced cell growth for all tested cell lines at a dose of about 30 µM. Lower doses than that had no effect on cell viability, but doses above 45 µM lowered the viability by about 10 to 15% compared to control. Interestingly, our western blot revealed no inhibition of mTORC1 and only a mild effect on active ß-Catenin. Instead, NTZ had a pronounced effect on reducing pAkt. In the mouse model, prophylactic NTZ treatment via the intraperitoneal and oral routes had some effects on reducing lung lesions and improving body weight retention, but the results remain inconclusive. Full article

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14 pages, 7945 KiB

Open AccessReview

Caenorhabditis elegans as a Model to Study Aging and Photoaging

by Saowanee Jeayeng, Jirapan Thongsroy and Sirithip Chuaijit

Biomolecules 2024, 14(10), 1235; https://doi.org/10.3390/biom14101235 - 30 Sep 2024

Abstract

Caenorhabditis elegans (C. elegans) has emerged as an outstanding model organism for investigating the aging process due to its shortened lifespan, well-defined genome, and accessibility of potent genetic tools. This review presents the current findings on chronological aging and photoaging in [...] Read more.

Caenorhabditis elegans (C. elegans) has emerged as an outstanding model organism for investigating the aging process due to its shortened lifespan, well-defined genome, and accessibility of potent genetic tools. This review presents the current findings on chronological aging and photoaging in C. elegans, exploring the elaborate molecular pathways that control these processes. The progression of chronological aging is characterized by a gradual deterioration of physiological functions and is influenced by an interaction of genetic and environmental factors, including the insulin/insulin-like signaling (IIS) pathway. In contrast, photoaging is characterized by increased oxidative stress, DNA damage, and activation of stress response pathways induced by UV exposure. Although the genetic mechanisms of chronological aging in C. elegans have been characterized by extensive research, the pathways regulating photoaging are comparatively less well-studied. Here, we provide an overview of the current understanding of aging research, including the crucial genes and genetic pathways involved in the aging and photoaging processes of C. elegans. Understanding the complex interactions between these factors will provide invaluable insights into the molecular mechanisms underlying chronological aging and photoaging and may lead to novel therapeutic approaches and further studies for promoting healthy aging in humans. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 2943 KiB

Open AccessArticle

An 11-mer Synthetic Peptide Suppressing Aggregation of Aβ25-35 and Resolving Its Aggregated Form Improves Test Performance in an Aβ25-35-Induced Alzheimer’s Mouse Model

by Rina Nakamura, Akira Matsuda, Youichirou Higashi, Yoshihiro Hayashi, Motomi Konishi, Motoaki Saito and Toshifumi Akizawa

Biomolecules 2024, 14(10), 1234; https://doi.org/10.3390/biom14101234 - 29 Sep 2024

Abstract

There is a high demand for the development of drugs against Alzheimer’s disease (AD), which is related to the misfolding and aggregation of Amyloid-β (Aβ), due to the increasing number of patients with AD. In our present study, we aimed to assess the [...] Read more.

There is a high demand for the development of drugs against Alzheimer’s disease (AD), which is related to the misfolding and aggregation of Amyloid-β (Aβ), due to the increasing number of patients with AD. In our present study, we aimed to assess the aggregation inhibitory effect of various synthetic YS-peptides on Aβ25-35 to identify an applicable peptide for clinical use for AD treatment and prevention. Suppression and aggregate resolution activities of YS-peptides against Aβ25-35 were evaluated using a Thioflavin T assay and scanning electron microscopy (SEM). Structure–activity relationship studies revealed that YS-RD11 (RETLVYLTHLD) and YS-RE16 (RETLVYLTHLDYDDTE) showed suppression and aggregate-resolution activities. The effect of YS-peptides on phagocytosis in microglial cells (BV-2 cells) demonstrated that YS-RD11 and YS-RE16 activated the phagocytic ability of microglia. In the Aβ25-35-induced AD mouse model, YS-RD11 prevented and improved the deficits in short-term memory. In conclusion, YS-RD11 is a suitable candidate therapeutic drug against AD and uses a strategy similar to that used for antibodies. Full article

(This article belongs to the Special Issue Amyloid-Beta and Alzheimer’s Disease)

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20 pages, 5597 KiB

Open AccessArticle

Isorhamnetin Alleviates Renal Fibrosis by Inducing Endogenous Hydrogen Sulfide and Regulating Thiol-Based Redox State in Obstructed Kidneys

by Zhen Zhang, Haiyan Zhang, Jianyu Shi, Zheng Wang, Yanni Liang, Jingao Yu, Hongbo Wang, Zhongxing Song, Zhishu Tang, Dongbo Zhang and Jian Yao

Biomolecules 2024, 14(10), 1233; https://doi.org/10.3390/biom14101233 - 29 Sep 2024

Abstract

Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against [...] Read more.

Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against renal fibrosis and the underlying mechanisms are still poorly understood. Given that many actions of ISO could be similarly attained by hydrogen sulfide (H₂S), we speculated that ISO may work through the induction of endogenous H₂S. To test the hypothesis, we established the unilateral ureteral obstruction (UUO) renal fibrosis rat model and transforming growth factor-β1(TGF-β1)-induced fibrosis in cultured renal tubular cells. ISO treatment inhibited epithelial–mesenchymal transition (EMT) formation, decreased extracellular matrix (ECM) deposition, and relieved renal fibrosis. Further analysis revealed that ISO stimulated the expression of the H₂S-synthesizing enzyme cystathionine lyase (CSE) and cystathionine beta-synthase (CBS), and promoted H₂S production in vivo and in vitro. The elevated H₂S attenuated oxidative stress and elevated the thiol level. It induced Keap1 sulfhydration, disrupted Keap1-Nrf2 interaction, and promoted the entry of Nrf2 into the nucleus. Finally, we found that circulating H₂S mainly derived from the liver, and not the kidney. Collectively, our study revealed that ISO alleviated renal fibrosis by inducing endogenous H₂S and regulating Keap1-Nrf2 interaction through sulfhydration of Keap1. Endogenous H₂S could be an important mediator underlying the pharmacological actions of ISO. Due to the multifunctional properties of H₂S, the H₂S-inducing nature of ISO could be exploited to treat various diseases. Full article

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15 pages, 4617 KiB

Open AccessArticle

Human Coronavirus 229E Uses Clathrin-Mediated Endocytosis as a Route of Entry in Huh-7 Cells

by Sabina Andreu, Inés Ripa, José Antonio López-Guerrero and Raquel Bello-Morales

Biomolecules 2024, 14(10), 1232; https://doi.org/10.3390/biom14101232 - 29 Sep 2024

Abstract

Human coronavirus 229E (HCoV-229E) is an endemic coronavirus responsible for approximately one-third of “common cold” cases. To infect target cells, HCoV-229E first binds to its receptor on the cell surface and then can follow different pathways, entering by direct fusion or by taking [...] Read more.

Human coronavirus 229E (HCoV-229E) is an endemic coronavirus responsible for approximately one-third of “common cold” cases. To infect target cells, HCoV-229E first binds to its receptor on the cell surface and then can follow different pathways, entering by direct fusion or by taking advantage of host cell mechanisms such as endocytosis. Based on the role of clathrin, the process can be classified into clathrin-dependent or -independent endocytosis. This study characterizes the role of clathrin-mediated endocytosis (CME) in HCoV-229E infection of the human hepatoma cell line Huh-7. Using specific CME inhibitory drugs, we demonstrated that blocking CME significantly reduces HCoV-229E infection. Additionally, CRISPR/Cas9-mediated knockout of the µ subunit of adaptor protein complex 2 (AP-2) further corroborated the role of CME, as KOs showed over a 50% reduction in viral infection. AP-2 plays an important role in clathrin recruitment and the maturation of clathrin-coated vesicles. Our study also confirmed that in Huh-7 cells, HCoV-229E requires endosomal acidification for successful entry, as viral entry decreased when treated with lysomotropic agents. Furthermore, the colocalization of HCoV-229E with early endosome antigen 1 (EEA-1), only present in early endosomes, suggested that the virus uses an endosomal route for entry. These findings highlight, for the first time, the role of CME in HCoV-229E infection and confirm previous data of the use of the endosomal route at a low pH in the experimental cell model Huh-7. Our results provide new insights into the mechanisms of entry of HCoV-229E and provide a new basis for the development of targeted antiviral therapies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Viral Infections)

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15 pages, 1028 KiB

Open AccessReview

Emerging Role of the Slit/Roundabout (Robo) Signaling Pathway in Glioma Pathogenesis and Potential Therapeutic Options

by Mariam Markouli, Athina Papachristou, Anastasios Politis, Efstathios Boviatsis and Christina Piperi

Biomolecules 2024, 14(10), 1231; https://doi.org/10.3390/biom14101231 - 29 Sep 2024

Abstract

Gliomas represent the most common primary Central Nervous System (CNS) tumors, characterized by increased heterogeneity, dysregulated intracellular signaling, extremely invasive properties, and a dismal prognosis. They are generally resistant to existing therapies and only a few molecular targeting options are currently available. In [...] Read more.

Gliomas represent the most common primary Central Nervous System (CNS) tumors, characterized by increased heterogeneity, dysregulated intracellular signaling, extremely invasive properties, and a dismal prognosis. They are generally resistant to existing therapies and only a few molecular targeting options are currently available. In search of signal transduction pathways with a potential impact in glioma growth and immunotherapy, the Slit guidance ligands (Slits) and their Roundabout (Robo) family of receptors have been revealed as key regulators of tumor cells and their microenvironment. Recent evidence indicates the implication of the Slit/Robo signaling pathway in inflammation, cell migration, angiogenesis, and immune cell infiltration of gliomas, suppressing or promoting the expression of pivotal proteins, such as cell adhesion molecules, matrix metalloproteinases, interleukins, angiogenic growth factors, and immune checkpoints. Herein, we discuss recent data on the significant implication of the Slit/Robo signaling pathway in glioma pathology along with the respective targeting options, including immunotherapy, monoclonal antibody therapy, and protein expression modifiers. Full article

(This article belongs to the Special Issue Signal Transduction to Transcription Factors in Health and Disease—Honorary Special Issue Commemorating the Work of Prof. Athanasios G. Papavassiliou)

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14 pages, 1591 KiB

Open AccessArticle

Boosting Serotonin Synthesis Is Not Sufficient to Improve Motor Coordination of Mecp2 Heterozygous Mouse Model of Rett Syndrome

by Claudia Villani, Giuseppina Sacchetti and Roberto W. Invernizzi

Biomolecules 2024, 14(10), 1230; https://doi.org/10.3390/biom14101230 - 29 Sep 2024

Abstract

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the methyl-CpG-binding protein2 (MECP2) gene. Serotonin reuptake inhibitors improve motor coordination in Mecp2 heterozygous (Het) mice and serotonin depletion prevented this [...] Read more.

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the methyl-CpG-binding protein2 (MECP2) gene. Serotonin reuptake inhibitors improve motor coordination in Mecp2 heterozygous (Het) mice and serotonin depletion prevented this effect. Here, we assess alterations in indole levels in various brain regions and whether boosting brain serotonin synthesis with the serotonin precursors tryptophan, 5-hydroxytryptophan and α-lactalbumin rescued motor coordination deficit of Mecp2 Het mice. Motor coordination was assessed in the accelerated rotarod during and after systemic administration of serotonin precursors for 2–3 weeks. Since no data are available, the effect of α-lactalbumin on tryptophan, serotonin and 5-hydroxyindoleacetic acid levels was evaluated in various brain regions in order to identify the dose of ALAC to evaluate on motor coordination. As compared to WT, Mecp2 Het mice show reduced levels of serotonin in the whole brain, hippocampus, brainstem and cerebral cortex, but not the striatum. Reduced levels of 5-hydroxyindoleacetic acid were observed in the hippocampus and brainstem. Doses of serotonin precursors increasing brain tryptophan and/or serotonin production and metabolism had no effect on motor coordination. The results indicate that boosting serotonin synthesis is not sufficient to improve motor coordination of Mecp2 Het mice. Full article

(This article belongs to the Special Issue Molecular Advances in Rett Syndrome and Other Chromatin Related Disorders)

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14 pages, 4098 KiB

Open AccessArticle

Nucleoside Analogs in ADAR Guide Strands Enable Editing at 5′-GA Sites

by Aashrita Manjunath, Jeff Cheng, Kristen B Campbell, Casey S. Jacobsen, Herra G. Mendoza, Leila Bierbaum, Victorio Jauregui-Matos, Erin E. Doherty, Andrew J. Fisher and Peter A. Beal

Biomolecules 2024, 14(10), 1229; https://doi.org/10.3390/biom14101229 - 29 Sep 2024

Abstract

Adenosine Deaminases Acting on RNA (ADARs) are members of a family of RNA editing enzymes that catalyze the conversion of adenosine into inosine in double-stranded RNA (dsRNA). ADARs’ selective activity on dsRNA presents the ability to correct mutations at the transcriptome level using [...] Read more.

Adenosine Deaminases Acting on RNA (ADARs) are members of a family of RNA editing enzymes that catalyze the conversion of adenosine into inosine in double-stranded RNA (dsRNA). ADARs’ selective activity on dsRNA presents the ability to correct mutations at the transcriptome level using guiding oligonucleotides. However, this approach is limited by ADARs’ preference for specific sequence contexts to achieve efficient editing. Substrates with a guanosine adjacent to the target adenosine in the 5′ direction (5′-GA) are edited less efficiently compared to substrates with any other canonical nucleotides at this position. Previous studies showed that a G/purine mismatch at this position results in more efficient editing than a canonical G/C pair. Herein, we investigate a series of modified oligonucleotides containing purine or size-expanded nucleoside analogs on guide strands opposite the 5′-G (−1 position). The results demonstrate that modified adenosine and inosine analogs enhance editing at 5′-GA sites. Additionally, the inclusion of a size-expanded cytidine analog at this position improves editing over a control guide bearing cytidine. High-resolution crystal structures of ADAR:/RNA substrate complexes reveal the manner by which both inosine and size-expanded cytidine are capable of activating editing at 5′-GA sites. Further modification of these altered guide sequences for metabolic stability in human cells demonstrates that the incorporation of specific purine analogs at the −1 position significantly improves editing at 5′-GA sites. Full article

(This article belongs to the Special Issue RNA Therapeutics)

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24 pages, 3772 KiB

Open AccessReview

The Important Role of Aquaglyceroporin 7 in Health and Disease

by Jing Liu, Ziwei Xia, Shuhong Peng, Juanjuan Xia, Ruixiang Xu, Xin Wang, Fei Li and Weifeng Zhu

Biomolecules 2024, 14(10), 1228; https://doi.org/10.3390/biom14101228 - 28 Sep 2024

Abstract

Aquaporins (AQPs) are highly conserved small transmembrane proteins that facilitate the transport of water and small solutes across cell membranes. Aquaglyceroporin 7 (AQP7), a significant member of the AQP family, is widely distributed throughout the body. For years, AQP7 was predominantly recognized for [...] Read more.

Aquaporins (AQPs) are highly conserved small transmembrane proteins that facilitate the transport of water and small solutes across cell membranes. Aquaglyceroporin 7 (AQP7), a significant member of the AQP family, is widely distributed throughout the body. For years, AQP7 was predominantly recognized for its role as a small-molecule transporter, facilitating the passage of small molecular substances. However, growing studies have revealed that AQP7 is also involved in the regulation of lipid synthesis, gluconeogenesis, and energy homeostasis, and it is intimately linked to a variety of diseases, such as obesity, type 2 diabetes mellitus, cardiovascular diseases, cancer, and inflammatory bowel disease. This article presents a comprehensive overview of the structure of AQP7, its regulatory mechanisms, its vital roles in both healthy and diseased states, and potential therapeutic advancements. We hope that these studies will serve as a valuable reference for the development of future treatments and diagnostic protocols targeting AQP7. Full article

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38 pages, 1324 KiB

Open AccessReview

Itching for Answers: A Comprehensive Review of Cholestatic Pruritus Treatments

by Filippo Gabrielli, Eleonora Crepaldi, Alessia Cavicchioli, Marco Rivi, Arianna Carmen Costanzo, Carmela Cursaro and Pietro Andreone

Biomolecules 2024, 14(10), 1227; https://doi.org/10.3390/biom14101227 - 28 Sep 2024

Abstract

Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it [...] Read more.

Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future. Full article

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18 pages, 25736 KiB

Open AccessArticle

Dipsacoside B Attenuates Atherosclerosis by Promoting Autophagy to Inhibit Macrophage Lipid Accumulation

by Wenjuan Quan, Taoli Sun, Bo Hu, Quanye Luo, Yancheng Zhong, Wen Chen and Qinhui Tuo

Biomolecules 2024, 14(10), 1226; https://doi.org/10.3390/biom14101226 - 27 Sep 2024

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and foam cell formation in the arterial wall. Promoting macrophage autophagy has emerged as a promising therapeutic strategy against atherosclerosis. Dipsacoside B (DB) is an oleanane-type pentacyclic triterpenoid saponin extracted from Lonicerae flos [...] Read more.

Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and foam cell formation in the arterial wall. Promoting macrophage autophagy has emerged as a promising therapeutic strategy against atherosclerosis. Dipsacoside B (DB) is an oleanane-type pentacyclic triterpenoid saponin extracted from Lonicerae flos with potential anti-atherosclerotic properties. In this study, we investigated the effects of DB on atherosclerosis progression in ApoE^−/− mice fed a high-fat diet and explored the underlying mechanisms in oxidized low-density lipoprotein (ox-LDL)-induced foam cells. DB treatment significantly reduced atherosclerotic lesion size, improved plaque stability, and regulated lipid metabolism without impairing liver and kidney function in ApoE^−/− mice. In vitro studies revealed that DB dose-dependently inhibited ox-LDL internalization and intracellular lipid accumulation in RAW264.7 macrophages. Mechanistically, DB induced autophagy, as evidenced by increased autophagosome formation and upregulated expression of autophagy markers LC3-II and p62 both in vivo and in vitro. Inhibition of autophagy by chloroquine abolished the antiatherosclerotic and pro-autophagic effects of DB. Furthermore, DB treatment increased LC3-II and p62 mRNA levels, suggesting transcriptional regulation of autophagy. Collectively, our findings demonstrate that DB exerts anti-atherosclerotic effects by inhibiting foam cell formation via autophagy induction, providing new insights into the pharmacological actions of DB and its potential as a therapeutic agent against atherosclerosis. Full article

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16 pages, 6653 KiB

Open AccessArticle

Chloramphenicol Interferes with 50S Ribosomal Subunit Maturation via Direct and Indirect Mechanisms

by Ting Yu and Fuxing Zeng

Biomolecules 2024, 14(10), 1225; https://doi.org/10.3390/biom14101225 - 27 Sep 2024

Abstract

Chloramphenicol (CAM), a well-known broad-spectrum antibiotic, inhibits peptide bond formation in bacterial ribosomes. It has been reported to affect ribosome assembly mainly through disrupting the balance of ribosomal proteins. The present study investigates the multifaceted effects of CAM on the maturation of the [...] Read more.

Chloramphenicol (CAM), a well-known broad-spectrum antibiotic, inhibits peptide bond formation in bacterial ribosomes. It has been reported to affect ribosome assembly mainly through disrupting the balance of ribosomal proteins. The present study investigates the multifaceted effects of CAM on the maturation of the 50S ribosomal subunit in Escherichia coli (E. coli). Using label-free quantitative mass spectrometry (LFQ-MS), we observed that CAM treatment also leads to the upregulation of assembly factors. Further cryo-electron microscopy (cryo-EM) analysis of the ribosomal precursors characterized the CAM-treatment-accumulated pre-50S intermediates. Heterogeneous reconstruction identified 26 distinct pre-50S intermediates, which were categorized into nine main states based on their structural features. Our structural analysis highlighted that CAM severely impedes the formation of the central protuberance (CP), H89, and H58 during 50S ribosomal subunit maturation. The ELISA assay further demonstrated the direct binding of CAM to the ribosomal precursors, suggesting that the interference with 50S maturation occurs through a combination of direct and indirect mechanisms. These findings provide new insights into the mechanism of the action of CAM and provide a foundation for a better understanding of the assembly landscapes of the ribosome. Full article

(This article belongs to the Special Issue The Structure and Function of Proteins, Lipids and Nucleic Acids)

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24 pages, 5640 KiB

Open AccessReview

Biopolymers as Sustainable and Active Packaging Materials: Fundamentals and Mechanisms of Antifungal Activities

by Fernanda González-Arancibia, Maribel Mamani, Cristian Valdés, Caterina Contreras-Matté, Eric Pérez, Javier Aguilera, Victoria Rojas, Howard Ramirez-Malule and Rodrigo Andler

Biomolecules 2024, 14(10), 1224; https://doi.org/10.3390/biom14101224 - 27 Sep 2024

Abstract

Developing bio-based and biodegradable materials has become important to meet current market demands, government regulations, and environmental concerns. The packaging industry, particularly for food and beverages, is known to be the world’s largest consumer of plastics. Therefore, the demand for sustainable alternatives in [...] Read more.

Developing bio-based and biodegradable materials has become important to meet current market demands, government regulations, and environmental concerns. The packaging industry, particularly for food and beverages, is known to be the world’s largest consumer of plastics. Therefore, the demand for sustainable alternatives in this area is needed to meet the industry’s requirements. This review presents the most commonly used bio-based and biodegradable packaging materials, bio-polyesters, and polysaccharide-based polymers. At the same time, a major problem in food packaging is presented: fungal growth and, consequently, food spoilage. Different types of antifungal compounds, both natural and synthetic, are explained in terms of structure and mechanism of action. The main uses of these antifungal compounds and their degree of effectiveness are detailed. State-of-the-art studies have shown a clear trend of increasing studies on incorporating antifungals in biodegradable materials since 2000. The bibliometric networks showed studies on active packaging, biodegradable polymers, films, antimicrobial and antifungal activities, essential oils, starch and polysaccharides, nanocomposites, and nanoparticles. The combination of the development of bio-based and biodegradable materials with the ability to control fungal growth promotes both sustainability and the innovative enhancement of the packaging sector. Full article

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