Cells

16 pages, 2568 KiB

Open AccessReview

Molecular Mechanisms of Autophagy Decline during Aging

by Shaun H. Y. Lim, Malene Hansen and Caroline Kumsta

Cells 2024, 13(16), 1364; https://doi.org/10.3390/cells13161364 (registering DOI) - 16 Aug 2024

Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. [...] Read more.

Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age. In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy. Full article

(This article belongs to the Special Issue Autophagy Meets Aging 2024)

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11 pages, 3984 KiB

Open AccessArticle

Role of Piezo1 in Terminal Density Reversal of Red Blood Cells

by Kuntal Dey, Ankie M. van Cromvoirt, Inga Hegemann, Jeroen S. Goede and Anna Bogdanova

Cells 2024, 13(16), 1363; https://doi.org/10.3390/cells13161363 (registering DOI) - 16 Aug 2024

Abstract

Density reversal of senescent red blood cells has been known for a long time, yet the identity of the candidate ion transporter(s) causing the senescent cells to swell is still elusive. While performing fractionation of RBCs from healthy individuals in Percoll density gradient [...] Read more.

Density reversal of senescent red blood cells has been known for a long time, yet the identity of the candidate ion transporter(s) causing the senescent cells to swell is still elusive. While performing fractionation of RBCs from healthy individuals in Percoll density gradient and characterization of the separated fractions, we identified a subpopulation of cells in low-density fraction (1.02% ± 0.47) showing signs of senescence such as loss of membrane surface area associated with a reduction in band 3 protein abundance, and Phosphatidylserine (PS) exposure to the outer membrane. In addition, we found that these cells are overloaded with Na⁺ and Ca²⁺. Using a combination of blockers and activators of ion pumps and channels, we revealed reduced activity of Plasma membrane Ca²⁺ ATPase and an increase in Ca²⁺ and Na⁺ leaks through ion channels in senescent-like cells. Our data revealed that Ca²⁺ overload in these cells is a result of reduced PMCA activity and facilitated Ca²⁺ uptake via a hyperactive Piezo1 channel. However, we could not exclude the contribution of other Ca²⁺-permeable ion channels in this scenario. In addition, we found, as a universal mechanism, that an increase in intracellular Ca²⁺ reduced the initially high selectivity of Piezo1 channel for Ca²⁺ and allowed higher Na⁺ uptake, Na⁺ accumulation, and swelling. Full article

(This article belongs to the Collection Collection of Cell Aging—The Road Map of Aging)

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13 pages, 2131 KiB

Open AccessArticle

Evidence of Immunoproteasome Expression Onset in the Formative State of Pluripotency in Mouse Cells

by Daria Kriger, Uliana I. Podenkova, Evgeny I. Bakhmet, Evgenii Potapenko, Elena Ivanova, Alexey N. Tomilin and Anna S. Tsimokha

Cells 2024, 13(16), 1362; https://doi.org/10.3390/cells13161362 - 15 Aug 2024

Abstract

Embryonic stem cells (ESCs) are remarkable for the high activity level of ubiquitin–proteasome system—the molecular machinery of protein degradation in the cell. Various forms of the proteasome complexes comprising different subunits and interacting regulators are responsible for the substrate selectivity and degradation. Immunoproteasomes [...] Read more.

Embryonic stem cells (ESCs) are remarkable for the high activity level of ubiquitin–proteasome system—the molecular machinery of protein degradation in the cell. Various forms of the proteasome complexes comprising different subunits and interacting regulators are responsible for the substrate selectivity and degradation. Immunoproteasomes are amongst these forms which play an important role in antigen presentation; however, a body of recent evidence suggests their functions in pluripotent stem cells. Previous studies have established three consecutive phases of pluripotency, featured by epiblast cells and their cultured counterparts: naïve, formative, and primed phase. In this work, we report that immunoproteasomes and their chaperone co-regulators are suppressed in the naïve state but are readily upregulated in the formative phase of the pluripotency continuum, featured by epiblast-like cells (EpiLCs). Our data lay ground for the further investigation of the biological functions of immunoproteasome in the regulation of proteostasis during early mammalian development. Full article

(This article belongs to the Special Issue Molecular Machines in Cells: Natural, Semi-artificial, and Bioinspired Designs)

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17 pages, 3403 KiB

Open AccessArticle

Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site

by Claire Ghilain, Olivia Vidal-Cruchez, Aurélia Joly, Michelle Debatisse, Eric Gilson and Marie-Josèphe Giraud-Panis

Cells 2024, 13(16), 1361; https://doi.org/10.3390/cells13161361 - 15 Aug 2024

Abstract

Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to [...] Read more.

Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to topological stress. While negative supercoiling was previously observed, thus proving the existence of telomeric topological constraints, positive supercoils were never probed due to the lack of an appropriate tool. Indeed, the few tools available currently could only investigate unwound (Trioxsalen) or overwound (GapR) DNA topology (variations in twist) but not the variations in writhe (supercoils and plectonemes). To address this question, we have designed innovative tools aimed at analyzing both positive and negative DNA writhe in cells. Using them, we could observe the build-up of positive supercoils following replication stress and inhibition of Topoisomerase 2 on telomeres. TRF2 depletion caused both telomere relaxation and an increase in positive supercoils while the inhibition of Histone Deacetylase I and II by TSA only caused telomere relaxation. Moving outside telomeres, we also observed a build-up of positive supercoils on the FRA3B fragile site following replication stress, suggesting a topological model of DNA fragility for this site. Full article

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20 pages, 5429 KiB

Open AccessArticle

Modulation of Phytochemical Pathways and Antioxidant Activity in Peppermint by Salicylic Acid and GR24: A Molecular Approach

by Parisa Jariani, Manijeh Sabokdast, Taraneh Karami Moghadam, Farzaneh Nabati and Beata Dedicova

Cells 2024, 13(16), 1360; https://doi.org/10.3390/cells13161360 - 15 Aug 2024

Abstract

This study uncovers the potential of salicylic acid (SA) and synthetic Strigolactone (GR24) in enhancing menthol biosynthesis and antioxidant defense mechanisms in Mentha piperita L. Our comprehensive analysis, which included a series of controlled experiments and data analysis of the effects of these [...] Read more.

This study uncovers the potential of salicylic acid (SA) and synthetic Strigolactone (GR24) in enhancing menthol biosynthesis and antioxidant defense mechanisms in Mentha piperita L. Our comprehensive analysis, which included a series of controlled experiments and data analysis of the effects of these phytohormones on enzymatic antioxidants catalase (CAT) and ascorbate peroxidase (APX) and non-enzymatic antioxidants, including carotenoids and proline, revealed promising results. The study also examined their impact on lipid peroxidation, hydrogen peroxide levels, and the expression of genes critical to menthol and menthofuran synthesis. The results indicated that SA and GR24 significantly increased menthol production and reduced the levels of menthofuran and pulegone, suggesting upregulation in the plant’s innate defense systems. Furthermore, the activities of CAT and APX were elevated, reflecting a strengthened antioxidant response. Interestingly, the menthofuran synthase (MFS) was higher in the control group. At the same time, pulegone reductase (PR) genes and menthol dehydrogenase (MDH) gene expression were upregulated, highlighting the protective effects of SA and GR24. These findings underscore the potential of SA and GR24 to serve as effective bio-stimulants, improving the quality and resilience of peppermint plants and thereby contributing to eco-friendly agricultural practices in pollution-stressed environments. Full article

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15 pages, 2694 KiB

Open AccessReview

Zinc and Diabetes: A Connection between Micronutrient and Metabolism

by Rahnuma Ahmad, Ronald Shaju, Azeddine Atfi and Mohammed S. Razzaque

Cells 2024, 13(16), 1359; https://doi.org/10.3390/cells13161359 - 15 Aug 2024

Abstract

Diabetes mellitus is a global health problem and a major contributor to mortality and morbidity. The management of this condition typically involves using oral antidiabetic medication, insulin, and appropriate dietary modifications, with a focus on macronutrient intake. However, several human studies have indicated [...] Read more.

Diabetes mellitus is a global health problem and a major contributor to mortality and morbidity. The management of this condition typically involves using oral antidiabetic medication, insulin, and appropriate dietary modifications, with a focus on macronutrient intake. However, several human studies have indicated that a deficiency in micronutrients, such as zinc, can be associated with insulin resistance as well as greater glucose intolerance. Zinc serves as a chemical messenger, acts as a cofactor to increase enzyme activity, and is involved in insulin formation, release, and storage. These diverse functions make zinc an important trace element for the regulation of blood glucose levels. Adequate zinc levels have also been shown to reduce the risk of developing diabetic complications. This review article explains the role of zinc in glucose metabolism and the effects of its inadequacy on the development, progression, and complications of diabetes mellitus. Furthermore, it describes the impact of zinc supplementation on preventing diabetes mellitus. The available information suggests that zinc has beneficial effects on the management of diabetic patients. Although additional large-scale randomized clinical trials are needed to establish zinc’s clinical utility further, efforts should be made to increase awareness of its potential benefits on human health and disease. Full article

(This article belongs to the Special Issue Diabetes-Induced Organ Damage: Cellular Mechanisms and Therapeutic Opportunities)

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20 pages, 3434 KiB

Open AccessArticle

Multiscale Modeling of Bistability in the Yeast Polarity Circuit

by Siarhei Hladyshau, Kaiyun Guan, Nivedita Nivedita, Beverly Errede, Denis Tsygankov and Timothy C. Elston

Cells 2024, 13(16), 1358; https://doi.org/10.3390/cells13161358 - 15 Aug 2024

Abstract

Cell polarity refers to the asymmetric distribution of proteins and other molecules along a specified axis within a cell. Polarity establishment is the first step in many cellular processes. For example, directed growth or migration requires the formation of a cell front and [...] Read more.

Cell polarity refers to the asymmetric distribution of proteins and other molecules along a specified axis within a cell. Polarity establishment is the first step in many cellular processes. For example, directed growth or migration requires the formation of a cell front and back. In many cases, polarity occurs in the absence of spatial cues. That is, the cell undergoes symmetry breaking. Understanding the molecular mechanisms that allow cells to break symmetry and polarize requires computational models that span multiple spatial and temporal scales. Here, we apply a multiscale modeling approach to examine the polarity circuit of yeast. In addition to symmetry breaking, experiments revealed two key features of the yeast polarity circuit: bistability and rapid dismantling of the polarity site following a loss of signal. We used modeling based on ordinary differential equations (ODEs) to investigate mechanisms that generate these behaviors. Our analysis revealed that a model involving positive and negative feedback acting on different time scales captured both features. We then extend our ODE model into a coarse-grained reaction–diffusion equation (RDE) model to capture the spatial profiles of polarity factors. After establishing that the coarse-grained RDE model qualitatively captures key features of the polarity circuit, we expand it to more accurately capture the biochemical reactions involved in the system. We convert the expanded model to a particle-based model that resolves individual molecules and captures fluctuations that arise from the stochastic nature of biochemical reactions. Our models assume that negative regulation results from negative feedback. However, experimental observations do not rule out the possibility that negative regulation occurs through an incoherent feedforward loop. Therefore, we conclude by using our RDE model to suggest how negative feedback might be distinguished from incoherent feedforward regulation. Full article

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17 pages, 2746 KiB

Open AccessReview

The Formation and Renewal of Photoreceptor Outer Segments

by Jingjin Xu, Chengtian Zhao and Yunsi Kang

Cells 2024, 13(16), 1357; https://doi.org/10.3390/cells13161357 - 15 Aug 2024

Abstract

The visual system is essential for humans to perceive the environment. In the retina, rod and cone photoreceptor neurons are the initial sites where vision forms. The apical region of both cone and rod photoreceptors contains a light-sensing organelle known as the outer [...] Read more.

The visual system is essential for humans to perceive the environment. In the retina, rod and cone photoreceptor neurons are the initial sites where vision forms. The apical region of both cone and rod photoreceptors contains a light-sensing organelle known as the outer segment (OS), which houses tens of thousands of light-sensitive opsins. The OSs of photoreceptors are not static; they require rhythmic renewal to maintain normal physiological functions. Disruptions in OS renewal can lead to various genetic disorders, such as retinitis pigmentosa (RP). Understanding the patterns and molecular mechanisms of photoreceptor OS renewal remains one of the most intriguing topics in visual biology. This review aims to elucidate the structure of photoreceptor OSs, the molecular mechanisms underlying photoreceptor OS renewal, and the retinal diseases resulting from defects in this renewal process. Additionally, we will explore retinal diseases related to photoreceptor OS renewal and potential therapeutic strategies, concluding with a discussion on future research directions for OS renewal. Full article

(This article belongs to the Special Issue Eye Development and Evolution: Cellular and Molecular Events)

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22 pages, 3369 KiB

Open AccessArticle

The Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association with Tumor Stromal Inflammation

by Raymond L. Konger, Xiaoling Xuei, Ethel Derr-Yellin, Fang Fang, Hongyu Gao and Yunlong Liu

Cells 2024, 13(16), 1356; https://doi.org/10.3390/cells13161356 - 15 Aug 2024

Abstract

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-^epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, [...] Read more.

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-^epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-/-^epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-^epi and publicly available human and/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity, while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPARδ has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs. Full article

(This article belongs to the Special Issue The Role of PPARs in Disease - Volume III)

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24 pages, 3616 KiB

Open AccessReview

Breath and Sputum Analyses in Asthmatic Patients: An Overview

by Piera Soccio, Carla Maria Irene Quarato, Pasquale Tondo, Donato Lacedonia, Anela Hoxhallari, Maria Pia Foschino Barbaro and Giulia Scioscia

Cells 2024, 13(16), 1355; https://doi.org/10.3390/cells13161355 - 14 Aug 2024

Abstract

Recent advancements in asthma management include non-invasive methodologies such as sputum analysis, exhaled breath condensate (EBC), and fractional exhaled nitric oxide (FeNO). These techniques offer a means to assess airway inflammation, a critical feature of asthma, without invasive procedures. Sputum analysis provides detailed [...] Read more.

Recent advancements in asthma management include non-invasive methodologies such as sputum analysis, exhaled breath condensate (EBC), and fractional exhaled nitric oxide (FeNO). These techniques offer a means to assess airway inflammation, a critical feature of asthma, without invasive procedures. Sputum analysis provides detailed insights into airway inflammation patterns and cellular composition, guiding personalized treatment strategies. EBC collection, reflecting bronchoalveolar lining fluid composition, provides a non-invasive window into airway physiology. FeNO emerges as a pivotal biomarker, offering insights into eosinophilic airway inflammation and aiding in asthma diagnosis, treatment monitoring, and the prediction of exacerbation risks. Despite inherent limitations, each method offers valuable tools for a more comprehensive assessment of asthma. Combining these techniques with traditional methods like spirometry may lead to more personalized treatment plans and improved patient outcomes. Future research is crucial to refine protocols, validate biomarkers, and establish comprehensive guidelines in order to enhance asthma management with tailored therapeutic strategies and improved patient outcomes. Full article

(This article belongs to the Special Issue Cell Biology: State-of-the-Art and Perspectives in Italy 2024)

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21 pages, 3455 KiB

Open AccessReview

Autophagy and Female Fertility: Mechanisms, Clinical Implications, and Emerging Therapies

by Abdel Halim Harrath, Md Ataur Rahman, Sujay Kumar Bhajan, Anup Kumar Bishwas, MD. Hasanur Rahman, Saleh Alwasel, Maroua Jalouli, Sojin Kang, Moon Nyeo Park and Bonglee Kim

Cells 2024, 13(16), 1354; https://doi.org/10.3390/cells13161354 - 14 Aug 2024

Abstract

Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, [...] Read more.

Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, and infertility. Existing research emphasizes the crucial significance of autophagy in embryo implantation, specifically in the endometrium, highlighting its necessity in ensuring proper fetal development. Although some knowledge has been gained, there is still a lack of research on the specific molecular impacts of autophagy on the quality of oocytes, the growth of follicles, and general reproductive health. Autophagy plays a role in the maturation, quality, and development of oocytes. It is also involved in reproductive aging, contributing to reductions in reproductive function that occur with age. This review explores the physiological functions of autophagy in the female reproductive system, its participation in reproductive toxicity, and its important connections with the endometrium and embryo. In addition, this study investigates the possibility of emerging treatment approaches that aim to modify autophagy, using both natural substances and synthetic molecules, to improve female fertility and reproductive outcomes. Additionally, this review intends to inspire future exploration into the intricate role of autophagy in female reproductive health by reviewing recent studies and pinpointing areas where current knowledge is lacking. Subsequent investigations should prioritize the conversion of these discoveries into practical uses in the medical field, which could potentially result in groundbreaking therapies for infertility and other difficulties related to reproduction. Therefore, gaining a comprehensive understanding of the many effects of autophagy on female fertility would not only further the field of reproductive biology but also open new possibilities for diagnostic and treatment methods. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gynecological Disorders)

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24 pages, 6002 KiB

Open AccessReview

The Interplay between Airway Cilia and Coronavirus Infection, Implications for Prevention and Control of Airway Viral Infections

by Xuyao Dai, Ruodan Xu and Ning Li

Cells 2024, 13(16), 1353; https://doi.org/10.3390/cells13161353 - 14 Aug 2024

Abstract

Coronaviruses (CoVs) are a class of respiratory viruses with the potential to cause severe respiratory diseases by infecting cells of the upper respiratory tract, bronchial epithelium, and lung. The airway cilia are distributed on the surface of respiratory epithelial cells, forming the first [...] Read more.

Coronaviruses (CoVs) are a class of respiratory viruses with the potential to cause severe respiratory diseases by infecting cells of the upper respiratory tract, bronchial epithelium, and lung. The airway cilia are distributed on the surface of respiratory epithelial cells, forming the first point of contact between the host and the inhaled coronaviruses. The function of the airway cilia is to oscillate and sense, thereby defending against and removing pathogens to maintain the cleanliness and patency of the respiratory tract. Following infection of the respiratory tract, coronaviruses exploit the cilia to invade and replicate in epithelial cells while also damaging the cilia to facilitate the spread and exacerbation of respiratory diseases. It is therefore imperative to investigate the interactions between coronaviruses and respiratory cilia, as well as to elucidate the functional mechanism of respiratory cilia following coronavirus invasion, in order to develop effective strategies for the prevention and treatment of respiratory viral infections. This review commences with an overview of the fundamental characteristics of airway cilia, and then, based on the interplay between airway cilia and coronavirus infection, we propose that ciliary protection and restoration may represent potential therapeutic approaches in emerging and re-emerging coronavirus pandemics. Full article

(This article belongs to the Special Issue Primary Cilia in Health and Diseases)

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15 pages, 3179 KiB

Open AccessArticle

CMTM3 Suppresses Proliferation and Osteogenic Transdifferentiation of C2C12 Myoblasts through p53 Upregulation

by Enzhao Shen, Meiyu Piao, Yuankuan Li, Yuecheng Wu, Sihang Li, Sung Ho Lee, Litai Jin and Kwang Youl Lee

Cells 2024, 13(16), 1352; https://doi.org/10.3390/cells13161352 - 14 Aug 2024

Abstract

CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3), a member of the CMTM family that is closely related to tumor occurrence and progression, plays crucial roles in the immune system, cardiovascular system, and male reproductive system. Recently, CMTM3 has emerged as a potential target for [...] Read more.

CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3), a member of the CMTM family that is closely related to tumor occurrence and progression, plays crucial roles in the immune system, cardiovascular system, and male reproductive system. Recently, CMTM3 has emerged as a potential target for treating diseases related to bone formation. However, additional studies are needed to understand the mechanisms by which CMTM3 regulates the process of osteogenic differentiation. In this study, we observed a significant downregulation of Cmtm3 expression during the transdifferentiation of C2C12 myoblasts into osteoblasts induced by BMP4. Cmtm3 overexpression suppressed proliferation and osteogenic differentiation in BMP4-induced C2C12 cells, whereas its knockdown conversely facilitated the process. Mechanistically, Cmtm3 overexpression upregulated both the protein and mRNA levels of p53 and p21. Conversely, Cmtm3 knockdown exerted the opposite effects. Additionally, we found that Cmtm3 interacts with p53 and increases protein stability by inhibiting proteasome-mediated ubiquitination and degradation. Notably, Trp53 downregulation abrogated the inhibitory effect of Cmtm3 on BMP4-induced proliferation and osteogenic differentiation of C2C12 myoblasts. Collectively, our findings provide key insights into the role of CMTM3 in regulating myoblast proliferation and transdifferentiation into osteoblasts, highlighting its significance in osteogenesis research. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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21 pages, 1867 KiB

Open AccessArticle

A Pilot Study on Proteomic Predictors of Mortality in Stable COPD

by Cesar Jessé Enríquez-Rodríguez, Carme Casadevall, Rosa Faner, Sergi Pascual-Guardia, Ady Castro-Acosta, José Luis López-Campos, Germán Peces-Barba, Luis Seijo, Oswaldo Antonio Caguana-Vélez, Eduard Monsó, Diego Rodríguez-Chiaradia, Esther Barreiro, Borja G. Cosío, Alvar Agustí, Joaquim Gea and on behalf of the BIOMEPOC Group

Cells 2024, 13(16), 1351; https://doi.org/10.3390/cells13161351 - 14 Aug 2024

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global mortality. Despite clinical predictors (age, severity, comorbidities, etc.) being established, proteomics offers comprehensive biological profiling to obtain deeper insights into COPD pathophysiology and survival prognoses. This pilot study aimed to identify [...] Read more.

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global mortality. Despite clinical predictors (age, severity, comorbidities, etc.) being established, proteomics offers comprehensive biological profiling to obtain deeper insights into COPD pathophysiology and survival prognoses. This pilot study aimed to identify proteomic footprints that could be potentially useful in predicting mortality in stable COPD patients. Plasma samples from 40 patients were subjected to both blind (liquid chromatography–mass spectrometry) and hypothesis-driven (multiplex immunoassays) proteomic analyses supported by artificial intelligence (AI) before a 4-year clinical follow-up. Among the 34 patients whose survival status was confirmed (mean age 69 ± 9 years, 29.5% women, FEV₁ 42 ± 15.3% ref.), 32% were dead in the fourth year. The analysis identified 363 proteins/peptides, with 31 showing significant differences between the survivors and non-survivors. These proteins predominantly belonged to different aspects of the immune response (12 proteins), hemostasis (9), and proinflammatory cytokines (5). The predictive modeling achieved excellent accuracy for mortality (90%) but a weaker performance for days of survival (Q² 0.18), improving mildly with AI-mediated blind selection of proteins (accuracy of 95%, Q² of 0.52). Further stratification by protein groups highlighted the predictive value for mortality of either hemostasis or pro-inflammatory markers alone (accuracies of 95 and 89%, respectively). Therefore, stable COPD patients’ proteomic footprints can effectively forecast 4-year mortality, emphasizing the role of inflammatory, immune, and cardiovascular events. Future applications may enhance the prognostic precision and guide preventive interventions. Full article

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17 pages, 11515 KiB

Open AccessArticle

Actin Cytoskeleton and Integrin Components Are Interdependent for Slit Diaphragm Maintenance in Drosophila Nephrocytes

by Megan Delaney, Yunpo Zhao, Joyce van de Leemput, Hangnoh Lee and Zhe Han

Cells 2024, 13(16), 1350; https://doi.org/10.3390/cells13161350 - 14 Aug 2024

Abstract

In nephrotic syndrome, the podocyte filtration structures are damaged in a process called foot process effacement. This is mediated by the actin cytoskeleton; however, which actins are involved and how they interact with other filtration components, like the basement membrane, remains poorly understood. [...] Read more.

In nephrotic syndrome, the podocyte filtration structures are damaged in a process called foot process effacement. This is mediated by the actin cytoskeleton; however, which actins are involved and how they interact with other filtration components, like the basement membrane, remains poorly understood. Here, we used the well-established Drosophila pericardial nephrocyte—the equivalent of podocytes in flies—knockdown models (RNAi) to study the interplay of the actin cytoskeleton (Act5C, Act57B, Act42A, and Act87E), alpha- and beta-integrin (basement membrane), and the slit diaphragm (Sns and Pyd). Knockdown of an actin gene led to variations of formation of actin stress fibers, the internalization of Sns, and a disrupted slit diaphragm cortical pattern. Notably, deficiency of Act5C, which resulted in complete absence of nephrocytes, could be partially mitigated by overexpressing Act42A or Act87E, suggesting at least partial functional redundancy. Integrin localized near the actin cytoskeleton as well as slit diaphragm components, but when the nephrocyte cytoskeleton or slit diaphragm was disrupted, this switched to colocalization, both at the surface and internalized in aggregates. Altogether, the data show that the interdependence of the slit diaphragm, actin cytoskeleton, and integrins is key to the structure and function of the Drosophila nephrocyte. Full article

(This article belongs to the Special Issue Drosophila Model in Molecular Mechanisms of Kidney Dysfunction)

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20 pages, 3931 KiB

Open AccessArticle

Delving into the Complexity of Valproate-Induced Autism Spectrum Disorder: The Use of Zebrafish Models

by Diletta Camussi, Valentina Naef, Letizia Brogi, Stefania Della Vecchia, Maria Marchese, Ferdinando Nicoletti, Filippo M. Santorelli and Rosario Licitra

Cells 2024, 13(16), 1349; https://doi.org/10.3390/cells13161349 - 14 Aug 2024

Abstract

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, [...] Read more.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose–response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 µM) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 µM worsened survival and hatching rates, while doses of 25 µM or more altered morphology, microglial status, and larval behaviours. VPA 50 µM also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD. Full article

(This article belongs to the Special Issue Modeling Developmental Processes and Disorders in Zebrafish)

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22 pages, 6337 KiB

Open AccessArticle

Co-Targeting of DTYMK and PARP1 as a Potential Therapeutic Approach in Uveal Melanoma

by Sylwia Oziębło, Jakub Mizera, Agata Górska, Mateusz Krzyziński, Paweł Karpiński, Anna Markiewicz, Maria Małgorzata Sąsiadek, Bożena Romanowska-Dixon, Przemysław Biecek, Mai P. Hoang, Antonina J. Mazur and Piotr Donizy

Cells 2024, 13(16), 1348; https://doi.org/10.3390/cells13161348 - 14 Aug 2024

Abstract

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with no standardized treatment for advanced disease. Based on preliminary bioinformatical analyses DTYMK and PARP1 were selected as potential therapeutic targets. High levels of both proteins were detected in uveal melanoma [...] Read more.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with no standardized treatment for advanced disease. Based on preliminary bioinformatical analyses DTYMK and PARP1 were selected as potential therapeutic targets. High levels of both proteins were detected in uveal melanoma cells and correlated with increased tumor growth and poor prognosis. In vitro tests on MP41 (BAP1 positive) and MP46 (BAP1 negative) cancer cell lines using inhibitors pamiparib (PARP1) and Ymu1 (DTYMK) demonstrated significant cytotoxic effects. Combined treatment had synergistic effects in MP41 and additive in MP46 cell lines, reducing cell proliferation and inhibiting the mTOR signaling pathway. Furthermore, the applied inhibitors in combination decreased cell motility and migration speed, especially for BAP1-negative cell lines. Our hypothesis of the double hit into tumoral DNA metabolism as a possible therapeutic option in uveal melanoma was confirmed since combined targeting of DTYMK and PARP1 affected all tested cytophysiological parameters with the highest efficiency. Our in vitro findings provide insights into novel therapeutic avenues for managing uveal melanoma, warranting further exploration in preclinical and clinical settings. Full article

(This article belongs to the Section Cellular Pathology)

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14 pages, 4563 KiB

Open AccessArticle

Sudden Intrauterine Unexplained Death (SIUD) and Oxidative Stress: Placental Immunohistochemical Markers

by Angelo Montana, Letizia Alfieri, Raffaella Marino, Pantaleo Greco, Cristina Taliento, Ezio Fulcheri, Anastasio Tini, Francesca Buffelli and Margherita Neri

Cells 2024, 13(16), 1347; https://doi.org/10.3390/cells13161347 - 13 Aug 2024

Abstract

Background: Intrauterine fetal death and perinatal death represent one of the most relevant medical scientific problems since, in many cases, even after extensive investigation, the causes remain unknown. The considerable increase in medical legal litigation in the obstetrical field that has witnessed in [...] Read more.

Background: Intrauterine fetal death and perinatal death represent one of the most relevant medical scientific problems since, in many cases, even after extensive investigation, the causes remain unknown. The considerable increase in medical legal litigation in the obstetrical field that has witnessed in recent years, especially in cases of stillborn births, has simultaneously involved the figure of the forensic pathologist in scientific research aimed at clarifying the pathophysiological processes underlying stillbirth. Methods: our study aims to analyze cases of sudden intrauterine unexplained death syndrome (SIUD) to evaluate the role of oxidative stress in the complex pathogenetic process of stillbirth. In particular, the immunohistochemical expression of specific oxidative stress markers (NOX2, NT, iNOS, 8-HODG, IL-6) was evaluated in tissue samples of placentas of SIUDs belonging to the extensive case series (20 cases), collected from autopsy cases of the University of Ferrara and Politecnica delle Marche between 2017 and 2023. Results: The study demonstrated the involvement of oxidative stress in intrauterine fetal deaths in the placenta of the cases examined. In SIUD, the most expressed oxidative stress markers were NOX2 and 8-HODG. Conclusions: The study contributes to investigating the role of oxidative stress in modulating different pathways in unexplained intrauterine fetal death (SIUD) tissues. Full article

(This article belongs to the Special Issue Signaling Pathways in Pregnancy)

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9 pages, 1547 KiB

Open AccessCommunication

Mutation in the Kinase Domain Alters the VEGFR2 Membrane Dynamics

by Michela Corsini, Cosetta Ravelli, Elisabetta Grillo, Mattia Domenichini and Stefania Mitola

Cells 2024, 13(16), 1346; https://doi.org/10.3390/cells13161346 - 13 Aug 2024

Abstract

Background: Recently, the substitution R1051Q in VEGFR2 has been described as a cancer-associated “gain of function” mutation. VEGFR2^R1051Q phosphorylation is ligand-independent and enhances the activation of intracellular pathways and cell growth both in vitro and in vivo. In cancer, this mutation is [...] Read more.

Background: Recently, the substitution R1051Q in VEGFR2 has been described as a cancer-associated “gain of function” mutation. VEGFR2^R1051Q phosphorylation is ligand-independent and enhances the activation of intracellular pathways and cell growth both in vitro and in vivo. In cancer, this mutation is found in heterozygosity, suggesting that an interaction between VEGFR2^R1051Q and VEGFR2^WT may occur and could explain, at least in part, how VEGFR2^R1051Q acts to promote VEGFR2 signaling. Despite this, the biochemical/biophysical mechanism of the activation of VEGFR2^R1051Q remains poorly understood. On these bases, the aim of our study is to address how VEGFR2R1051Q influences the biophysical behavior (dimerization and membrane dynamics) of the co-expressed VEGFR2^WT. Methods: We employed quantitative FLIM/FRET and FRAP imaging techniques using CHO cells co-transfected with the two forms of VEGFR2 to mimic heterozygosity. Results: Membrane protein biotinylation reveals that VEGFR2^WT is more exposed on the cell membrane with respect to VEGFR2^R1051Q. The imaging analyses show the ability of VEGFR2^WT to form heterodimers with VEGFR2^R1051Q and this interaction alters its membrane dynamics. Indeed, when the co-expression of VEGFR2^WT/VEGFR2^R1051Q occurs, VEGFR2^WT shows reduced lateral motility and a minor pool of mobile fraction. Conclusions: This study demonstrates that active VEGFR2^R1051Q can affect the membrane behavior of the VEGFR2^WT. Full article

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