Cells

24 pages, 12607 KiB

Open AccessArticle

Initial WNT/β-Catenin or BMP Activation Modulates Inflammatory Response of Mesodermal Progenitors Derived from Human Induced Pluripotent Stem Cells

by Yulia Suzdaltseva, Anastasia Selezneva, Nikita Sergeev and Sergey L. Kiselev

Cells 2024, 13(21), 1820; https://doi.org/10.3390/cells13211820 - 4 Nov 2024

Viewed by 653

Abstract

Wound healing in adults largely depends on the functional state of multipotent mesenchymal stromal cells (MSCs). Human fetal tissues at the early stages of development are known to heal quickly with a full-quality restoration of the original structure. The differences in the molecular [...] Read more.

Wound healing in adults largely depends on the functional state of multipotent mesenchymal stromal cells (MSCs). Human fetal tissues at the early stages of development are known to heal quickly with a full-quality restoration of the original structure. The differences in the molecular mechanisms that determine the functional activity of mesodermal cells in fetuses and adults remain virtually unknown. Using two independent human induced pluripotent stem cell (iPSC) lines, we examined the effects of the initial WNT and BMP activation on the differentiation of iPSCs via mesodermal progenitors into MSCs and highlighted the functions of these cells that are altered by the proinflammatory microenvironment. The WNT-induced mesoderm commitment of the iPSCs enhanced the expression of paraxial mesoderm (PM)-specific markers, while the BMP4-primed iPSCs exhibited increased levels of lateral mesoderm (LM)-specific genes. The inflammatory status and migration rate of the isogenic iPSC-derived mesoderm cells were assessed via gene expression analysis and scratch assay under the receptor-dependent activation of the proinflammatory IFN-γ or TNF-α signaling pathway. Reduced IDO1 and ICAM1 expression levels were detected in the WNT- and BMP-induced MSC progenitors compared to the isogenic MSCs in response to stimulation with IFN-γ and TNF-α. The WNT- and BMP-induced MSC progenitors exhibited a higher migration rate than isogenic MSCs upon IFN-γ exposure. The established isogenic cellular model will provide new opportunities to elucidate the mechanisms of regeneration and novel therapeutics for wound healing. Full article

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19 pages, 10760 KiB

Open AccessArticle

Celastrol-Loaded Hyaluronic Acid/Cancer Cell Membrane Lipid Nanoparticles for Targeted Hepatocellular Carcinoma Prevention

by Peng He, Manshu Zou, Chanjuan Zhang, Yaning Shi and Li Qin

Cells 2024, 13(21), 1819; https://doi.org/10.3390/cells13211819 - 4 Nov 2024

Viewed by 724

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its prevention and treatment face severe challenges. It is crucial to improve the targeting of drugs on tumor cells and tissues. Celastrol (CeT), as an active ingredient of traditional Chinese [...] Read more.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its prevention and treatment face severe challenges. It is crucial to improve the targeting of drugs on tumor cells and tissues. Celastrol (CeT), as an active ingredient of traditional Chinese medicine, possesses strong antitumor effects, especially in triggering apoptosis of HCC. However, due to its toxicity and lack of targeting, its application is greatly limited. HMCLPs, a nano-biomimetic platform carrying CeT with controllable drug release, enhanced targeting, and immunocompatibility, were developed for the first time, which can be used for the treatment of HCC. By utilizing homologous cell membranes and hyaluronic acid (HA), HMCLPs can precisely target tumor regions and release CeT in a controlled manner. Both in vitro and in vivo studies have demonstrated that HMCLPs loaded with CeT significantly increased the accumulation of reactive oxygen species (ROS), induced mitochondrial damage, and triggered apoptosis of HCC cells, resulting in effective treatment with minimal adverse reaction. The development of HMCLPs as a nanocarrier system for CeT delivery offers a promising therapeutic strategy for HCC. This innovative approach improves the targeted delivery and bioavailability of CeT, dramatically induces apoptosis in HCC cells, and exerts its powerful antitumor effects while minimizing systemic toxicity. The present study highlights the potential of combining innovative nanocarriers with powerful natural compounds such as CeT to enhance efficacy and reduce toxicity. Full article

(This article belongs to the Special Issue New Advances and Perspectives in Nanotechnology for the Treatment of Cancer Cells)

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21 pages, 3368 KiB

Open AccessReview

Fish Cell Spheroids, a Promising In Vitro Model to Mimic In Vivo Research: A Review

by Antonio Gómez-Mercader, Luis Monzón-Atienza, Daniel Montero, Jimena Bravo and Félix Acosta

Cells 2024, 13(21), 1818; https://doi.org/10.3390/cells13211818 - 4 Nov 2024

Viewed by 935

Abstract

In vitro cell culture systems serve as instrumental platforms for probing biological phenomena and elucidating intricate cellular mechanisms. These systems afford researchers the opportunity to scrutinize cellular responses within a regulated environment, thereby circumventing the ethical and logistical challenges associated with in vivo [...] Read more.

In vitro cell culture systems serve as instrumental platforms for probing biological phenomena and elucidating intricate cellular mechanisms. These systems afford researchers the opportunity to scrutinize cellular responses within a regulated environment, thereby circumventing the ethical and logistical challenges associated with in vivo experimentation. Three-dimensional (3D) cell cultures have emerged as a viable alternative to mimic in vivo environments. Within this context, spheroids are recognized as one of the most straightforward and efficacious models, presenting a promising substitute for conventional monolayer cultures. The application of 3D cultures of fish cells remains limited, focusing mainly on physiological and morphological characterization studies. However, given the capacity of spheroids to emulate in vivo conditions, researchers are exploring diverse applications of these 3D cultures. These include eco-toxicology, immunology, drug screening, endocrinology, and metabolism studies, employing a variety of cell types such as fibroblasts, hepatocytes, embryonic cells, gonadal cells, gastrointestinal cells, and pituitary cells. This review provides a succinct overview, concentrating on the most frequently employed methods for generating fish cell spheroids and their applications to date. The aim is to compile and highlight the significant contributions of these methods to the field and their potential for future research. Full article

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Graphical abstract

3 pages, 3343 KiB

Open AccessCorrection

Correction: Svobodová Kovaříková et al. N⁶-Adenosine Methylation in RNA and a Reduced m₃G/TMG Level in Non-Coding RNAs Appear at Microirradiation-Induced DNA Lesions. Cells 2020, 9, 360

by Alena Svobodová Kovaříková, Lenka Stixová, Aleš Kovařík, Denisa Komůrková, Soňa Legartová, Paolo Fagherazzi and Eva Bártová

Cells 2024, 13(21), 1817; https://doi.org/10.3390/cells13211817 - 4 Nov 2024

Viewed by 358

Abstract

The affiliation number 1, “Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65 Brno, Czech Republic” changed its zip code to 612 00 [...] Full article

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20 pages, 6391 KiB

Open AccessArticle

NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy

by Alessandra Ferraresi, Ian Ghezzi, Amreen Salwa, Andrea Esposito, Danny N. Dhanasekaran and Ciro Isidoro

Cells 2024, 13(21), 1816; https://doi.org/10.3390/cells13211816 - 4 Nov 2024

Viewed by 801

Abstract

Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. [...] Read more.

Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. Here, we further elucidate this mechanism by focusing on the molecular and cellular events regulating autophagy. Transcriptomic and Western blotting analyses revealed NKX3-2, a transcriptional factor, to be among the genes hyperexpressed in LPA-stimulated ovarian cancer cells. Bioinformatic analyses revealed that in ovarian cancer patients, the expression of NKX3-2 positively correlates with genes involved in cell motility and migration, while it negatively correlates with macromolecular catabolic pathways. In various ovarian cancer cell lines, NKX3-2 silencing abrogated LPA-induced cell migration. Mechanistically, this effect is linked to the restoration of the HDAC6-mediated relocation of the lysosomes in the para-golgian area, and this results in an increase in autolysosome formation and the overall upregulation of autophagy. Silencing the expression of ATG7 or BECN1, two autophagy genes, rescued the migratory phenotype of the NKX3-2-silenced ovarian cancer cells. Taken together, these data reveal the mechanism by which the LPA-NKX3-2 axis promotes the invasiveness of ovarian cancer cells and supports the possibility of targeting NKX3-2 to reduce the migratory capacity of cancer cells in response to a permissive microenvironment. Full article

(This article belongs to the Section Intracellular and Plasma Membranes)

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27 pages, 1918 KiB

Open AccessReview

VEGF—Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications

by Cristina Sánchez-Martínez, Esther Grueso, Tania Calvo-López, Jorge Martinez-Ortega, Ana Ruiz and José M. Almendral

Cells 2024, 13(21), 1815; https://doi.org/10.3390/cells13211815 - 4 Nov 2024

Viewed by 999

Abstract

Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in [...] Read more.

Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses’ systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF’s functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF–virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system. Full article

(This article belongs to the Special Issue Vascular Endothelial Functions in Health and Diseases)

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36 pages, 1559 KiB

Open AccessReview

The Crosstalk of Apoptotic and Non-Apoptotic Signaling in CD95 System

by Kamil Seyrek, Johannes Espe, Elisabeth Reiss and Inna N. Lavrik

Cells 2024, 13(21), 1814; https://doi.org/10.3390/cells13211814 - 3 Nov 2024

Viewed by 733

Abstract

The mechanisms of CD95 (Fas/APO-1)-mediated extrinsic apoptotic pathway in cancer cells have been extensively studied. The majority of human cells express CD95, but not all these cells can induce extrinsic apoptosis. Accumulating evidence has shown that CD95 is a multifunctional protein, and its [...] Read more.

The mechanisms of CD95 (Fas/APO-1)-mediated extrinsic apoptotic pathway in cancer cells have been extensively studied. The majority of human cells express CD95, but not all these cells can induce extrinsic apoptosis. Accumulating evidence has shown that CD95 is a multifunctional protein, and its stimulation can also elicit non-apoptotic or even survival signals. It has become clear that under certain cellular contexts, due to the various checkpoints, CD95 activation can trigger both apoptotic and non-apoptotic signals. The crosstalk of death and survival signals may occur at different levels of signal transduction. The strength of the CD95 stimulation, initial levels of anti-apoptotic proteins, and posttranslational modifications of the core DISC components have been proposed to be the most important factors in the life/death decisions at CD95. Successful therapeutic targeting of CD95 signaling pathways will require a better understanding of the crosstalk between CD95-induced apoptotic and cell survival pathways. In this review, in order to gain a systematic understanding of the crosstalk between CD95-mediated apoptosis and non-apoptotic signaling, we will discuss these issues in a step-by-step way. Full article

(This article belongs to the Special Issue Apoptosis in Cancers)

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14 pages, 10549 KiB

Open AccessArticle

The Effect of the Acid-Base Imbalance on the Shape and Structure of Red Blood Cells

by Snezhanna Kandrashina, Ekaterina Sherstyukova, Mikhail Shvedov, Vladimir Inozemtsev, Roman Timoshenko, Alexander Erofeev, Maxim Dokukin and Viktoria Sergunova

Cells 2024, 13(21), 1813; https://doi.org/10.3390/cells13211813 - 3 Nov 2024

Viewed by 752

Abstract

Red blood cells respond to fluctuations in blood plasma pH by changing the rate of biochemical and physical processes that affect the specific functions of individual cells. This study aimed to analyze the effect of pH changes on red blood cell morphology and [...] Read more.

Red blood cells respond to fluctuations in blood plasma pH by changing the rate of biochemical and physical processes that affect the specific functions of individual cells. This study aimed to analyze the effect of pH changes on red blood cell morphology and structure. The findings revealed that an increase or decrease in pH above or below the physiological level of pH 7.4 results in the transformation of discocytes into echinocytes and causes significant alterations in the membrane, including its roughness, cytoskeleton structure, and the cell’s elastic modulus. Furthermore, the study shown a strong connection between critical acidosis and alkalosis with increased intracellular reactive oxygen species production. Full article

(This article belongs to the Special Issue Advances in Biophysics of Cellular Membranes)

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21 pages, 5533 KiB

Open AccessReview

Regulatory Mechanism of Protein Crotonylation and Its Relationship with Cancer

by Siyi Yang, Xinyi Fan and Wei Yu

Cells 2024, 13(21), 1812; https://doi.org/10.3390/cells13211812 - 2 Nov 2024

Viewed by 918

Abstract

Crotonylation is a recently discovered protein acyl modification that shares many enzymes with acetylation. However, it possesses a distinct regulatory mechanism and biological function due to its unique crotonyl structure. Since the discovery of crotonylation in 2011, numerous crotonylation sites have been identified [...] Read more.

Crotonylation is a recently discovered protein acyl modification that shares many enzymes with acetylation. However, it possesses a distinct regulatory mechanism and biological function due to its unique crotonyl structure. Since the discovery of crotonylation in 2011, numerous crotonylation sites have been identified in both histones and other proteins. In recent studies, crotonylation was found to play a role in various diseases and biological processes. This paper reviews the initial discovery and regulatory mechanisms of crotonylation, including various writer, reader, and eraser proteins. Finally, we emphasize the relationship of dysregulated protein crotonylation with eight common malignancies, including cervical, prostate, liver, and lung cancer, providing new potential therapeutic targets. Full article

(This article belongs to the Section Cellular Metabolism)

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16 pages, 3272 KiB

Open AccessArticle

Proof-of-Concept for Long-Term Human Endometrial Epithelial Organoids in Modeling Menstrual Cycle Responses

by Yanyu Jiang, Arturo Reyes Palomares, Patricia Munoz, Ivan Nalvarte, Ganesh Acharya, Jose Inzunza, Mukesh Varshney and Kenny Alexandra Rodriguez-Wallberg

Cells 2024, 13(21), 1811; https://doi.org/10.3390/cells13211811 - 2 Nov 2024

Viewed by 1414

Abstract

Endometrial disorders, such as infertility and endometriosis, significantly impact reproductive health, thus necessitating better models to study endometrial function. Current in vitro models fail to replicate the complexity of the human endometrium throughout the entire menstrual cycle. This study aimed to assess the [...] Read more.

Endometrial disorders, such as infertility and endometriosis, significantly impact reproductive health, thus necessitating better models to study endometrial function. Current in vitro models fail to replicate the complexity of the human endometrium throughout the entire menstrual cycle. This study aimed to assess the physiological response of human endometrial organoids (hEOs) to in vitro hormonal treatments designed to mimic the hormonal fluctuations of the menstrual cycle. Endometrial biopsies from three healthy women were used to develop hEOs, which were treated over 28 days with three hormonal stimulation strategies: (1) estrogen only (E) to mimic the proliferative phase, (2) the addition of progesterone (EP) to simulate the secretory phase, and (3) the further addition of cAMP (EPC) to enhance the secretory functions of hEOs. Gene and protein expression were analyzed using qPCR, IHC, and ELISA. The hEOs exhibited proliferation, gland formation, and appropriate expression of markers such as E-cadherin and Ki67. The hormonal treatments induced significant changes in PR, HSD17B1, PAEP, SPP1, and other genes relevant to endometrial function, closely mirroring in vivo physiological responses. The prominent changes were observed in EPC-treated hEOs (week 4) with significantly high expression of uterine milk components such as glycodelin (PAEP) and osteopontin (SPP1), reflecting mid- to late-secretory phase physiology. This model successfully recapitulates human menstrual cycle dynamics and offers a promising platform for studying endometrial disorders and advancing personalized treatments in gynecology. Full article

(This article belongs to the Section Reproductive Cells and Development)

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16 pages, 6979 KiB

Open AccessArticle

A Necessary Role for Cyclin D2 Induction During Colon Cancer Progression Mediated by L1

by Arka Saha, Nancy Gavert, Thomas Brabletz and Avri Ben-Ze’ev

Cells 2024, 13(21), 1810; https://doi.org/10.3390/cells13211810 - 2 Nov 2024

Viewed by 739

Abstract

The cell adhesion molecule L1CAM (L1), mainly known for its function in brain cells, is a Wnt/β-catenin signaling target gene in colorectal cancer (CRC) cells, where it promotes invasion and liver metastasis. We interrogated which genes are expressed at increased levels in human [...] Read more.

The cell adhesion molecule L1CAM (L1), mainly known for its function in brain cells, is a Wnt/β-catenin signaling target gene in colorectal cancer (CRC) cells, where it promotes invasion and liver metastasis. We interrogated which genes are expressed at increased levels in human CRC tissue and induced in CRC cell lines overexpressing L1. We found increased cyclin D2 levels in CRC tissue and LS 174T and HCT 116 human CRC cells overexpressing L1. Increased cyclin D2 in CRC cells was associated with higher proliferation rates, faster motility, tumorigenesis, and liver metastasis. The suppression of cyclin D2 expression by shRNA to cyclin D2 blocked the increase in these cellular properties of L1-expressing cells. The overexpression of cyclin D2 in the absence of L1 also conferred tumorigenic properties similar to L1 expression. The pathways involved in the elevation of cyclin D2 by L1 include NF-κB, Akt, and β-catenin signaling but not the Erk pathway. We found that in a significant percentage of human CRC tissue samples, cyclin D2 is expressed at high levels in the nuclei of cancer cells. At the same time, the adjacent normal mucosa was negative for cyclin D2 staining. The results suggest that the increased cyclin D2 expression by L1 is required to induce proliferative, motile tumor development in CRC tissue and can serve as a diagnostic marker and a target for CRC therapy. Full article

(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer—Second Edition)

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17 pages, 2428 KiB

Open AccessArticle

Functional Adaptation in the Brain Habenulo–Mesencephalic Pathway During Cannabinoid Withdrawal

by Sonia Aroni, Claudia Sagheddu, Marco Pistis and Anna Lisa Muntoni

Cells 2024, 13(21), 1809; https://doi.org/10.3390/cells13211809 - 1 Nov 2024

Viewed by 629

Abstract

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula [...] Read more.

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb–RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ⁹-tetrahydrocannabinol (THC) dependence, adult male Sprague–Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5–7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo–mesencephalic circuit are implicated in the mechanisms underlying substance use disorders. Full article

(This article belongs to the Special Issue From Research to Legalization: How Cannabis Exploits the Endocannabinoid System)

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24 pages, 9065 KiB

Open AccessArticle

Sonic Hedgehog Is an Early Oligodendrocyte Marker During Remyelination

by Mariagiovanna Russo, Amina Zahaf, Abdelmoumen Kassoussi, Ariane Sharif, Hélène Faure, Elisabeth Traiffort and Martial Ruat

Cells 2024, 13(21), 1808; https://doi.org/10.3390/cells13211808 - 1 Nov 2024

Viewed by 679

Abstract

Failure of myelin regeneration by oligodendrocytes contributes to progressive decline in many neurological diseases. Here, using in vitro and in vivo rodent models, functional blockade, and mouse brain demyelination, we demonstrate that Sonic hedgehog (Shh) expression in a subset of oligodendrocyte progenitor cells [...] Read more.

Failure of myelin regeneration by oligodendrocytes contributes to progressive decline in many neurological diseases. Here, using in vitro and in vivo rodent models, functional blockade, and mouse brain demyelination, we demonstrate that Sonic hedgehog (Shh) expression in a subset of oligodendrocyte progenitor cells precedes the expression of myelin basic protein (MBP), a major myelin sheath protein. Primary cultures of rodent cortical oligodendrocytes show that Shh mRNA and protein are upregulated during oligodendrocyte maturation before the upregulation of MBP expression. Importantly, almost all MBP-positive cells are Shh positive during differentiation. During remyelination, we identify a rapid induction of Shh mRNA and peptide in oligodendroglial cells present in the demyelinated corpus callosum of mice, including a population of PDGFRα-expressing cells. Shh invalidation by an adeno-associated virus strategy demonstrates that the downregulation of Shh impairs the differentiation of oligodendrocytes in vitro and decreases MBP and myelin proteolipid protein expression in the demyelinated mouse brain at late stages of remyelination. We also report a parallel expression of Shh and MBP in oligodendroglial cells during early post-natal myelination of the mouse brain. Thus, we identify a crucial Shh signal involved in oligodendroglial cell differentiation and remyelination, with potential interest in the design of better-targeted remyelinating therapeutic strategies. Full article

(This article belongs to the Special Issue Hedgehog Signaling in Myelin Diseases and Inflammatory Disorders of the Nervous System—Second Edition)

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23 pages, 3447 KiB

Open AccessArticle

Hypoxia-Induced Mitochondrial ROS and Function in Pulmonary Arterial Endothelial Cells

by Harrison Wang, Teng-Yao Song, Jorge Reyes-García and Yong-Xiao Wang

Cells 2024, 13(21), 1807; https://doi.org/10.3390/cells13211807 - 1 Nov 2024

Viewed by 770

Abstract

Pulmonary artery endothelial cells (PAECs) are a major contributor to hypoxic pulmonary hypertension (PH) due to the possible roles of reactive oxygen species (ROS). However, the molecular mechanisms and functional roles of ROS in PAECs are not well established. In this study, we [...] Read more.

Pulmonary artery endothelial cells (PAECs) are a major contributor to hypoxic pulmonary hypertension (PH) due to the possible roles of reactive oxygen species (ROS). However, the molecular mechanisms and functional roles of ROS in PAECs are not well established. In this study, we first used Amplex UltraRed reagent to assess hydrogen peroxide (H₂O₂) generation. The result indicated that hypoxic exposure resulted in a significant increase in Amplex UltraRed-derived fluorescence (i.e., H₂O₂ production) in human PAECs. To complement this result, we employed lucigenin as a probe to detect superoxide (O₂⁻) production. Our assays showed that hypoxia largely increased O₂⁻ production. Hypoxia also enhanced H₂O₂ production in the mitochondria from PAECs. Using the genetically encoded H₂O₂ sensor HyPer, we further revealed the hypoxic ROS production in PAECs, which was fully blocked by the mitochondrial inhibitor rotenone or myxothiazol. Interestingly, hypoxia caused an increase in the migration of PAECs, determined by scratch wound assay. In contrast, nicotine, a major cigarette or e-cigarette component, had no effect. Moreover, hypoxia and nicotine co-exposure further increased migration. Transfection of lentiviral shRNAs specific for the mitochondrial Rieske iron–sulfur protein (RISP), which knocked down its expression and associated ROS generation, inhibited the hypoxic migration of PAECs. Hypoxia largely increased the proliferation of PAECs, determined using Ki67 staining and direct cell number accounting. Similarly, nicotine caused a large increase in proliferation. Moreover, hypoxia/nicotine co-exposure elicited a further increase in cell proliferation. RISP knockdown inhibited the proliferation of PAECs following hypoxia, nicotine exposure, and hypoxia/nicotine co-exposure. Taken together, our data demonstrate that hypoxia increases RISP-mediated mitochondrial ROS production, migration, and proliferation in human PAECs; nicotine has no effect on migration, increases proliferation, and promotes hypoxic proliferation; the effects of nicotine are largely mediated by RISP-dependent mitochondrial ROS signaling. Conceivably, PAECs may contribute to PH via the RISP-mediated mitochondrial ROS. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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40 pages, 5543 KiB

Open AccessReview

Progress in Dentin-Derived Bone Graft Materials: A New Xenogeneic Dentin-Derived Material with Retained Organic Component Allows for Broader and Easier Application

by Lari Sapoznikov and Martin Humphrey

Cells 2024, 13(21), 1806; https://doi.org/10.3390/cells13211806 - 31 Oct 2024

Viewed by 584

Abstract

The optimal repair of rigid mineralized tissues, such as bone, in cases of fracture, surgical resection, or prosthetic placement, is a complex process often necessitating the use of bone graft materials. Autogenous bone from the patient is generally the gold standard in terms [...] Read more.

The optimal repair of rigid mineralized tissues, such as bone, in cases of fracture, surgical resection, or prosthetic placement, is a complex process often necessitating the use of bone graft materials. Autogenous bone from the patient is generally the gold standard in terms of outcomes but also has disadvantages, which have resulted in extensive research in the field of tissue engineering to develop better and more convenient alternatives. In the dental field, several initiatives have demonstrated that the dentin material derived from extracted teeth produces excellent results in terms of repairing bone defects and supporting dental implants. Dentin is acellular and thus, in contrast to autogenous bone, cannot provide osteoblasts or other cellular elements to the grafted region, but it does contain growth and differentiation factors, and has other properties that make it an impressive material for bone repair. In this review, the beneficial properties of dentin and the ways it interacts with the host bone are described in the context of bone graft materials. Autogenous tooth material has limitations, particularly in terms of the need for tooth extraction and the limited amount available, which currently restrict its use to particular dental procedures. The development of a xenograft dentin-derived material, which retains the properties of autogenous dentin, is described. Such a material could potentially enable the use of dentin-derived material more widely, particularly in orthopedic indications where its properties may be advantageous. Full article

(This article belongs to the Special Issue Signaling Regulation of Bone and Tooth Development)

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22 pages, 4829 KiB

Open AccessArticle

Host Genetics Background Affects Intestinal Cancer Development Associated with High-Fat Diet-Induced Obesity and Type 2 Diabetes

by Aya Ghnaim, Kareem Midlej, Osayd Zohud, Sama Karram, Arne Schaefer, Yael Houri-Haddad, Iqbal M. Lone and Fuad A. Iraqi

Cells 2024, 13(21), 1805; https://doi.org/10.3390/cells13211805 - 31 Oct 2024

Viewed by 538

Abstract

Background: Obesity and type 2 diabetes (T2D) promote inflammation, increasing the risk of colorectal cancer (CRC). High-fat diet (HFD)-induced obesity is key to these diseases through biological mechanisms. This study examined the impact of genetic background on the multimorbidity of intestinal cancer, T2D, [...] Read more.

Background: Obesity and type 2 diabetes (T2D) promote inflammation, increasing the risk of colorectal cancer (CRC). High-fat diet (HFD)-induced obesity is key to these diseases through biological mechanisms. This study examined the impact of genetic background on the multimorbidity of intestinal cancer, T2D, and inflammation due to HFD-induced obesity. Methods: A cohort of 357 Collaborative Cross (CC) mice from 15 lines was fed either a control chow diet (CHD) or HFD for 12 weeks. Body weight was tracked biweekly, and blood glucose was assessed at weeks 6 and 12 via intraperitoneal glucose tolerance tests (IPGTT). At the study’s endpoint, intestinal polyps were counted, and cytokine profiles were analyzed to evaluate the inflammatory response. Results: HFD significantly increased blood glucose levels and body weight, with males showing higher susceptibility to T2D and obesity. Genetic variation across CC lines influenced glucose metabolism, body weight, and polyp development. Mice on HFD developed more intestinal polyps, with males showing higher counts than females. Cytokine analysis revealed diet-induced variations in pro-inflammatory markers like IL-6, IL-17A, and TNF-α, differing by genetic background and sex. Conclusions: Host genetics plays a crucial role in susceptibility to HFD-induced obesity, T2D, CRC, and inflammation. Genetic differences across CC lines contributed to variability in disease outcomes, providing insight into the genetic underpinnings of multimorbidity. This study supports gene-mapping efforts to develop personalized prevention and treatment strategies for these diseases. Full article

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24 pages, 7445 KiB

Open AccessArticle

Old Passengers as New Drivers: Chromosomal Passenger Proteins Engage in Translesion Synthesis

by Katharina Falke, Elisabeth Schröder, Stefanie Mosel, Cansu N. Yürük, Sophie Feldmann, Désirée Gül, Paul Stahl, Roland H. Stauber and Shirley K. Knauer

Cells 2024, 13(21), 1804; https://doi.org/10.3390/cells13211804 - 31 Oct 2024

Viewed by 640

Abstract

Survivin is known for its dual biological role in apoptosis inhibition and mitotic progression. In addition to its being part of the chromosomal passenger complex (CPC), recent findings suggest additional roles for Survivin in the DNA damage response, further contributing to therapy resistance. [...] Read more.

Survivin is known for its dual biological role in apoptosis inhibition and mitotic progression. In addition to its being part of the chromosomal passenger complex (CPC), recent findings suggest additional roles for Survivin in the DNA damage response, further contributing to therapy resistance. In this study, we investigated the role of Survivin and the CPC proteins in the cellular response to irradiation with a focus on DNA replication processes. As is known, ionizing radiation leads to an increased expression of Survivin and its accumulation in nuclear foci, which we now know to be specifically localized to centromeric heterochromatin. The depletion of Survivin and Aurora B increases the DNA damage marker γH2AX, indicative of an impaired repair capacity. The presence of Survivin and the CPC in nuclear foci that we already identified during the S phase co-localize with the proliferating cell nuclear antigen (PCNA), further implying a potential role during replication. Indeed, Survivin knockdown reduced replication fork speed as assessed via DNA fiber assays. Mechanistically, we identified a PIP-box motif in INCENP mediating the interaction with PCNA to assist in managing damage-induced replication stress. Survivin depletion forces cells to undergo unphysiological genome replication via mitotic DNA synthesis (MiDAS), resulting in chromosome breaks. Finally, we revealed that Aurora B kinase liberates Pol η by phosphorylating polymerase delta-interacting protein 2 (POLDIP2) to resume the replication of damaged sites via translesion synthesis. In this study, we assigned a direct function to the CPC in the transition from stalled replication forks to translesion synthesis, further emphasizing the ubiquitous overexpression of Survivin particularly in tumors. This study, for the first time, assigns a direct function to the chromosomal passenger complex, CPC, including Survivin, Aurora B kinase, Borealin, and INCENP, in the transition from stalled replication forks (involving PCNA binding) to translesion synthesis (liberating Pol η by phosphorylating POLDIP2), and thus in maintaining genomic integrity. Full article

(This article belongs to the Special Issue Advances in DNA Repair Disorders Research: Molecular Mechanisms, Novel Therapies and Implications for Understanding Aging, Neurological Dysfunction and Cancer Progression)

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15 pages, 2356 KiB

Open AccessArticle

Knockdown of Keratin 6 Within Arsenite-Transformed Human Urothelial Cells Decreases Basal/Squamous Expression, Inhibits Growth, and Increases Cisplatin Sensitivity

by Nelofar Nargis, Donald A. Sens and Aaron A. Mehus

Cells 2024, 13(21), 1803; https://doi.org/10.3390/cells13211803 - 31 Oct 2024

Viewed by 711

Abstract

Urothelial carcinoma (UC) is prevalent, especially in elderly males. The high rate of recurrence, treatment regime, and follow-up monitoring make UC a global health and economic burden. Arsenic is a ubiquitous toxicant that can be found in drinking water, and it is known [...] Read more.

Urothelial carcinoma (UC) is prevalent, especially in elderly males. The high rate of recurrence, treatment regime, and follow-up monitoring make UC a global health and economic burden. Arsenic is a ubiquitous toxicant that can be found in drinking water, and it is known that exposure to arsenic is associated with UC development. Around 25% of diagnosed UC cases are muscle-invasive (MIUC) which have poor prognosis and develop chemoresistance, especially if tumors are associated with squamous differentiation (SD). The immortalized UROtsa cell line is derived from normal human urothelium and our lab has malignantly transformed these cells using arsenite (As³⁺). These cells represent a basal subtype model of MIUC and the tumors derived from the As³⁺-transformed cells histologically and molecularly resemble clinical cases of the basal subtype of MIUC that have focal areas SD and expression of the basal keratins (KRT1, 5, 6, 14, and 16). Our previous data demonstrate that KRT6 protein expression correlates to areas of SD within the tumors. For this study, we performed a lentiviral knockdown of KRT6 in As³⁺-transformed UROtsa cells to evaluate the effects on morphology, gene/protein expression, growth, colony formation, and cisplatin sensitivity. The knockdown of KRT6 resulted in decreased expression of the basal keratins, decreased growth, decreased colony formation, and increased sensitivity to cisplatin, the standard treatment for MIUC. The results of this study suggest that KRT6 plays a role in UC cell growth and is an exploitable target to increase cisplatin sensitivity for MIUC tumors that may have developed resistance to cisplatin treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)

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18 pages, 7822 KiB

Open AccessArticle

ALDH1A3 Contributes to Radiation-Induced Inhibition of Self-Renewal and Promotes Proliferative Activity of p53-Deficient Glioblastoma Stem Cells at the Onset of Differentiation

by Andreas Müller, Bogdan Lyubarskyy, Jurij Tchoumakov, Maike Wagner, Bettina Sprang, Florian Ringel and Ella L. Kim

Cells 2024, 13(21), 1802; https://doi.org/10.3390/cells13211802 - 31 Oct 2024

Viewed by 545

Abstract

ALDH1A3 is a marker for mesenchymal glioblastomas characterized by a greater degree of aggressiveness compared to other major subtypes. ADH1A3 has been implicated in the regulation of stemness and radioresistance mediated by glioblastoma stem cells. Mechanisms by which ALDH1A3 promotes malignant progression of [...] Read more.

ALDH1A3 is a marker for mesenchymal glioblastomas characterized by a greater degree of aggressiveness compared to other major subtypes. ADH1A3 has been implicated in the regulation of stemness and radioresistance mediated by glioblastoma stem cells. Mechanisms by which ALDH1A3 promotes malignant progression of glioblastoma remain elusive posing a challenge for rationalization of ALDH1A3 targeting in glioblastoma, and it is also unclear how ALDH1A3 regulates glioblastoma cells stemness. Usage of different models with diverse genetic backgrounds and often unknown degree of stemness is one possible reason for discrepant views on the role of ALDH1A3 in glioblastoma stem cells. This study clarifies ALDH1A3 impacts on glioblastoma stem cells by modelling ALDH1A3 expression in an otherwise invariable genetic background with consideration of the impacts of inherent plasticity and proliferative changes associated with transitions between cell states. Our main finding is that ALDH1A3 exerts cell-state dependent impact on proliferation of glioblastoma stem cells. We provide evidence that ALDH1A3 augments radiation-induced inhibition of self-renewal and promotes the proliferation of differentiated GSC progenies. Congruent effects ALDH1A3 and radiation on self-renewal and proliferation provides a framework for promoting glioblastoma growth under radiation treatment. Full article

(This article belongs to the Special Issue Cell Death Mechanisms and Therapeutic Opportunities in Glioblastoma)

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20 pages, 6017 KiB

Open AccessArticle

Expression Profiling Identified TRPM7 and HER2 as Potential Targets for the Combined Treatment of Cancer Cells

by Miyuki Egawa, Eva Schmücker, Christian Grimm, Thomas Gudermann and Vladimir Chubanov

Cells 2024, 13(21), 1801; https://doi.org/10.3390/cells13211801 - 31 Oct 2024

Viewed by 873

Abstract

TRPM7 is a divalent cation-permeable channel that is highly active in cancer cells. The pharmacological inhibitors of TRPM7 have been shown to suppress the proliferation of tumor cells, highlighting TRPM7 as a new anticancer drug target. However, the potential benefit of combining TRPM7 [...] Read more.

TRPM7 is a divalent cation-permeable channel that is highly active in cancer cells. The pharmacological inhibitors of TRPM7 have been shown to suppress the proliferation of tumor cells, highlighting TRPM7 as a new anticancer drug target. However, the potential benefit of combining TRPM7 inhibitors with conventional anticancer therapies remains unexplored. Here, we used genome-wide transcriptome profiling of human leukemia HAP1 cells to examine cellular responses caused by the application of NS8593, the potent inhibitor of the TRPM7 channel, in comparison with two independent knockout mutations in the TRPM7 gene introduced by the CRISPR/Cas9 approach. This analysis revealed that TRPM7 regulates the expression levels of several transcripts, including HER2 (ERBB2). Consequently, we examined the TRPM7/HER2 axis in several non-hematopoietic cells to show that TRPM7 affects the expression of HER2 protein in a Zn²⁺-dependent fashion. Moreover, we found that co-administration of pharmacological inhibitors of HER2 and TRPM7 elicited a synergistic antiproliferative effect on HER2-overexpressing SKBR3 cells but not on HER2-deficient MDA-MB-231 breast cancer cells. Hence, our study proposes a new combinatorial strategy for treating HER2-positive breast cancer cells. Full article

(This article belongs to the Special Issue Ion Channels in Cancer: An Update)

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15 pages, 5854 KiB

Open AccessArticle

Mechanism of Marinobufagenin-Induced Hyperpermeability of Human Brain Microvascular Endothelial Cell Monolayer: A Potential Pathogenesis of Seizure in Preeclampsia

by Ahmed F. Pantho, Manisha Singh, Syeda H. Afroze, Kelsey R. Kelso, Jessica C. Ehrig, Niraj Vora, Thomas J. Kuehl, Steven R. Lindheim and Mohammad N. Uddin

Cells 2024, 13(21), 1800; https://doi.org/10.3390/cells13211800 - 30 Oct 2024

Viewed by 538

Abstract

Preeclampsia (preE) is a hypertensive disorder in pregnancies. It is the third leading cause of mortality among pregnant women and fetuses worldwide, and there is much we have yet to learn about its pathophysiology. One complication includes cerebral edema, which causes a breach [...] Read more.

Preeclampsia (preE) is a hypertensive disorder in pregnancies. It is the third leading cause of mortality among pregnant women and fetuses worldwide, and there is much we have yet to learn about its pathophysiology. One complication includes cerebral edema, which causes a breach of the blood–brain barrier (BBB). Urinary marinobufagenin (MBG) is elevated in a preE rat model prior to developing hypertension and proteinuria. We investigated what effect MBG has on the endothelial cell permeability of the BBB. Human brain microvascular endothelial cells (HBMECs) were utilized to examine the permeability caused by MBG. The phosphorylation of ERK1/2, Jnk, p38, and Src was evaluated after the treatment with MBG. Apoptosis was evaluated by examining caspase 3/7. MBG ≥ 1 nM inhibited the proliferation of HBMECs by 46–50%. MBG induced monolayer permeability, causing a decrease in the phosphorylation of ERK1/2 and the activated phosphorylation of Jnk, p38, and Src. MBG increased the caspase 3/7 expression, indicating the activation of apoptosis. Apoptotic signaling or the disruption of endothelia tight junction proteins was not observed when using the p38 inhibitor as a pretreatment in MBG-treated cells. The MBG-induced enhancement of the HBMEC monolayer permeability occurs by the downregulation of ERK1/2, the activation of Jnk, p38, Src, and apoptosis, resulting in the cleavage of tight junction proteins, and are attenuated by p38 inhibition. Full article

(This article belongs to the Section Cell Signaling)

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26 pages, 4918 KiB

Open AccessArticle

Novel Approach to Skin Anti-Aging: Boosting Pharmacological Effects of Exogenous Nicotinamide Adenine Dinucleotide (NAD⁺) by Synergistic Inhibition of CD38 Expression

by Seongsu Kang, Jiwon Park, Zhihong Cheng, Sanghyun Ye, Seung-Hyun Jun and Nae-Gyu Kang

Cells 2024, 13(21), 1799; https://doi.org/10.3390/cells13211799 - 30 Oct 2024

Viewed by 798

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is indispensable for the regulation of biological metabolism. Previous studies have revealed its role in aging and degenerative diseases, while crucially showing that supplementation with NAD⁺ or its precursors could ameliorate or reverse the progression of [...] Read more.

Nicotinamide adenine dinucleotide (NAD⁺) is indispensable for the regulation of biological metabolism. Previous studies have revealed its role in aging and degenerative diseases, while crucially showing that supplementation with NAD⁺ or its precursors could ameliorate or reverse the progression of aging. Despite extensive evidence for the role and action of NAD⁺ in aging, its pharmacological activity on the skin, or even its mechanism, has not been elucidated. In this study, we established a novel approach to effectively utilize NAD⁺ for skin anti-aging by enhancing the pharmacological efficacy of exogenous NAD⁺ using a phytochemical complex consisting of quercetin, and enoxolone through inhibition of CD38. Through the comprehensive in vitro experiments based on human fibroblasts, we observed that exogenous NAD⁺ could exert protective effects against both extrinsic aging induced by ultraviolet light exposure and intrinsic aging. Additionally, we found that its effects were significantly boosted by quercetin and enoxolone. In this in-depth study, we demonstrated that these beneficial effects are mediated by improved sirtuin activation, autophagy, and mitochondrial functionality. Our approach is expected to verify the applicability of the topical application of NAD⁺ and offer more effective solutions for the unmet needs of patients and consumers who demand more effective anti-aging effects. Full article

(This article belongs to the Special Issue Molecular Studies of Aging and Anti-Aging Strategies in Animals and Humans)

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14 pages, 4183 KiB

Open AccessArticle

Ubiquitin-Specific Protease 1 Promotes Bladder Cancer Progression by Stabilizing c-MYC

by Xia Zhang, Peng Peng, Li-Wei Bao, An-Qi Zhang, Bo Yu, Tao Li, Jing Lei, Hui-Hui Zhang and Shang-Ze Li

Cells 2024, 13(21), 1798; https://doi.org/10.3390/cells13211798 - 30 Oct 2024

Viewed by 710

Abstract

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study aimed to analyze USP1 expression and study its [...] Read more.

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study aimed to analyze USP1 expression and study its roles in bladder cancer. Methods: The web server GEPIA was used to analyze the USP1 expression. To explore USP1’s function in bladder cancer, we constructed USP1-knockout cell lines in UMUC3 cells. A FLAG-USP1 (WT USP1) plasmid and a plasmid FLAG-USP1 C90S (catalytic–inactive mutant) were used to overexpress USP1 in T24 cells. CCK8, colony formation, and Transwell assays were used to assess cell viability, proliferation, and migration. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays were performed to screen the pathway. Co-immunoprecipitation and immunofluorescence were used to explore the interaction between USP1 and c-MYC. A xenograft mouse model was used to study the role of USP1 in bladder cancer. Results: USP1 expression was upregulated in human bladder cancer cells and correlated with poor patient prognosis. USP1 overexpression promoted cell proliferation, clone formation, and migration, and this was attenuated by genetic ablation of USP1. Furthermore, we observed that USP1 deficiency inhibited tumor formation in vivo. Mechanistically, the c-MYC pathway was remarkably activated compared with the other pathways. Furthermore, USP1 could interact with c-MYC and increase c-MYC’s stability depending on the catalytic activity of USP1. Conclusions: Our results suggested that high expression of USP1 promotes bladder cancer progression by stabilizing c-MYC; hence, USP1 may serve as a novel therapeutic target for treating bladder cancer. Full article

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21 pages, 3504 KiB

Open AccessReview

Avian Models for Human Carcinogenesis—Recent Findings from Molecular and Clinical Research

by Julia Niebora, Krzysztof Data, Dominika Domagała, Małgorzata Józkowiak, Saoirse Barrett, Tannaz Norizadeh Abbariki, Artur Bryja, Magdalena Kulus, Sławomir Woźniak, Hanna Ziemak, Hanna Piotrowska-Kempisty, Paweł Antosik, Dorota Bukowska, Paul Mozdziak, Piotr Dzięgiel and Bartosz Kempisty

Cells 2024, 13(21), 1797; https://doi.org/10.3390/cells13211797 - 30 Oct 2024

Viewed by 721

Abstract

Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was [...] Read more.

Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was that of non-viral genesis, as it enabled the discovery of oncogenes. Furthermore, studies on avian viruses provided initial insights into Kaposi’s sarcoma and EBV-induced diseases. However, the role of birds in human carcinogenesis extends beyond the realm of virology research. Utilization of CAM, the chorioallantoic membrane, an easily accessible extraembryonic tissue with rich vasculature, has enabled studies on tumor-induced angiogenesis and metastasis and the efficient screening of potential anti-cancer compounds. Also, the chick embryo alone is an effective preclinical in vivo patient-derived xenograft model, which is important for the development of personalized therapies. Furthermore, adult birds may also closely resemble human oncogenesis, as evidenced by the laying hen, which is the only animal model of a spontaneous form of ovarian cancer. Avian models may create an interesting alternative compared with mammalian models, enabling the creation of a relatively cost-effective and easy-to-maintain platform to address key questions in cancer biology. Full article

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17 pages, 2283 KiB

Open AccessArticle

Stress Granule Assembly in Pulmonary Arterial Hypertension

by Kosmas Kosmas, Aimilia Eirini Papathanasiou, Fotios Spyropoulos, Rakhshinda Rehman, Ashley Anne Cunha, Laura E. Fredenburgh, Mark A. Perrella and Helen Christou

Cells 2024, 13(21), 1796; https://doi.org/10.3390/cells13211796 - 30 Oct 2024

Viewed by 578

Abstract

The role of stress granules (SGs) in pulmonary arterial hypertension (PAH) is unknown. We hypothesized that SG formation contributes to abnormal vascular phenotypes, and cardiac and skeletal muscle dysfunction in PAH. Using the rat Sugen/hypoxia (SU/Hx) model of PAH, we demonstrate the formation [...] Read more.

The role of stress granules (SGs) in pulmonary arterial hypertension (PAH) is unknown. We hypothesized that SG formation contributes to abnormal vascular phenotypes, and cardiac and skeletal muscle dysfunction in PAH. Using the rat Sugen/hypoxia (SU/Hx) model of PAH, we demonstrate the formation of SG puncta and increased expression of SG proteins compared to control animals in lungs, right ventricles, and soleus muscles. Acetazolamide (ACTZ) treatment ameliorated the disease and reduced SG formation in all of these tissues. Primary pulmonary artery smooth muscle cells (PASMCs) from diseased animals had increased SG protein expression and SG number after acute oxidative stress and this was ameliorated by ACTZ. Pharmacologic inhibition of SG formation or genetic ablation of the SG assembly protein (G3BP1) altered the SU/Hx-PASMC phenotype by decreasing proliferation, increasing apoptosis and modulating synthetic and contractile marker expression. In human PAH lungs, we found increased SG puncta in pulmonary arteries compared to control lungs and in human PAH-PASMCs we found increased SGs after acute oxidative stress compared to healthy PASMCs. Genetic ablation of G3BP1 in human PAH-PASMCs resulted in a phenotypic switch to a less synthetic and more contractile phenotype. We conclude that increased SG formation in PASMCs and other tissues may contribute to PAH pathogenesis. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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10 pages, 1298 KiB

Open AccessPerspective

Unveiling GATOR2 Function: Novel Insights from Drosophila Research

by Lucia Bettedi, Yingbiao Zhang, Shu Yang and Mary A. Lilly

Cells 2024, 13(21), 1795; https://doi.org/10.3390/cells13211795 - 30 Oct 2024

Viewed by 532

Abstract

The multiprotein Target of Rapamycin (TOR) Complex 1 (TORC1) is a serine/threonine kinase that stimulates anabolic metabolism and suppresses catabolism. Deregulation of TORC1 is implicated in various human pathologies, including cancer, epilepsy, and neurodegenerative disorders. The Gap Activity Towards Rags (GATOR) complex contains [...] Read more.

The multiprotein Target of Rapamycin (TOR) Complex 1 (TORC1) is a serine/threonine kinase that stimulates anabolic metabolism and suppresses catabolism. Deregulation of TORC1 is implicated in various human pathologies, including cancer, epilepsy, and neurodegenerative disorders. The Gap Activity Towards Rags (GATOR) complex contains two subcomplexes: GATOR1, which inhibits TORC1 activity; and GATOR2, which counteracts GATOR1s function. Structural and biochemical studies have elucidated how GATOR1 regulates TORC1 activity by acting as a GTPase activating protein for Rag GTPase. However, while cryogenic electron microscopy has determined that the structure of the multi-protein GATOR2 complex is conserved from yeast to humans, how GATOR2 inhibits GATOR1 remains unclear. Here, we describe recent whole-animal studies in Drosophila that have yielded novel insights into GATOR2 function, including identifying a novel role for the GATOR2 subunit WDR59, redefining the core proteins sufficient for GATOR2 activity, and defining a TORC1-independent role for GATOR2 in the regulation of the lysosomal autophagic endomembrane system. Additionally, the recent characterization of a novel methionine receptor in Drosophila that acts through the GATOR2 complex suggests an attractive model for the evolution of species-specific nutrient sensors. Research on GATOR2 function in Drosophila highlights how whole-animal genetic models can be used to dissect intracellular signaling pathways to identify tissue-specific functions and functional redundancies that may be missed in studies confined to rapidly proliferating cell lines. Full article

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24 pages, 2902 KiB

Open AccessReview

Advancing CRISPR-Based Solutions for COVID-19 Diagnosis and Therapeutics

by Roaa Hadi, Abhishek Poddar, Shivakumar Sonnaila, Venkata Suryanarayana Murthy Bhavaraju and Shilpi Agrawal

Cells 2024, 13(21), 1794; https://doi.org/10.3390/cells13211794 - 30 Oct 2024

Viewed by 1082

Abstract

Since the onset of the COVID-19 pandemic, a variety of diagnostic approaches, including RT-qPCR, RAPID, and LFA, have been adopted, with RT-qPCR emerging as the gold standard. However, a significant challenge in COVID-19 diagnostics is the wide range of symptoms presented by patients, [...] Read more.

Since the onset of the COVID-19 pandemic, a variety of diagnostic approaches, including RT-qPCR, RAPID, and LFA, have been adopted, with RT-qPCR emerging as the gold standard. However, a significant challenge in COVID-19 diagnostics is the wide range of symptoms presented by patients, necessitating early and accurate diagnosis for effective management. Although RT-qPCR is a precise molecular technique, it is not immune to false-negative results. In contrast, CRISPR-based detection methods for SARS-CoV-2 offer several advantages: they are cost-effective, time-efficient, highly sensitive, and specific, and they do not require sophisticated instruments. These methods also show promise for scalability, enabling diagnostic tests. CRISPR technology can be customized to target any genomic region of interest, making it a versatile tool with applications beyond diagnostics, including therapeutic development. The CRISPR/Cas systems provide precise gene targeting with immense potential for creating next-generation diagnostics and therapeutics. One of the key advantages of CRISPR/Cas-based therapeutics is the ability to perform multiplexing, where different sgRNAs or crRNAs can target multiple sites within the same gene, reducing the likelihood of viral escape mutants. Among the various CRISPR systems, CRISPR/Cas13 and CARVER (Cas13-assisted restriction of viral expression and readout) are particularly promising. These systems can target a broad range of single-stranded RNA viruses, making them suitable for the diagnosis and treatment of various viral diseases, including SARS-CoV-2. However, the efficacy and safety of CRISPR-based therapeutics must be thoroughly evaluated in pre-clinical and clinical settings. While CRISPR biotechnologies have not yet been fully harnessed to control the current COVID-19 pandemic, there is an optimism that the limitations of the CRISPR/Cas system can be overcome soon. This review discusses how CRISPR-based strategies can revolutionize disease diagnosis and therapeutic development, better preparing us for future viral threats. Full article

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20 pages, 14873 KiB

Open AccessArticle

Thyroid Hormone Supplementation Restores Cognitive Deficit, Insulin Signaling, and Neuroinflammation in the Hippocampus of a Sporadic Alzheimer’s-like Disease Rat Model

by Paulina Sepúlveda, Ana Flavia Fernandes Ferreira, Cristian Sandoval, Giovanna Bergoc, Ana Caroline Rippi Moreno, Maria Tereza Nunes and Andréa da Silva Torrão

Cells 2024, 13(21), 1793; https://doi.org/10.3390/cells13211793 - 30 Oct 2024

Viewed by 1039

Abstract

Thyroid hormones play a crucial role in the development of the central nervous system and are considered pivotal to cognitive functions in the adult brain. Recently, thyroid dysfunction has been associated with Alzheimer’s disease. The aim of this study was to assess the [...] Read more.

Thyroid hormones play a crucial role in the development of the central nervous system and are considered pivotal to cognitive functions in the adult brain. Recently, thyroid dysfunction has been associated with Alzheimer’s disease. The aim of this study was to assess the neuroprotective effects of triiodothyronine (T3) on insulin signaling, neuroinflammation, apoptosis, and cognitive function in a streptozotocin (STZ)-induced sporadic Alzheimer’s disease-like model. Male Wistar rats underwent stereotaxic surgery for intracerebroventricular injections of streptozotocin (STZ; 2 mg/kg) or vehicle in the lateral ventricles to induce an AD-like model. The animals received a daily dose of 1.5 μg of T3/100 g body weight or the same volume of vehicle for 30 days and were subdivided into four experimental groups: (1) animals receiving citrate treated with saline (Control = CTL); (2) animals receiving citrate treated with T3 (T3); (3) animals receiving STZ treated with saline (STZ); and (4) animals receiving STZ treated with T3 (STZ + T3). The novel object recognition test was used to measure cognitive function. Serum analysis, real-time RT-PCR, immunohistochemistry, and immunoblotting analyses were also carried out. Our results demonstrated that T3 treatment reversed cognitive impairment and increased Akt and GSK3 phosphorylation in the treated group, while also reducing microglial activation (Iba-1) and GFAP expression (reactive astrocytes), along with TNF-α, IL-6, and IL-1β levels in the hippocampus. Additionally, T3 treatment increased levels of the anti-apoptotic protein Bcl-2 and reduced the expression of the pro-apoptotic protein BAX in the hippocampus. Our study demonstrated that T3 could potentially protect neurons in an AD model induced by STZ. Full article

(This article belongs to the Collection Novel Biomarkers for Alzheimer’s Disease and Other Neurodegenerative Diseases)

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14 pages, 2461 KiB

Open AccessArticle

Low Iron Diet Improves Clinical Arthritis in the Mouse Model of Collagen-Induced Arthritis

by Godehard A. Scholz, Sisi Xie, Tasneem Arsiwala, Daniel Guggisberg, Monique Vogel, Martin Bachmann and Burkhard Möller

Cells 2024, 13(21), 1792; https://doi.org/10.3390/cells13211792 - 29 Oct 2024

Viewed by 724

Abstract

Background: In response to inflammation, the absorption of nutritional iron is restricted. Since the pathophysiological significance of the presence and uptake of iron in chronic inflammation is still unknown, we tested the effect of a low iron diet on the clinical course of [...] Read more.

Background: In response to inflammation, the absorption of nutritional iron is restricted. Since the pathophysiological significance of the presence and uptake of iron in chronic inflammation is still unknown, we tested the effect of a low iron diet on the clinical course of arthritis in the mouse model of collagen-induced arthritis (CIA). Methods: Six- to eight-week-old male DBA/1 mice were fed either a normal (51 mg/kg) or a low iron diet (5 mg/kg) starting four weeks before the first immunization. From day 4 after the second collagen booster made on day 25, the development of arthritis was regularly monitored until the end of the experiment (day 34), using a standard clinical arthritis score. Concentrations of mouse anti-bovine and anti-mouse collagen type 2 IgG antibodies were measured by ELISA; blood cell counts were performed and mediators of inflammation, tissue matrix degradation, oxygenation and oxidative stress were measured in the mouse sera of both diet groups at the end of the experiment by bead-based multiplex assay. Fe²⁺, Fe³⁺, oxidized and reduced glutathione (GSH and GSSG) and malondialdehyde (MDA) were quantified in whole paw tissue by ELISA. Quantitative PCR was performed in the tissues for glutathione peroxidase 4 and other key regulator genes of iron metabolism and ferroptosis. We used nonparametric tests to compare cross-sectional data. Nonlinear regression models were used for longitudinal data of the arthritis scores. Results: Mice fed a low iron diet showed a significantly less severe course of arthritis compared to mice fed a normal iron diet (p < 0.001). The immune response against bovine and mouse type 2 collagen did not differ between the two diet groups. Mice fed a low iron diet exhibited significantly lower serum levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), a central regulator of inflammation and tissue matrix degradation (p < 0.05). In addition, a low iron diet led to a significant reduction in red blood cell indices, indicating restricted iron uptake and latent iron deficiency, but had no effect on hemoglobin concentrations or red blood cell counts. There were no differences between the dietary groups in Fe²⁺ or Fe³⁺ content in the paws. Based on calculation of the GSH/GSSG ratio and high MDA levels, high oxidative stress and lipid peroxidation were likewise detected in the paws of both diet groups of mice. Consequently, no differences associated with gene expression of key regulators of iron metabolism and ferroptosis could be detected between the paws of both diet groups. Conclusions: Restricted dietary iron intake alleviates immune-mediated inflammation in CIA without causing anemia. This finding suggests a promising option for dietary treatment of arthritis in inflammation. The underlying mechanism causing reduced arthritis may be linked to the complex regulatory network of TIMP-1 and appears to be independent from the local iron levels, oxidative stress and ferroptosis in the synovial tissues. Full article

(This article belongs to the Topic Oxidative Stress and Inflammation, 2nd Volume)

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18 pages, 1655 KiB

Open AccessReview

Omega-3 Fatty Acids and Neuroinflammation in Depression: Targeting Damage-Associated Molecular Patterns and Neural Biomarkers

by Ikbal Andrian Malau, Jane Pei-Chen Chang, Yi-Wen Lin, Cheng-Chen Chang, Wei-Che Chiu and Kuan-Pin Su

Cells 2024, 13(21), 1791; https://doi.org/10.3390/cells13211791 - 29 Oct 2024

Viewed by 1295

Abstract

Major Depressive Disorder (MDD) is a prevalent mental health condition with a complex pathophysiology involving neuroinflammation, neurodegeneration, and disruptions in neuronal and glial cell function. Microglia, the innate immune cells of the central nervous system, release inflammatory cytokines in response to pathological changes [...] Read more.

Major Depressive Disorder (MDD) is a prevalent mental health condition with a complex pathophysiology involving neuroinflammation, neurodegeneration, and disruptions in neuronal and glial cell function. Microglia, the innate immune cells of the central nervous system, release inflammatory cytokines in response to pathological changes associated with MDD. Damage-associated molecular patterns (DAMPs) act as alarms, triggering microglial activation and subsequent inflammatory cytokine release. This review examines the cellular mechanisms underlying MDD pathophysiology, focusing on the lipid-mediated modulation of neuroinflammation. We explore the intricate roles of microglia and astrocytes in propagating inflammatory cascades and discuss how these processes affect neuronal integrity at the cellular level. Central to our analysis are three key molecules: High Mobility Group Box 1 (HMGB1) and S100 Calcium Binding Protein β (S100β) as alarmins, and Neuron-Specific Enolase (NSE) as an indicator of neuronal stress. We present evidence from in vitro and ex vivo studies demonstrating how these molecules reflect and contribute to the neuroinflammatory milieu characteristic of MDD. The review then explores the potential of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) as neuroinflammation modulators, examining their effects on microglial activation, cytokine production, and neuronal resilience in cellular models of depression. We critically analyze experimental data on how ω-3 PUFA supplementation influences the expression and release of HMGB1, S100β, and NSE in neuronal and glial cultures. By integrating findings from lipidomic and cellular neurobiology, this review aims to elucidate the mechanisms by which ω-3 PUFAs may exert their antidepressant effects through modulation of neuroinflammatory markers. These insights contribute to our understanding of lipid-mediated neuroprotection in MDD and may inform the development of targeted, lipid-based therapies for both depression and neurodegenerative disorders. Full article

(This article belongs to the Special Issue Lipids and Lipidomics in Neurodegenerative Diseases)

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