Cells

11 pages, 484 KiB

Open AccessReview

Human Endometrial Pericytes: A Comprehensive Overview of Their Physiological Functions and Implications in Uterine Disorders

by Yiqun Tang, Caroline Frisendahl, Terhi T. Piltonen, Riikka K. Arffman, Parameswaran Grace Lalitkumar and Kristina Gemzell-Danielsson

Cells 2024, 13(17), 1510; https://doi.org/10.3390/cells13171510 - 9 Sep 2024

Viewed by 1027

Abstract

Pericytes are versatile cells integral to the blood vessel walls of the microcirculation, where they exhibit specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, and maintaining homeostasis and are involved in the tissue repair process. The human [...] Read more.

Pericytes are versatile cells integral to the blood vessel walls of the microcirculation, where they exhibit specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, and maintaining homeostasis and are involved in the tissue repair process. The human endometrium is a unique and complex tissue that serves as a natural scar-free healing model with its cyclical repair and regeneration process every month. The regulation of pericytes has gained increasing attention due to their involvement in various physiological and pathological processes. However, endometrial pericytes are less well studied compared to the pericytes in other organs. This review aims to provide a comprehensive overview of endometrial pericytes, with a focus on elucidating their physiological function and potential implications in uterine disorders. Full article

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15 pages, 1195 KiB

Open AccessReview

Potential Therapeutic Interventions Targeting NAD⁺ Metabolism for ALS

by Samuel Lundt and Shinghua Ding

Cells 2024, 13(17), 1509; https://doi.org/10.3390/cells13171509 - 9 Sep 2024

Viewed by 1687

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD⁺) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD⁺ can be synthesized from three different intracellular pathways, but it is the NAD⁺ salvage pathway that generates the largest proportion of NAD⁺. Impaired NAD⁺ homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD⁺ homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD⁺ metabolism, either by administering NAD⁺ precursor metabolites or small molecules that alter NAD⁺-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD⁺ metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models. Full article

(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))

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12 pages, 1948 KiB

Open AccessReview

Reporter Mice for Gene Editing: A Key Tool for Advancing Gene Therapy of Rare Diseases

by Siang Li and Cord Brakebusch

Cells 2024, 13(17), 1508; https://doi.org/10.3390/cells13171508 - 9 Sep 2024

Viewed by 1062

Abstract

Most rare diseases are caused by mutations and can have devastating consequences. Precise gene editing by CRISPR/Cas is an exciting possibility for helping these patients, if no irreversible developmental defects have occurred. To optimize gene editing therapy, reporter mice for gene editing have [...] Read more.

Most rare diseases are caused by mutations and can have devastating consequences. Precise gene editing by CRISPR/Cas is an exciting possibility for helping these patients, if no irreversible developmental defects have occurred. To optimize gene editing therapy, reporter mice for gene editing have been generated which, by expression of reporter genes, indicate the efficiency of precise and imprecise gene editing. These mice are important tools for testing and comparing novel gene editing methodologies. This review provides a comprehensive overview of reporter mice for gene editing which all have been used for monitoring CRISPR/Cas-mediated gene editing involving DNA double-strand breaks (DSBs). Furthermore, we discuss how reporter mice can be used for quickly checking genetic alterations by base editing (BE) or prime editing (PE). Full article

(This article belongs to the Section Cell Nuclei: Function, Transport and Receptors)

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17 pages, 3441 KiB

Open AccessArticle

Functional Insights in PLS3-Mediated Osteogenic Regulation

by Wenchao Zhong, Janine Neugebauer, Janak L. Pathak, Xingyang Li, Gerard Pals, M. Carola Zillikens, Elisabeth M. W. Eekhoff, Nathalie Bravenboer, Qingbin Zhang, Matthias Hammerschmidt, Brunhilde Wirth and Dimitra Micha

Cells 2024, 13(17), 1507; https://doi.org/10.3390/cells13171507 - 9 Sep 2024

Viewed by 873

Abstract

Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional [...] Read more.

Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensation by actin-bundling proteins ACTN1, ACTN4, and FSCN1 was investigated in zebrafish following morpholino-mediated pls3 knockdown. Primary dermal fibroblasts from six patients with a PLS3 variant were also used to examine expression of these proteins during osteogenic differentiation. In addition, Pls3 knockdown in the murine MLO-Y4 cell line was employed to provide insights in global gene expression. Our results showed that ACTN1 and ACTN4 can rescue the skeletal deformities in zebrafish after pls3 knockdown, but this was inadequate for FSCN1. Patients’ fibroblasts showed the same osteogenic transdifferentiation ability as healthy donors. RNA-seq results showed differential expression in Wnt1, Nos1ap, and Myh3 after Pls3 knockdown in MLO-Y4 cells, which were also associated with the Wnt and Th17 cell differentiation pathways. Moreover, WNT2 was significantly increased in patient osteoblast-like cells compared to healthy donors. Altogether, our findings in different bone cell types indicate that the mechanism of PLS3-related pathology extends beyond actin-bundling proteins, implicating broader pathways of bone metabolism. Full article

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14 pages, 12901 KiB

Open AccessArticle

Class Effect Unveiled: PPARγ Agonists and MEK Inhibitors in Cancer Cell Differentiation

by Rakefet Ben-Yishay, Opher Globus, Nora Balint-Lahat, Sheli Arbili-Yarhi, Neta Bar-Hai, Vered Bar, Sara Aharon, Anna Kosenko, Adi Zundelevich, Raanan Berger and Dana Ishay-Ronen

Cells 2024, 13(17), 1506; https://doi.org/10.3390/cells13171506 - 9 Sep 2024

Viewed by 800

Abstract

Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation [...] Read more.

Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells, we demonstrated a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFβ, with Cobimetinib showing the most prominent effects. A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance. Full article

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

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24 pages, 2454 KiB

Open AccessReview

Adipose-Derived Stem Cell Therapy in Spinal Cord Injury

by Jad El Masri, Hiba Fadlallah, Rahaf Al Sabsabi, Ahmad Afyouni, Mohamed Al-Sayegh and Wassim Abou-Kheir

Cells 2024, 13(17), 1505; https://doi.org/10.3390/cells13171505 - 9 Sep 2024

Viewed by 1788

Abstract

Spinal cord injury (SCI) is a serious condition accompanied by severe adverse events that affect several aspects of the patient’s life, such as motor, sensory, and functional impairment. Despite its severe consequences, definitive treatment for these injuries is still missing. Therefore, researchers have [...] Read more.

Spinal cord injury (SCI) is a serious condition accompanied by severe adverse events that affect several aspects of the patient’s life, such as motor, sensory, and functional impairment. Despite its severe consequences, definitive treatment for these injuries is still missing. Therefore, researchers have focused on developing treatment strategies aimed at ensuring full recovery post-SCI. Accordingly, attention has been drawn toward cellular therapy using mesenchymal stem cells. Considering their wide availability, decreased immunogenicity, wide expansion capacity, and impressive effectiveness in many therapeutic approaches, adipose-derived stem cell (ADSC) injections in SCI cases have been investigated and showed promising results. In this review, SCI pathophysiology and ADSC transplantation benefits are discussed independently, together with SCI animal models and adipose stem cell preparation and application techniques. The mechanisms of healing in an SCI post-ADSC injection, the outcomes of this therapeutic approach, and current clinical trials are also deliberated, in addition to the challenges and future perspectives, aiming to encourage further research in this field. Full article

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24 pages, 8603 KiB

Open AccessArticle

CCDC78: Unveiling the Function of a Novel Gene Associated with Hereditary Myopathy

by Diego Lopergolo, Gian Nicola Gallus, Giuseppe Pieraccini, Francesca Boscaro, Gianna Berti, Giovanni Serni, Nila Volpi, Patrizia Formichi, Silvia Bianchi, Denise Cassandrini, Vincenzo Sorrentino, Daniela Rossi, Filippo Maria Santorelli, Nicola De Stefano and Alessandro Malandrini

Cells 2024, 13(17), 1504; https://doi.org/10.3390/cells13171504 - 8 Sep 2024

Viewed by 1256

Abstract

CCDC78 was identified as a novel candidate gene for autosomal dominant centronuclear myopathy-4 (CNM4) approximately ten years ago. However, to date, only one family has been described, and the function of CCDC78 remains unclear. Here, we analyze for the first time a family [...] Read more.

CCDC78 was identified as a novel candidate gene for autosomal dominant centronuclear myopathy-4 (CNM4) approximately ten years ago. However, to date, only one family has been described, and the function of CCDC78 remains unclear. Here, we analyze for the first time a family harboring a CCDC78 nonsense mutation to better understand the role of CCDC78 in muscle. Methods: We conducted a comprehensive histopathological analysis on muscle biopsies, including immunofluorescent assays to detect multiple sarcoplasmic proteins. We examined CCDC78 transcripts and protein using WB in CCDC78-mutated muscle tissue; these analyses were also performed on muscle, lymphocytes, and fibroblasts from healthy subjects. Subsequently, we conducted RT-qPCR and transcriptome profiling through RNA-seq to evaluate changes in gene expression associated with CCDC78 dysfunction in muscle. Lastly, coimmunoprecipitation (Co-Ip) assays and mass spectrometry (LC-MS/MS) studies were carried out on extracted muscle proteins from both healthy and mutated subjects. Results: The histopathological features in muscle showed novel histological hallmarks, which included areas of dilated and swollen sarcoplasmic reticulum (SR). We provided evidence of nonsense-mediated mRNA decay (NMD), identified the presence of novel CCDC78 transcripts in muscle and lymphocytes, and identified 1035 muscular differentially expressed genes, including several involved in the SR. Through the Co-Ip assays and LC-MS/MS studies, we demonstrated that CCDC78 interacts with two key SR proteins: SERCA1 and CASQ1. We also observed interactions with MYH1, ACTN2, and ACTA1. Conclusions: Our findings provide insight, for the first time, into the interactors and possible role of CCDC78 in skeletal muscle, locating the protein in the SR. Furthermore, our data expand on the phenotype previously associated with CCDC78 mutations, indicating potential histopathological hallmarks of the disease in human muscle. Based on our data, we can consider CCDC78 as the causative gene for CNM4. Full article

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17 pages, 10948 KiB

Open AccessFeature PaperArticle

LIP1 Regulates the Plant Circadian Oscillator by Modulating the Function of the Clock Component GIGANTEA

by Anita Hajdu, Dóra Nyári, Kata Terecskei, Péter Gyula, Éva Ádám, Orsolya Dobos, Zsuzsanna Mérai and László Kozma-Bognár

Cells 2024, 13(17), 1503; https://doi.org/10.3390/cells13171503 - 8 Sep 2024

Viewed by 770

Abstract

Circadian clocks are biochemical timers regulating many physiological and molecular processes according to the day/night cycles. The function of the oscillator relies on negative transcriptional/translational feedback loops operated by the so-called clock genes and the encoded clock proteins. Previously, we identified the small [...] Read more.

Circadian clocks are biochemical timers regulating many physiological and molecular processes according to the day/night cycles. The function of the oscillator relies on negative transcriptional/translational feedback loops operated by the so-called clock genes and the encoded clock proteins. Previously, we identified the small GTPase LIGHT INSENSITIVE PERIOD 1 (LIP1) as a circadian-clock-associated protein that regulates light input to the clock in the model plant Arabidopsis thaliana. We showed that LIP1 is also required for suppressing red and blue light-mediated photomorphogenesis, pavement cell shape determination and tolerance to salt stress. Here, we demonstrate that LIP1 is present in a complex of clock proteins GIGANTEA (GI), ZEITLUPE (ZTL) and TIMING OF CAB 1 (TOC1). LIP1 participates in this complex via GUANINE EX-CHANGE FACTOR 7. Analysis of genetic interactions proved that LIP1 affects the oscillator via modulating the function of GI. We show that LIP1 and GI independently and additively regulate photomorphogenesis and salt stress responses, whereas controlling cell shape and photoperiodic flowering are not shared functions of LIP1 and GI. Collectively, our results suggest that LIP1 affects a specific function of GI, possibly by altering binding of GI to downstream signalling components. Full article

(This article belongs to the Special Issue Structure, Function, and Regulation of the Circadian Clock in Plants)

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15 pages, 2800 KiB

Open AccessFeature PaperArticle

Importance of Transcript Variants in Transcriptome Analyses

by Kevin Vo, Yashica Sharma, Anohita Paul, Ryan Mohamadi, Amelia Mohamadi, Patrick E. Fields and M. A. Karim Rumi

Cells 2024, 13(17), 1502; https://doi.org/10.3390/cells13171502 - 8 Sep 2024

Viewed by 1074

Abstract

RNA sequencing (RNA-Seq) has become a widely adopted technique for studying gene expression. However, conventional RNA-Seq analyses rely on gene expression (GE) values that aggregate all the transcripts produced under a single gene identifier, overlooking the complexity of transcript variants arising from different [...] Read more.

RNA sequencing (RNA-Seq) has become a widely adopted technique for studying gene expression. However, conventional RNA-Seq analyses rely on gene expression (GE) values that aggregate all the transcripts produced under a single gene identifier, overlooking the complexity of transcript variants arising from different transcription start sites or alternative splicing. Transcript variants may encode proteins with diverse functional domains, or noncoding RNAs. This study explored the implications of neglecting transcript variants in RNA-Seq analyses. Among the 1334 transcription factor (TF) genes expressed in mouse embryonic stem (ES) or trophoblast stem (TS) cells, 652 were differentially expressed in TS cells based on GE values (365 upregulated and 287 downregulated, ≥absolute 2-fold changes, false discovery rate (FDR) p-value ≤ 0.05). The 365 upregulated genes expressed 883 transcript variants. Further transcript expression (TE) based analyses identified only 174 (<20%) of the 883 transcripts to be upregulated. The remaining 709 transcripts were either downregulated or showed no significant changes. Meanwhile, the 287 downregulated genes expressed 856 transcript variants and only 153 (<20%) of the 856 transcripts were downregulated. The other 703 transcripts were either upregulated or showed no significant change. Additionally, the 682 insignificant TF genes (GE values < absolute 2-fold changes and/or FDR p-values > 0.05) between ES and TS cells expressed 2215 transcript variants. These included 477 (>21%) differentially expressed transcripts (276 upregulated and 201 downregulated, ≥absolute 2-fold changes, FDR p-value ≤ 0.05). Hence, GE based RNA-Seq analyses do not represent accurate expression levels due to divergent transcripts expression from the same gene. Our findings show that by including transcript variants in RNA-Seq analyses, we can generate a precise understanding of a gene’s functional and regulatory landscape; ignoring the variants may result in an erroneous interpretation. Full article

(This article belongs to the Section Cell and Gene Therapy)

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20 pages, 4321 KiB

Open AccessArticle

HGA Triggers SAA Aggregation and Accelerates Fibril Formation in the C20/A4 Alkaptonuria Cell Model

by Pierfrancesco Mastroeni, Alfonso Trezza, Michela Geminiani, Luisa Frusciante, Anna Visibelli and Annalisa Santucci

Cells 2024, 13(17), 1501; https://doi.org/10.3390/cells13171501 - 7 Sep 2024

Viewed by 961

Abstract

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene, leading to the accumulation of homogentisic acid (HGA), causing severe inflammatory conditions. Recently, the presence of serum amyloid A (SAA) has been reported in AKU [...] Read more.

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene, leading to the accumulation of homogentisic acid (HGA), causing severe inflammatory conditions. Recently, the presence of serum amyloid A (SAA) has been reported in AKU tissues, classifying AKU as novel secondary amyloidosis; AA amyloidosis is characterized by the extracellular tissue deposition of fibrils composed of fragments of SAA. AA amyloidosis may complicate several chronic inflammatory conditions, like rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, chronic infections, neoplasms, etc. Treatments of AA amyloidosis relieve inflammatory disorders by reducing SAA concentrations; however, no definitive therapy is currently available. SAA regulation is a crucial step to improve AA secondary amyloidosis treatments. Here, applying a comprehensive in vitro and in silico approach, we provided evidence that HGA is a disruptor modulator of SAA, able to enhance its polymerization, fibril formation, and aggregation upon SAA/SAP colocalization. In silico studies deeply dissected the SAA misfolding molecular pathway and SAA/HGA binding, suggesting novel molecular insights about it. Our results could represent an important starting point for identifying novel therapeutic strategies in AKU and AA secondary amyloidosis-related diseases. Full article

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8 pages, 194 KiB

Open AccessEditorial

PI3K/AKT/mTOR Signaling Network in Human Health and Diseases

by Tolulope O. Omolekan, Jean Christopher Chamcheu, Claudia Buerger and Shile Huang

Cells 2024, 13(17), 1500; https://doi.org/10.3390/cells13171500 - 6 Sep 2024

Viewed by 1245

Abstract

Transduction of molecular signaling is a fundamental mechanism that allows a living cell to communicate internally with other cells and its environment through chemical or physical signals, thereby maintaining its structural integrity and triggering physiological responses [...] Full article

(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases)

14 pages, 2695 KiB

Open AccessArticle

Dysregulation of miR-223, miR-146a, and miR-193a Expression Profile in Acute and Chronic Phases of Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice

by Saba Gharibi, Bahram Moghimi, Mohammad Bagher Mahmoudi, Ensieh Shahvazian, Ehsan Farashahi Yazd, Maryam Yadegari, Mohammad Taher Tahoori, Esmaeil Yazdanpanah, Dariush Haghmorad and Valentyn Oksenych

Cells 2024, 13(17), 1499; https://doi.org/10.3390/cells13171499 - 6 Sep 2024

Viewed by 884

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease with an unknown etiology. The purpose of this research was to assess miR-223, miR-146a, and miR-193a in acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) mice to consider the possible role of these genes [...] Read more.

Multiple sclerosis (MS) is a chronic autoimmune disease with an unknown etiology. The purpose of this research was to assess miR-223, miR-146a, and miR-193a in acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) mice to consider the possible role of these genes in the pathogenesis of MS. EAE induction was given by myelin oligodendrocyte glycoprotein peptide on female C57BL/6 mice. Clinical scores and other criteria were followed daily until day 21 for the acute group and day 77 for the chronic group. At the end of the course, inflammation and demyelination of the central nervous system (CNS) were assessed by histological analysis. MicroRNA expression levels were assessed by real-time PCR. EAE development attenuated in the chronic group, and histological analysis showed less infiltration and demyelination in the chronic group compared to the acute group. The upper expression of miR-223 is demonstrated in the acute phase of EAE. Moreover, the expression levels of miR-146a and miR-193a decreased in the chronic phase of EAE. MiR-223 showed a highly coordinated elevation in the acute phase both in vivo and in vitro. MiR-146a shares a pathway with miR-223 through effecting IL-6 expression. Further studies are needed to reveal their impact on EAE and possible applications as drug targets and biomarkers. Full article

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17 pages, 4216 KiB

Open AccessArticle

An Essential Role for Calnexin in ER-Phagy and the Unfolded Protein Response

by Daniel Wolf, Chiara Röder, Michael Sendtner and Patrick Lüningschrör

Cells 2024, 13(17), 1498; https://doi.org/10.3390/cells13171498 - 6 Sep 2024

Viewed by 881

Abstract

ER-phagy is a specialized form of autophagy, defined by the lysosomal degradation of ER subdomains. ER-phagy has been implicated in relieving the ER from misfolded proteins during ER stress upon activation of the unfolded protein response (UPR). Here, we identified an essential role [...] Read more.

ER-phagy is a specialized form of autophagy, defined by the lysosomal degradation of ER subdomains. ER-phagy has been implicated in relieving the ER from misfolded proteins during ER stress upon activation of the unfolded protein response (UPR). Here, we identified an essential role for the ER chaperone calnexin in regulating ER-phagy and the UPR in neurons. We showed that chemical induction of ER stress triggers ER-phagy in the somata and axons of primary cultured motoneurons. Under basal conditions, the depletion of calnexin leads to an enhanced ER-phagy in axons. However, upon ER stress induction, ER-phagy did not further increase in calnexin-deficient motoneurons. In addition to increased ER-phagy under basal conditions, we also detected an elevated proteasomal turnover of insoluble proteins, suggesting enhanced protein degradation by default. Surprisingly, we detected a diminished UPR in calnexin-deficient early cortical neurons under ER stress conditions. In summary, our data suggest a central role for calnexin in orchestrating both ER-phagy and the UPR to maintain protein homeostasis within the ER. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress in Neurodegenerative Diseases)

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12 pages, 2361 KiB

Open AccessArticle

D4Z4 Hypomethylation in Human Germ Cells

by Ramya Potabattula, Jana Durackova, Sarah Kießling, Alina Michler, Thomas Hahn, Martin Schorsch, Tom Trapphoff, Stefan Dieterle and Thomas Haaf

Cells 2024, 13(17), 1497; https://doi.org/10.3390/cells13171497 - 6 Sep 2024

Viewed by 798

Abstract

Expression of the double homeobox 4 (DUX4) transcription factor is highly regulated in early embryogenesis and is subsequently epigenetically silenced. Ectopic expression of DUX4 due to hypomethylation of the D4Z4 repeat array on permissive chromosome 4q35 alleles is associated with facioscapulohumeral [...] Read more.

Expression of the double homeobox 4 (DUX4) transcription factor is highly regulated in early embryogenesis and is subsequently epigenetically silenced. Ectopic expression of DUX4 due to hypomethylation of the D4Z4 repeat array on permissive chromosome 4q35 alleles is associated with facioscapulohumeral muscular dystrophy (FSHD). In peripheral blood samples from 188 healthy individuals, D4Z4 methylation was highly variable, ranging from 19% to 76%, and was not affected by age. In 48 FSHD2 patients, D4Z4 methylation varied from 3% to 30%. Given that DUX4 is one of the earliest transcribed genes after fertilization, the D4Z4 array is expected to be unmethylated in mature germ cells. Deep bisulfite sequencing of 188 mainly normozoospermic sperm samples revealed an average methylation of 2.5% (range 0.3–22%). Overall, the vast majority (78%) of individual sperm cells displayed no methylation at all. In contrast, only 19 (17.5%) of 109 individual germinal vesicle (GV) oocytes displayed D4Z4 methylation <2.5%. However, it is not unexpected that immature GV oocytes which are not usable for assisted reproduction are endowed with D4Z4 (up to 74%) hypermethylation and/or abnormal (PEG3 and GTL2) imprints. Although not significant, it is interesting to note that the pregnancy rate after assisted reproduction was higher for donors of sperm samples and oocytes with <2.5% methylation. Full article

(This article belongs to the Special Issue Recent Advances in Mammalian Reproductive Biology—a Focus on Development of Gametes and Embryos)

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24 pages, 3809 KiB

Open AccessArticle

The Proteasome and Cul3-Dependent Protein Ubiquitination Is Required for Gli Protein-Mediated Activation of Gene Expression in the Hedgehog Pathway

by Tomasz Uśpieński and Paweł Niewiadomski

Cells 2024, 13(17), 1496; https://doi.org/10.3390/cells13171496 - 6 Sep 2024

Viewed by 807

Abstract

Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin–proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal [...] Read more.

Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin–proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway. Full article

(This article belongs to the Special Issue The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation)

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15 pages, 1305 KiB

Open AccessArticle

The Tumor Suppressor Par-4 Regulates Adipogenesis by Transcriptional Repression of PPARγ

by James Sledziona, Ravshan Burikhanov, Nathalia Araujo, Jieyun Jiang, Nikhil Hebbar and Vivek M. Rangnekar

Cells 2024, 13(17), 1495; https://doi.org/10.3390/cells13171495 - 5 Sep 2024

Viewed by 970

Abstract

Prostate apoptosis response-4 (Par-4, also known as PAWR) is a ubiquitously expressed tumor suppressor protein that induces apoptosis selectively in cancer cells, while leaving normal cells unaffected. Our previous studies indicated that genetic loss of Par-4 promoted hepatic steatosis, adiposity, and insulin-resistance in [...] Read more.

Prostate apoptosis response-4 (Par-4, also known as PAWR) is a ubiquitously expressed tumor suppressor protein that induces apoptosis selectively in cancer cells, while leaving normal cells unaffected. Our previous studies indicated that genetic loss of Par-4 promoted hepatic steatosis, adiposity, and insulin-resistance in chow-fed mice. Moreover, low plasma levels of Par-4 are associated with obesity in human subjects. The mechanisms underlying obesity in rodents and humans are multi-faceted, and those associated with adipogenesis can be functionally resolved in cell cultures. We therefore used pluripotent mouse embryonic fibroblasts (MEFs) or preadipocyte cell lines responsive to adipocyte differentiation cues to determine the potential role of Par-4 in adipocytes. We report that pluripotent MEFs from Par-4^−/− mice underwent rapid differentiation to mature adipocytes with an increase in lipid droplet accumulation relative to MEFs from Par-4^+/+ mice. Knockdown of Par-4 in 3T3-L1 pre-adipocyte cultures by RNA-interference induced rapid differentiation to mature adipocytes. Interestingly, basal expression of PPARγ, a master regulator of de novo lipid synthesis and adipogenesis, was induced during adipogenesis in the cell lines, and PPARγ induction and adipogenesis caused by Par-4 loss was reversed by replenishment of Par-4. Mechanistically, Par-4 downregulates PPARγ expression by directly binding to its upstream promoter, as judged by chromatin immunoprecipitation and luciferase-reporter studies. Thus, Par-4 transcriptionally suppresses the PPARγ promoter to regulate adipogenesis. Full article

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

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13 pages, 643 KiB

Open AccessArticle

E-Selectin and Asymmetric Dimethylarginine Levels in Adult Cyanotic Congenital Heart Disease: Their Relation to Biochemical Parameters, Vascular Function, and Clinical Status

by Sonia Alicja Nartowicz, Ludwina Szczepaniak-Chicheł, Dawid Lipski, Izabela Miechowicz, Agnieszka Bartczak-Rutkowska, Marcin Gabriel, Maciej Lesiak and Olga Trojnarska

Cells 2024, 13(17), 1494; https://doi.org/10.3390/cells13171494 - 5 Sep 2024

Viewed by 698

Abstract

Background and Aim: Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contribute to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and [...] Read more.

Background and Aim: Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contribute to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and e-selectin (e-sel) are valuable biomarkers for endothelial and vascular dysfunction. Their concentration levels in blood serum have the potential to be an accessible tool that reflects the severity of the disease. We aimed to assess e-sel and ADMA levels and their relationship with the clinical status and endothelial and vascular function. Methods: A cross-sectional study, including 36 adult CHD cyanotic patients [(17 males) (42.3 ± 16.3 years)] with an arterial blood oxygen saturation less than 92% and 20 healthy controls [(10 males) (38.2 ± 8.5 years)], was performed. All the patients underwent a clinical examination, blood testing, and cardiopulmonary tests. Their endothelial function was assessed using the intima media thickness and flow-mediated dilatation. Vascular function, using applanation tonometry methods, was determined using the aortic systolic pressure, aortic pulse pressure, augmentation pressure, augmentation index, pulse pressure amplification, and pulse wave velocity. Results: The concentrations of e-sel and ADMA were significantly higher in the patients with CHD. The E-sel levels correlated positively with red blood cells, hemoglobin concentration, hematocrit, and augmentation pressure; they correlated negatively with blood oxygen saturation, the forced expiratory one-second volume, forced vital capacity, and oxygen uptake. The ADMA levels were found to correlate only with age. Conclusions: The E-sel level, unlike ADMA concentration, reflects the severity of erythrocytosis and hypoxia and, thus, the physical status of patients with cyanotic CHD. Full article

(This article belongs to the Collection Cardiovascular Disease: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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14 pages, 770 KiB

Open AccessReview

A Review of Pathophysiology and Therapeutic Strategies Targeting TGF-β in Graves’ Ophthalmopathy

by Hsin-Ho Chang, Shi-Bei Wu and Chieh-Chih Tsai

Cells 2024, 13(17), 1493; https://doi.org/10.3390/cells13171493 - 5 Sep 2024

Viewed by 1019

Abstract

TGF-β plays a pivotal role in the pathogenesis of GO by promoting orbital tissue remodeling and fibrosis. This process involves the stimulation of orbital fibroblasts, leading to myofibroblast differentiation, increased production of inflammatory mediators, and hyaluronan accumulation. Studies have elucidated TGF-β’s role in [...] Read more.

TGF-β plays a pivotal role in the pathogenesis of GO by promoting orbital tissue remodeling and fibrosis. This process involves the stimulation of orbital fibroblasts, leading to myofibroblast differentiation, increased production of inflammatory mediators, and hyaluronan accumulation. Studies have elucidated TGF-β’s role in driving fibrosis and scarring processes through both canonical and non-canonical pathways, particularly resulting in the activation of orbital myofibroblasts and the excessive accumulation of extracellular matrix. Additionally, recent in vitro and in vivo studies have been summarized, highlighting the therapeutic potential of targeting TGF-β signaling pathways, which may offer promising treatment interventions for GO. This review aims to consolidate the current understanding of the multifaceted role of TGF-β in the molecular and cellular pathophysiology in Graves’ ophthalmopathy (GO) by exploring its contributions to fibrosis, inflammation, and immune dysregulation. Additionally, the review investigates the therapeutic potential of inhibiting TGF-β signaling pathways as a strategy for treating GO. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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22 pages, 725 KiB

Open AccessReview

Emerging and Biological Concepts in Pediatric High-Grade Gliomas

by Abigail Yoel, Shazia Adjumain, Yuqing Liang, Paul Daniel, Ron Firestein and Vanessa Tsui

Cells 2024, 13(17), 1492; https://doi.org/10.3390/cells13171492 - 5 Sep 2024

Viewed by 1421

Abstract

Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO [...] Read more.

Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO CNS classification identifies four subtypes of pHGGs, including Grade 4 Diffuse midline glioma H3K27-altered, Grade 4 Diffuse hemispheric gliomas H3-G34-mutant, Grade 4 pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, and infant-type hemispheric gliomas. In recent years, we have seen promising advancements in treatment strategies for pediatric high-grade gliomas, including immunotherapy, CAR-T cell therapy, and vaccine approaches, which are currently undergoing clinical trials. These therapies are underscored by the integration of molecular features that further stratify HGG subtypes. Herein, we will discuss the molecular features of pediatric high-grade gliomas and the evolving landscape for treating these challenging tumors. Full article

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15 pages, 1625 KiB

Open AccessArticle

The Relationship between HERV, Interleukin, and Transcription Factor Expression in ZIKV Infected versus Uninfected Trophoblastic Cells

by Anderson Luís da Costa, Paula Prieto-Oliveira, Márcia Duarte-Barbosa, Robert Andreata-Santos, Cristina M. Peter, Thamires Prolo de Brito, Fernando Antoneli, Ricardo Durães-Carvalho, Marcelo R. S. Briones, Juliana T. Maricato, Paolo M. A. Zanotto, Denis Jacob Machado and Luiz M. R. Janini

Cells 2024, 13(17), 1491; https://doi.org/10.3390/cells13171491 - 5 Sep 2024

Viewed by 909

Abstract

Zika virus (ZIKV) is an arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV triggers an immune defense in the [...] Read more.

Zika virus (ZIKV) is an arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV triggers an immune defense in the placenta. This immune response counts with the participation of interleukins and transcription factors. Additionally, it has the potential involvement of human endogenous retroviruses (HERVS). Interleukins are immune response regulators that aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. HERVs are remnants of ancient viral infections that integrate into the genome and produce syncytin proteins crucial for placental development. Since ZIKV can infect trophoblast cells, we analyzed the relationship between ZIKV infection, HERV, interleukin, and transcription factor modulations in the placenta. To investigate the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asian–Brazilian) using Taqman and RT2 Profiler PCR Array assays. Our results indicate that early ZIKV infection (24–72 h) does not induce differential interleukins, transcription factors, and HERV expression. However, we show that the expression of a few of these host defense genes appears to be linked independently of ZIKV infection. Future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and transcription factors in the placenta. Full article

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14 pages, 820 KiB

Open AccessArticle

Evaluation of Known Markers of Ferroptosis in Semen of Patients with Different Reproductive Pathologies and Fertile Men

by Elena Moretti, Cinzia Signorini, Laura Liguori, Roberta Corsaro, Fabiola Nerucci, Marcello Fiorini, Silvia Menchiari and Giulia Collodel

Cells 2024, 13(17), 1490; https://doi.org/10.3390/cells13171490 - 5 Sep 2024

Viewed by 679

Abstract

This study aims to investigate the role of ferroptosis, an iron-dependent form of regulated cell death, in male infertility. The motivation behind this research stems from the increasing recognition of oxidative stress and iron metabolism dysregulation as critical factors in male reproductive health. [...] Read more.

This study aims to investigate the role of ferroptosis, an iron-dependent form of regulated cell death, in male infertility. The motivation behind this research stems from the increasing recognition of oxidative stress and iron metabolism dysregulation as critical factors in male reproductive health. In this study, 28 infertile patients (grouped by the presence of urogenital infections or varicocele) and 19 fertile men were selected. Spermiograms were performed by light microscopy (WHO, 2021). Testosterone, ferritin, transferrin-bound iron, transferrin, and F₂-isoprostanes (F₂-IsoPs) were detected in seminal plasma. Glutathione peroxidase 4 (GPX4) and acyl coenzyme A synthetase long chain family member 4 (ACSL4) were also assessed in sperm cells using enzyme-linked immunosorbent assays (ELISA). All the variables were correlated (statistically significant Spearman’s rank correlations) in the whole population, and then the comparison between variables of the different groups of men were carried out. Seminal ferritin and transferrin positively correlated with seminal F₂-IsoPs, which had positive correlations with ACSL4 detected in sperm cells. Ferritin and ACSL4 negatively correlated with the seminal parameters. No correlation was detected for GPX4. Comparing the variables in the three examined groups, elevated levels of ACSL4 were observed in infertile patients with urogenital infections and varicocele; GPX4 levels were similar in the three groups. These results suggested a mechanism of ferroptosis, identified by increased ACSL4 levels and the occurrence of lipid peroxidation. Such events appear to be GPX4-independent in reproductive pathologies such as varicocele and urogenital infections. Full article

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12 pages, 936 KiB

Open AccessReview

A Comparative Review of Cytokines and Cytokine Targeting in Sepsis: From Humans to Horses

by Kallie J. Hobbs, Rosemary Bayless and M. Katie Sheats

Cells 2024, 13(17), 1489; https://doi.org/10.3390/cells13171489 - 5 Sep 2024

Viewed by 1214

Abstract

With the emergence of COVID-19, there is an increased focus in human literature on cytokine production, the implications of cytokine overproduction, and the development of novel cytokine-targeting therapies for use during sepsis. In addition to viral infections such as COVID-19, bacterial infections resulting [...] Read more.

With the emergence of COVID-19, there is an increased focus in human literature on cytokine production, the implications of cytokine overproduction, and the development of novel cytokine-targeting therapies for use during sepsis. In addition to viral infections such as COVID-19, bacterial infections resulting in exposure to endotoxins and exotoxins in humans can also lead to sepsis, resulting in organ failure and death. Like humans, horses are exquisitely sensitive to endotoxin and are among the veterinary species that develop clinical sepsis similar to humans. These similarities suggest that horses may serve as a naturally occurring model of human sepsis. Indeed, evidence shows that both species experience cytokine dysregulation, severe neutropenia, the formation of neutrophil extracellular traps, and decreased perfusion parameters during sepsis. Sepsis treatments that target cytokines in both species include hemoperfusion therapy, steroids, antioxidants, and immunomodulation therapy. This review will present the shared cytokine physiology across humans and horses as well as historical and updated perspectives on cytokine-targeting therapy. Finally, this review will discuss the potential benefits of increased knowledge of equine cytokine mechanisms and their potential positive impact on human medicine. Full article

(This article belongs to the Topic Application of Animal Models: From Physiology to Pathology)

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17 pages, 327 KiB

Open AccessReview

Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor Alpha and Gamma Agonists on Myocardial Damage: Molecular Mechanisms and Clinical Evidence—A Narrative Review

by María Esther Rubio-Ruíz, Juan Carlos Plata-Corona, Elizabeth Soria-Castro, Julieta Anabell Díaz-Juárez and María Sánchez-Aguilar

Cells 2024, 13(17), 1488; https://doi.org/10.3390/cells13171488 - 5 Sep 2024

Viewed by 929

Abstract

Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies [...] Read more.

Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed. Full article

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

20 pages, 2215 KiB

Open AccessArticle

The Role of αvβ3 Integrin in Lamina Cribrosa Cell Mechanotransduction in Glaucoma

by Mustapha Irnaten, Ellen Gaynor and Colm O’Brien

Cells 2024, 13(17), 1487; https://doi.org/10.3390/cells13171487 - 5 Sep 2024

Viewed by 1023

Abstract

Purpose: Glaucoma, one of the leading causes of irreversible blindness, is a common progressive optic neuropathy characterised by visual field defects and structural changes to the optic nerve head (ONH). There is extracellular matrix (ECM) accumulation and fibrosis of the lamina cribrosa (LC) [...] Read more.

Purpose: Glaucoma, one of the leading causes of irreversible blindness, is a common progressive optic neuropathy characterised by visual field defects and structural changes to the optic nerve head (ONH). There is extracellular matrix (ECM) accumulation and fibrosis of the lamina cribrosa (LC) in the ONH, and consequently increased tissue stiffness of the LC connective tissue. Integrins are cell surface proteins that provide the key molecular link connecting cells to the ECM and serve as bidirectional sensors transmitting signals between cells and their environment to promote cell adhesion, proliferation, and remodelling of the ECM. Here, we investigated the expression of αVβ3 integrin in glaucoma LC cell, and its effect on stiffness-induced ECM gene transcription and cellular proliferation rate in normal (NLC) and glaucoma (GLC) LC cells, by down-regulating αVβ3 integrin expression using cilengitide (a known potent αVβ3 and αVβ5 inhibitor) and β3 integrin siRNA knockdown. Methods: GLC cells were compared to age-matched controls NLC to determine differential expression levels of αVβ3 integrin, ECM genes (Col1A1, α-SMA, fibronectin, vitronectin), and proliferation rates. The effects of αVβ3 integrin blockade (with cilengitide) and silencing (with a pool of four predesigned αVβ3 integrin siRNAs) on ECM gene expression and proliferation rates were evaluated using both reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting in the human NLC cells cultured on soft (4 kPa) and stiff (100 kPa) substrate and in GLC cells grown on standard plastic plates. Results: αVβ3 integrin gene and protein expression were enhanced (p < 0.05) in GLC cells as compared to NLC. Both cilengitide and siRNA significantly reduced αVβ3 expression in GLC. When NLC were grown in the stiff substrate, cilengitide and siRNA also significantly reduced the increased expression in αVβ3, ECM components, and proliferation rate. Conclusions: Here, we provide evidence of cilengitide- and siRNA-mediated silencing of αVβ3 integrin expression, and inhibition of ECM synthesis in LC cells. Therefore, αVβ3 integrin may be a promising target for the development of novel anti-fibrotic therapies for treating the LC cupping of the ONH in glaucoma. Full article

(This article belongs to the Special Issue Fibrosis in Chronic Inflammatory Diseases)

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19 pages, 5498 KiB

Open AccessArticle

Gestational CBD Shapes Insular Cortex in Adulthood

by Daniela Iezzi, Alba Cáceres-Rodríguez, Jessica Pereira-Silva, Pascale Chavis and Olivier Jacques José Manzoni

Cells 2024, 13(17), 1486; https://doi.org/10.3390/cells13171486 - 4 Sep 2024

Viewed by 692

Abstract

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular [...] Read more.

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated IC’s cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5–E18; 3 mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring. Full article

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

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14 pages, 2225 KiB

Open AccessArticle

Supplementation with Fish Oil and Selenium Protects Lipolytic and Thermogenic Depletion of Adipose in Cachectic Mice Treated with an EGFR Inhibitor

by Hang Wang, Yi-Lin Chan, Yi-Han Chiu, Tsung-Han Wu, Simon Hsia and Chang-Jer Wu

Cells 2024, 13(17), 1485; https://doi.org/10.3390/cells13171485 - 4 Sep 2024

Viewed by 890

Abstract

Lung cancer and cachexia are the leading causes of cancer-related deaths worldwide. Cachexia is manifested by weight loss and white adipose tissue (WAT) atrophy. Limited nutritional supplements are conducive to lung cancer patients, whereas the underlying mechanisms are poorly understood. In this study, [...] Read more.

Lung cancer and cachexia are the leading causes of cancer-related deaths worldwide. Cachexia is manifested by weight loss and white adipose tissue (WAT) atrophy. Limited nutritional supplements are conducive to lung cancer patients, whereas the underlying mechanisms are poorly understood. In this study, we used a murine cancer cachexia model to investigate the effects of a nutritional formula (NuF) rich in fish oil and selenium yeast as an adjuvant to enhance the drug efficacy of an EGFR inhibitor (Tarceva). In contrast to the healthy control, tumor-bearing mice exhibited severe cachexia symptoms, including tissue wasting, hypoalbuminemia, and a lower food efficiency ratio. Experimentally, Tarceva reduced pEGFR and HIF-1α expression. NuF decreased the expression of pEGFR and HIF-2α, suggesting that Tarceva and NuF act differently in prohibiting tumor growth and subsequent metastasis. NuF blocked LLC tumor-induced PTHrP and expression of thermogenic factor UCP1 and lipolytic enzymes (ATGL and HSL) in WAT. NuF attenuated tumor progression, inhibited PTHrP-induced adipose tissue browning, and maintained adipose tissue integrity by modulating heat shock protein (HSP) 72. Added together, Tarceva in synergy with NuF favorably improves cancer cachexia as well as drug efficacy. Full article

(This article belongs to the Special Issue Second Edition of Advances in Adipose Tissue Biology)

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16 pages, 3183 KiB

Open AccessArticle

HOTAIR Promotes the Hyperactivation of PI3K/Akt and Wnt/β-Catenin Signaling Pathways via PTEN Hypermethylation in Cervical Cancer

by Samuel Trujano-Camacho, David Cantú-de León, Eloy Pérez-Yepez, Carlos Contreras-Romero, Jossimar Coronel-Hernandez, Oliver Millan-Catalan, Mauricio Rodríguez-Dorantes, Cesar López-Camarillo, Concepción Gutiérrez-Ruiz, Nadia Jacobo-Herrera and Carlos Pérez-Plasencia

Cells 2024, 13(17), 1484; https://doi.org/10.3390/cells13171484 - 4 Sep 2024

Viewed by 1503

Abstract

The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/β-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression [...] Read more.

The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/β-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression—either by knockdown or overexpression—significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/β-catenin pathways. Additionally, we discovered that HIF1α directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1α in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/β-catenin pathways through the HOTAIR/HIF1α axis, thereby contributing to the oncogenic phenotype of cervical cancer. Full article

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15 pages, 958 KiB

Open AccessReview

The Role of circHIPK3 in Tumorigenesis and Its Potential as a Biomarker in Lung Cancer

by Eryk Siedlecki, Piotr Remiszewski and Rafał Stec

Cells 2024, 13(17), 1483; https://doi.org/10.3390/cells13171483 - 4 Sep 2024

Viewed by 1003

Abstract

Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, [...] Read more.

Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, where it plays a crucial role in lung cancer tumorigenesis. CircHIPK3 promotes lung cancer progression by sponging oncosuppressive miRNAs such as miR-124, miR-381-3p, miR-149, and miR-107, which results in increased cell proliferation, migration, and resistance to therapies. Inhibiting circHIPK3 has been demonstrated to suppress tumour growth and induce apoptosis, which suggests its potential use in the development of new lung cancer treatment strategies targeting circHIPK3-related pathways. As a biomarker, circHIPK3 shows promise for early detection and monitoring of lung cancer. CircHIPK3 increased expression levels in lung cancer cells, and its potential link to metastasis risk highlights its clinical relevance. Given the promising preliminary findings, more clinical trials are needed to validate circHIPK3 efficacy as a biomarker. Moreover, future research should determine if the mechanisms discovered in NSCLC apply to small cell lung cancer (SCLC) to investigate circHIPK3-targeted therapies for SCLC. Full article

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14 pages, 4547 KiB

Open AccessArticle

Inhibition of KDM2/7 Promotes Notochordal Differentiation of hiPSCs

by Martha E. Diaz-Hernandez, Kimihide Murakami, Shizumasa Murata, Nazir M. Khan, Sreekala P. V. Shenoy, Katrin Henke, Hiroshi Yamada and Hicham Drissi

Cells 2024, 13(17), 1482; https://doi.org/10.3390/cells13171482 - 4 Sep 2024

Viewed by 814

Abstract

Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal [...] Read more.

Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal diseases. Therefore, adult somatic cells reprogrammed into human induced pluripotent stem cells (hiPSCs) represent an attractive cell source for the derivation of notochordal-like cells (NCs) as a first step towards the development of a regenerative therapy for IDD. Utilizing a differentiation method involving treatment with a four-factor cocktail targeting the BMP, FGF, retinoic acid, and Wnt signaling pathways, we differentiate CRISPR/Cas9-generated mCherry-reporter knock-in hiPSCs into notochordal-like cells. Comprehensive analysis of transcriptomic changes throughout the differentiation process identified regulation of histone methylation as a pivotal driver facilitating the differentiation of hiPSCs into notochordal-like cells. We further provide evidence that specific inhibition of histone demethylases KDM2A and KDM7A/B enhanced the lineage commitment of hiPSCs towards notochordal-like cells. Our results suggest that inhibition of KDMs could be leveraged to alter the epigenetic landscape of hiPSCs to control notochord-specific gene expression. Thus, our study highlights the importance of epigenetic regulators in stem cell-based regenerative approaches for the treatment of disc degeneration. Full article

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20 pages, 9382 KiB

Open AccessArticle

Enhancing the Antibody Production Efficiency of Chinese Hamster Ovary Cells through Improvement of Disulfide Bond Folding Ability and Apoptosis Resistance

by Chen Zhang, Yunhui Fu, Wenyun Zheng, Feng Chang, Yue Shen, Jinping Niu, Yangmin Wang and Xingyuan Ma

Cells 2024, 13(17), 1481; https://doi.org/10.3390/cells13171481 - 4 Sep 2024

Viewed by 957

Abstract

The complex structure of monoclonal antibodies (mAbs) expressed in Chinese hamster ovary (CHO) cells may result in the accumulation of unfolded proteins, triggering endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). If the protein folding ability cannot maintain ER homeostasis, the [...] Read more.

The complex structure of monoclonal antibodies (mAbs) expressed in Chinese hamster ovary (CHO) cells may result in the accumulation of unfolded proteins, triggering endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). If the protein folding ability cannot maintain ER homeostasis, the cell will shut down protein translation and ultimately induce apoptosis. We co-overexpressed HsQSOX1b and survivin proteins in the antibody-producing cell line CHO-PAb to obtain a new cell line, CHO-PAb-QS. Compared with CHO-PAb cells, the survival time of CHO-PAb-QS cells in batch culture was extended by 2 days, and the antibody accumulation and productivity were increased by 52% and 45%, respectively. The proportion of (HC-LC)₂ was approximately doubled in the CHO-PAb-QS cells, which adapted to the accelerated disulfide bond folding capacity by upregulating the UPR’s strength and increasing the ER content. The results of the apoptosis assays indicated that the CHO-PAb-QS cell line exhibited more excellent resistance to apoptosis induced by ER stress. Finally, CHO-PAb-QS cells exhibited mild oxidative stress but did not significantly alter the redox status. This study demonstrated that strategies based on HsQSOX1b and survivin co-overexpression could facilitate protein disulfide bond folding and anti-apoptosis ability, enhancing antibody production efficiency in CHO cell lines. Full article

(This article belongs to the Collection Advances in Cell Culture and Tissue Engineering)

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