Cells

12 pages, 480 KiB

Open AccessArticle

Mixed T-Cell Chimerism Following Hematopoietic Cell Transplantation for Non-Malignant Disorders is Common, Facilitates Anti-Viral Immunity, and Is Not Associated with Graft Failure in Pediatric Patients

by Rubiya Nadaf, Helena Lee, Denise Bonney, Ramya Hanasoge-Nataraj, Srividhya Senthil, Claire Horgan, Malcolm Guiver, Kay Poulton and Robert Wynn

Cells 2024, 13(24), 2119; https://doi.org/10.3390/cells13242119 (registering DOI) - 20 Dec 2024

Abstract

Myeloid chimerism better reflects donor stem cell engraftment than whole-blood chimerism in assessing graft function following allogeneic hematopoietic stem cell transplant (HCT). We describe our experience with 130 patients aged younger than 18 years, treated with allogeneic HCT using bone marrow or PBSC [...] Read more.

Myeloid chimerism better reflects donor stem cell engraftment than whole-blood chimerism in assessing graft function following allogeneic hematopoietic stem cell transplant (HCT). We describe our experience with 130 patients aged younger than 18 years, treated with allogeneic HCT using bone marrow or PBSC from HLA-matched donors for non-malignant diseases, whose pre-transplant conditioning therapy included alemtuzumab and who were monitored with lineage-specific chimerism after transplant. At 6 years post-transplant, overall survival (OS) was 91.1% and event-free survival (EFS) was 81.5%, with no grade III-IV acute GvHD or chronic GVHD observed. Recipient T-cells did not contribute to graft loss. Mixed T-cell chimerism (MC) did not affect EFS, and there was no connection between T-cell chimerism and myeloid chimerism in patients with MC or graft loss. MC significantly correlated with virus infection; more children with MC were CMV seropositive than those with complete chimerism (CC). Additionally, MC was more common in patients with CMV viramia post-transplant. CD8 T-cell reconstitution was affected by viral reactivation, including CMV, with CD8 T-cell counts higher in the MC group than in the CC group. Mixed T-cell chimerism is due to autologous, virus-specific, predominantly CD8, T-cell expansion, and is protective and not deleterious to the recipient. Full article

(This article belongs to the Special Issue State of the Art and Future Prospects in Stem Cell Transplantation)

19 pages, 2537 KiB

Open AccessArticle

Integrative Analysis of Chromatin Accessibility and Transcriptional Landscape Identifies Key Genes During Muscle Development in Pigs

by Dongjie Zhang, Qian Zhang, Xiaoxu Wu, Liang Wang, Xiaohan Zhang, Di Liu and Xiuqin Yang

Cells 2024, 13(24), 2118; https://doi.org/10.3390/cells13242118 (registering DOI) - 20 Dec 2024

Abstract

Many efforts have been made to reveal the mechanisms underlying skeletal muscle development because of its importance in animals. However, knowledge on chromatin accessibility, a prerequisite for gene expression, remains limited. Here, dynamic changes in chromatin accessibility were analyzed in the skeletal muscles [...] Read more.

Many efforts have been made to reveal the mechanisms underlying skeletal muscle development because of its importance in animals. However, knowledge on chromatin accessibility, a prerequisite for gene expression, remains limited. Here, dynamic changes in chromatin accessibility were analyzed in the skeletal muscles of Min pigs at the ages of 30, 90, and 210 d using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). A total of 16,301 differentially accessible regions (DARs) associated with 7455 genes were identified among three developmental stages. Seven out of eight DARs selected for a functional analysis were found to regulate reporter gene expression significantly (p < 0.05), indicating that DARs are active in gene expression. A total of 2219 differentially expressed genes (DEGs) were identified with RNA sequencing (RNA-seq). Through integrated analyses of ATAC-seq and RNA-seq data, 54 DEG_DAR_genes and 61 transcription factors (TFs) were characterized as critical for muscle development. Among them, Kruppel-like factor 5 (KLF5), targeted to 36 DEG_DAR_genes, was the most important TF. The effects of KLF5 on DEG_DAR_gene expression were then analyzed with molecular biology techniques. KLF5 was found to regulate SLPI (secretory leukocyte proteinase inhibitor) expression by directly binding to the promoter; KLF5 was also involved in APOA1 (apolipoprotein A-I) expression through affecting the regulatory role of DAR located in the intron. These results indicate that the TFs identified were functional. Altogether, the chromatin accessibility region, TFs, and genes important for muscle development in Min pigs were identified. The results provide novel data for further revealing the mechanisms underlying the epigenetic regulation of muscle development. Full article

(This article belongs to the Special Issue Skeletal Muscle Differentiation and Epigenetics - Volume II)

13 pages, 2587 KiB

Open AccessFeature PaperArticle

A Simplified Model of Adenine-Induced Chronic Kidney Disease Using SKH1 Mice

by Benjamin W. French, Joshua D. Breidenbach, Shereen G. Yassine, Bella Z. Khatib-Shahidi, Sara Kazmi, Caitlin M. Murphy, Humza S. Bashir, Evan M. Benson, Bivek Timalsina, Upasana Shrestha, Dhilhani Faleel, Satkeerth Boyapalli, Prabhatchandra Dube, Apurva Lad, Irum Syed, Deepak Malhotra, Amira Gohara, David J. Kennedy and Steven T. Haller

Cells 2024, 13(24), 2117; https://doi.org/10.3390/cells13242117 (registering DOI) - 20 Dec 2024

Abstract

Commonly used adenine-induced chronic kidney disease (CKD) murine models often employ C57BL/6 mice; however, this strain has inherent limitations due to its natural resistance to developing key pathological features of CKD, such as tubulointerstitial fibrosis and inflammation. There have been attempts to overcome [...] Read more.

Commonly used adenine-induced chronic kidney disease (CKD) murine models often employ C57BL/6 mice; however, this strain has inherent limitations due to its natural resistance to developing key pathological features of CKD, such as tubulointerstitial fibrosis and inflammation. There have been attempts to overcome these barriers by using multiple concentrations of adenine-supplemented diets or by performing prolonged experiments up to 20 weeks. Here, we demonstrate that SKH1 Elite mice develop clinically relevant CKD phenotypes (e.g., polyuria, proteinuria, inflammation, and renal fibrosis) over the course of only 6 weeks of low-dose (0.15%) adenine supplementation. As a docile, immunocompetent, and hairless strain, SKH1 Elite mice offer several logistical advantages over C57BL/6 mice, including ease of handling and the ability to study dermal conditions, which are often secondary to CKD. Full article

(This article belongs to the Special Issue Cellular and Molecular Basis in Chronic Kidney Disease)

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18 pages, 2299 KiB

Open AccessReview

Breaking Left–Right Symmetry by the Interplay of Planar Cell Polarity, Calcium Signaling and Cilia

by De-Li Shi

Cells 2024, 13(24), 2116; https://doi.org/10.3390/cells13242116 - 20 Dec 2024

Abstract

The formation of the embryonic left–right axis is a fundamental process in animals, which subsequently conditions both the shape and the correct positioning of internal organs. During vertebrate early development, a transient structure, known as the left–right organizer, breaks the bilateral symmetry in [...] Read more.

The formation of the embryonic left–right axis is a fundamental process in animals, which subsequently conditions both the shape and the correct positioning of internal organs. During vertebrate early development, a transient structure, known as the left–right organizer, breaks the bilateral symmetry in a manner that is critically dependent on the activity of motile and immotile cilia or asymmetric cell migration. Extensive studies have partially elucidated the molecular pathways that initiate left–right asymmetric patterning and morphogenesis. Wnt/planar cell polarity signaling plays an important role in the biased orientation and rotational motion of motile cilia. The leftward fluid flow generated in the cavity of the left–right organizer is sensed by immotile cilia through complex mechanisms to trigger left-sided calcium signaling and lateralized gene expression pattern. Disrupted asymmetric positioning or impaired structure and function of cilia leads to randomized left–right axis determination, which is closely linked to laterality defects, particularly congenital heart disease. Despite of the formidable progress made in deciphering the critical contribution of cilia to establishing the left–right asymmetry, a strong challenge remains to understand how cilia generate and sense fluid flow to differentially activate gene expression across the left–right axis. This review analyzes mechanisms underlying the asymmetric morphogenesis and function of the left–right organizer in left–right axis formation. It also aims to identify important questions that are open for future investigations. Full article

(This article belongs to the Special Issue Cilia-Based New Discoveries: Ciliogenesis, Function, and Human Diseases)

22 pages, 2994 KiB

Open AccessReview

Apolipoprotein-L Functions in Membrane Remodeling

by Etienne Pays

Cells 2024, 13(24), 2115; https://doi.org/10.3390/cells13242115 - 20 Dec 2024

Abstract

The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some of which are involved in the control of membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 and APOL3 appear to control membrane remodeling linked to pathogen infection. Through its association [...] Read more.

The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some of which are involved in the control of membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 and APOL3 appear to control membrane remodeling linked to pathogen infection. Through its association with Non-Muscular Myosin-2A (NM2A), APOL1 controls Golgi-derived trafficking of vesicles carrying the lipid scramblase Autophagy-9A (ATG9A). These vesicles deliver APOL3 together with phosphatidylinositol-4-kinase-B (PI4KB) and activated Stimulator of Interferon Genes (STING) to mitochondrion–endoplasmic reticulum (ER) contact sites (MERCSs) for the induction and completion of mitophagy and apoptosis. Through direct interactions with PI4KB and PI4KB activity controllers (Neuronal Calcium Sensor-1, or NCS1, Calneuron-1, or CALN1, and ADP-Ribosylation Factor-1, or ARF1), APOL3 controls PI(4)P synthesis. PI(4)P is required for different processes linked to infection-induced inflammation: (i) STING activation at the Golgi and subsequent lysosomal degradation for inflammation termination; (ii) mitochondrion fission at MERCSs for induction of mitophagy and apoptosis; and (iii) phagolysosome formation for antigen processing. In addition, APOL3 governs mitophagosome fusion with endolysosomes for mitophagy completion, and the APOL3-like murine APOL7C is involved in phagosome permeabilization linked to antigen cross-presentation in dendritic cells. Similarly, APOL3 can induce the fusion of intracellular bacterial membranes, and a role in membrane fusion can also be proposed for endothelial APOLd1 and adipocyte mAPOL6, which promote angiogenesis and adipogenesis, respectively, under inflammatory conditions. Thus, different APOL isoforms play distinct roles in membrane remodeling associated with inflammation. Full article

(This article belongs to the Special Issue Evolution, Structure, and Functions of Apolipoproteins L)

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17 pages, 2859 KiB

Open AccessFeature PaperArticle

The Tumor Metabolite 5′-Deoxy-5′Methylthioadenosine (MTA) Inhibits Maturation and T Cell-Stimulating Capacity of Dendritic Cells

by Christina Brummer, Katrin Singer, Frederik Henrich, Katrin Peter, Carolin Strobl, Bernadette Neueder, Christina Bruss, Kathrin Renner, Tobias Pukrop, Wolfgang Herr, Michael Aigner and Marina Kreutz

Cells 2024, 13(24), 2114; https://doi.org/10.3390/cells13242114 - 20 Dec 2024

Abstract

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5′-deoxy-5′methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it [...] Read more.

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5′-deoxy-5′methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells. Full article

(This article belongs to the Collection Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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13 pages, 13655 KiB

Open AccessArticle

Structure of the WIPI3/ATG16L1 Complex Reveals the Molecular Basis for the Recruitment of the ATG12~ATG5-ATG16L1 Complex by WIPI3

by Xinyu Gong, Yingli Wang, Yuqian Zhou and Lifeng Pan

Cells 2024, 13(24), 2113; https://doi.org/10.3390/cells13242113 - 20 Dec 2024

Abstract

Macroautophagy deploys a wealth of autophagy-related proteins to synthesize the double-membrane autophagosome, in order to engulf cytosolic components for lysosome-dependent degradation. The recruitment of the ATG12~ATG5-ATG16L1 complex by WIPI family proteins is a crucial step in autophagosome formation. Nevertheless, the molecular mechanism by [...] Read more.

Macroautophagy deploys a wealth of autophagy-related proteins to synthesize the double-membrane autophagosome, in order to engulf cytosolic components for lysosome-dependent degradation. The recruitment of the ATG12~ATG5-ATG16L1 complex by WIPI family proteins is a crucial step in autophagosome formation. Nevertheless, the molecular mechanism by which WIPI3 facilitates the recruitment of the ATG12~ATG5-ATG16L1 complex remains largely unknown. Here, we uncover that WIPI3 can directly interact with the coiled-coil domain of ATG16L1. By determining the crystal structure of WIPI3 in complex with ATG16L1 coiled-coil, we elucidate the molecular basis underpinning the specific recruitment of the ATG12~ATG5-ATG16L1 complex by WIPI3. Moreover, we demonstrate that WIPI2 and WIPI3 are competitive for interacting with ATG16L1 coiled-coil, and ATG16L1 and ATG2 are mutually exclusive in binding to WIPI3. In all, our findings provide mechanistic insights into the WIPI3/ATG16L1 interaction, and are valuable for further understanding the activation mechanism of the ATG12~ATG5-ATG16L1 complex as well as the working mode of WIPI3 in autophagy. Full article

(This article belongs to the Section Autophagy)

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16 pages, 22416 KiB

Open AccessArticle

A Combinatory Therapy of Metformin and Dexamethasone Reduces the Foreign Body Reaction to Intraneural Electrodes

by Bruno Rodríguez-Meana, Jaume del Valle and Xavier Navarro

Cells 2024, 13(24), 2112; https://doi.org/10.3390/cells13242112 - 20 Dec 2024

Abstract

Neural electrodes used for bidirectional communication between the nervous system and external devices like prosthetic limbs have advanced in neuroprosthetic applications. However, their effectiveness is hindered by the foreign body reaction, a natural immune response causing inflammation and fibrosis around the implanted device. [...] Read more.

Neural electrodes used for bidirectional communication between the nervous system and external devices like prosthetic limbs have advanced in neuroprosthetic applications. However, their effectiveness is hindered by the foreign body reaction, a natural immune response causing inflammation and fibrosis around the implanted device. This process involves protein adsorption, immune cell recruitment, cytokine release, and fibroblast activation, leading to a fibrous capsule formation and a decrease in electrode functionality. Anti-inflammatory and antifibrotic strategies have the potential to diminish the impact of the foreign body response. In this work, we have evaluated long-term metformin administration and short-term dexamethasone administration as a combined therapy to modulate the foreign body reaction induced by a polyimide intraneural implant in the sciatic nerve of rats. After a 12-week implant, the foreign body reaction was significantly reduced only in the group administered both drugs. Full article

(This article belongs to the Section Cells of the Nervous System)

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11 pages, 1974 KiB

Open AccessArticle

Nuclear Factor-κB Signaling Regulates the Nociceptin Receptor but Not Nociceptin Itself

by Lan Zhang, Ulrike M. Stamer, Robin Moolan-Vadackumchery and Frank Stüber

Cells 2024, 13(24), 2111; https://doi.org/10.3390/cells13242111 - 20 Dec 2024

Abstract

The nociceptin receptor (NOP) and nociceptin are involved in the pathways of pain and inflammation. The potent role of nuclear factor-κB (NFκB) in the modulation of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β on the nociceptin system in human THP-1 cells under inflammatory [...] Read more.

The nociceptin receptor (NOP) and nociceptin are involved in the pathways of pain and inflammation. The potent role of nuclear factor-κB (NFκB) in the modulation of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β on the nociceptin system in human THP-1 cells under inflammatory conditions were investigated. Cells were stimulated without/with phorbol-myristate-acetate (PMA), TNF-α, IL-1β, or PMA combined with individual cytokines. To examine NFκB’s contribution to the regulation of the nociceptin system, PMA-stimulated cells were treated with NFκB inhibitor BAY 11-7082, JSH-23, or anacardic acid before culturing with TNF-α or IL-1β. NOP and prepronociceptin (ppNOC) mRNA were quantified by RT-qPCR; cell membrane NOP and intracellular nociceptin protein levels were measured by flow cytometry. Phosphorylation and localization of NFκB/p65 were determined using ImageStream. PMA + TNF-α decreased NOP mRNA compared to stimulation with PMA alone, while PMA + IL-1β did not. BAY 11-7082 and JSH-23 reversed the repression of NOP by PMA + TNF-α. TNF-α and IL-1β attenuated PMA’s upregulating effects on ppNOC. None of the inhibitors preserved the upregulation of ppNOC in PMA + TNF-α and PMA + IL-1β cultures. TNF-α strongly mediated the nuclear translocation of NFκB/p65 in PMA-treated cells, while IL-1β did not. Proinflammatory cytokines suppressed NOP and ppNOC mRNA in PMA-induced human THP-1 cells. NFκB signaling seems to be an important regulator controlling the transcription of NOP. These findings suggest that the nociceptin system may play an anti-inflammatory role during immune responses. Full article

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23 pages, 7484 KiB

Open AccessArticle

Unraveling the Mechanism of Impaired Osteogenic Differentiation in Osteoporosis: Insights from ADRB2 Gene Polymorphism

by Olga Krasnova, Julia Sopova, Anastasiia Kovaleva, Polina Semenova, Anna Zhuk, Daria Smirnova, Daria Perepletchikova, Olga Bystrova, Marina Martynova, Vitaly Karelkin, Olga Lesnyak and Irina Neganova

Cells 2024, 13(24), 2110; https://doi.org/10.3390/cells13242110 - 20 Dec 2024

Abstract

Osteoporosis is characterized by increased resorption and decreased bone formation; it is predominantly influenced by genetic factors. G-protein coupled receptors (GPCRs) play a vital role in bone homeostasis, and mutations in these genes are associated with osteoporosis. This study aimed to investigate the [...] Read more.

Osteoporosis is characterized by increased resorption and decreased bone formation; it is predominantly influenced by genetic factors. G-protein coupled receptors (GPCRs) play a vital role in bone homeostasis, and mutations in these genes are associated with osteoporosis. This study aimed to investigate the impact of single nucleotide polymorphism (SNP) rs1042713 in the ADRB2 gene, encoding the beta-2-adrenergic receptor, on osteoblastogenesis. Herein, using quantitative polymerase chain reaction, western immunoblotting, immunofluorescence assays, and flow cytometry, we examined the expression of ADRB2 and markers of bone matrix synthesis in mesenchymal stem cells (MSCs) derived from osteoporosis patient (OP-MSCs) carrying ADRB2 SNP in comparison with MSCs from healthy donor (HD-MSCs). The results showed significantly reduced ADRB2 expression in OP-MSCs at both the mRNA and protein levels, alongside decreased type 1 collagen expression, a key bone matrix component. Notably, OP-MSCs exhibited increased ERK kinase expression during differentiation, indicating sustained cell cycle progression, unlike that going to HD-MSC. These results provide novel insights into the association of ADRB2 gene polymorphisms with osteogenic differentiation. The preserved proliferative activity of OP-MSCs with rs1042713 in ADRB2 contributes to their inability to undergo effective osteogenic differentiation. This research suggests that targeting genetic factors may offer new therapeutic strategies to mitigate osteoporosis progression. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Bone and Cartilage Damage and Regeneration)

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18 pages, 9914 KiB

Open AccessArticle

Receptor-Interacting Protein Kinase-3 Expression Impacts Ocular Vascular Development and Pathological Neovascularization

by Yong-Seok Song, Shoujian Wang, Sun-Young Park, Barbara Hanna, Kelsey J. Johnson, Soesiawati R. Darjatmoko, Mohammad Ali Saghiri, Ali Mohammad Saghiri, Bo Liu, Christine M. Sorenson and Nader Sheibani

Cells 2024, 13(24), 2109; https://doi.org/10.3390/cells13242109 - 20 Dec 2024

Abstract

Functional cell death pathways are essential for normal ocular vascular development and tissue homeostasis. As our understanding of necrosis-based cell death pathways has expanded, the inclusion of regulated forms, including necroptosis, ferroptosis, and oxytosis, has occurred. Although the existence of these pathways is [...] Read more.

Functional cell death pathways are essential for normal ocular vascular development and tissue homeostasis. As our understanding of necrosis-based cell death pathways has expanded, the inclusion of regulated forms, including necroptosis, ferroptosis, and oxytosis, has occurred. Although the existence of these pathways is well described, our understanding of their role during vascular development and pathological neovascularization is very limited. Here, we examined the role of receptor-interacting protein kinase-3 (Ripk3), a key regulator of necroptosis, in postnatal retinal vascularization and retinal and choroidal neovascularization under pathological conditions. Postnatal vascularization of the retinal superficial layer in the absence of Ripk3 (Ripk3^−/−) was not significantly different from wild-type mice. However, we noted decreased retinal endothelial cells and pericyte numbers at 3 weeks of age when the formation of the retinal primary vascular plexus was complete. In contrast, choroidal and retinal neovascularization following laser treatment and oxygen-induced ischemic retinopathy increased in the absence of Ripk3 expression, respectively. In addition, the inhibition of RIPK1/3 activity suppressed choroidal neovascularization. Thus, Ripk3 expression and/or activity may have unique roles during normal and pathological ocular vascularization through its interactions with Caspase 8 and modulation of cell death processes. Full article

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

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31 pages, 1710 KiB

Open AccessArticle

Anandamide Inhibits Vascular Smooth Muscle Migration, Endothelial Adhesion Protein Expression and Monocyte Adhesion of Human Coronary Artery Cells

by Elane Blessing, Elisa Teichmann and Burkhard Hinz

Cells 2024, 13(24), 2108; https://doi.org/10.3390/cells13242108 - 19 Dec 2024

Abstract

Endocannabinoids have been shown to play a complex role in the pathophysiology of a number of cardiovascular disorders. In the present study, the effects of the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were investigated in human coronary artery smooth muscle cells [...] Read more.

Endocannabinoids have been shown to play a complex role in the pathophysiology of a number of cardiovascular disorders. In the present study, the effects of the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were investigated in human coronary artery smooth muscle cells (HCASMC) and human coronary artery endothelial cells (HCAEC) with regard to potential atheroprotective and anti-inflammatory effects. In HCASMC, AEA showed an inhibitory effect on platelet-derived growth factor-induced migration, but not proliferation, independent of major cannabinoid-activatable receptors (CB₁, CB₂, TRPV1), while 2-AG left both responses unaffected. In HCAEC, AEA at concentrations of 6 and 10 µM significantly inhibited the interleukin (IL)-1β- and lipopolysaccharide (LPS)-stimulated expression of vascular cell adhesion molecule-1 (VCAM-1) and LPS-induced intercellular adhesion molecule-1 (ICAM-1), again independently of the abovementioned receptors. Corresponding effects were observed to a lesser extent in the presence of 2-AG, in most cases not significantly. The detection of activated phosphoproteins as well as experiments with inhibitors of corresponding signaling pathways suggest that AEA interferes with IL-1β-induced VCAM-1 expression via inhibition of protein kinase B/Akt and Src kinase activation and attenuates LPS-induced VCAM-1 and ICAM-1 expression via inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation. As expected, AEA also led to a significant inhibition of monocyte adhesion to IL-1β- and LPS-stimulated HCAEC, with siRNA experiments confirming the functional role of VCAM-1 and ICAM-1 in this assay. 2-AG showed a comparatively weaker but, in the case of LPS stimulation, still significant inhibition of adhesion. In summary, the results emphasize the potential of AEA as a protective regulator of atherosclerotic and inflammation-related changes in HCASMC and HCAEC and encourage further corresponding preclinical studies with this endocannabinoid. Full article

(This article belongs to the Section Cells of the Cardiovascular System)

28 pages, 1404 KiB

Open AccessReview

The Role and Mechanism of TRIM Proteins in Gastric Cancer

by Wangxi Wu, Jinyu Yang, Tian Yu, Zhuoling Zou and Xuan Huang

Cells 2024, 13(24), 2107; https://doi.org/10.3390/cells13242107 - 19 Dec 2024

Abstract

Tripartite motif (TRIM) family proteins, distinguished by their N-terminal region that includes a Really Interesting New Gene (RING) domain with E3 ligase activity, two B-box domains, and a coiled-coil region, have been recognized as significant contributors in carcinogenesis, primarily via the ubiquitin–proteasome system [...] Read more.

Tripartite motif (TRIM) family proteins, distinguished by their N-terminal region that includes a Really Interesting New Gene (RING) domain with E3 ligase activity, two B-box domains, and a coiled-coil region, have been recognized as significant contributors in carcinogenesis, primarily via the ubiquitin–proteasome system (UPS) for degrading proteins. Mechanistically, these proteins modulate a variety of signaling pathways, including Wnt/β-catenin, PI3K/AKT, and TGF-β/Smad, contributing to cellular regulation, and also impact cellular activities through non-signaling mechanisms, including modulation of gene transcription, protein degradation, and stability via protein–protein interactions. Currently, growing evidence indicates that TRIM proteins emerge as potential regulators in gastric cancer, exhibiting both tumor-suppressive and oncogenic roles. Given their critical involvement in cellular processes and the notable challenges of gastric cancer, exploring the specific contributions of TRIM proteins to this disease is necessary. Consequently, this review elucidates the roles and mechanisms of TRIM proteins in gastric cancer, emphasizing their potential as therapeutic targets and prognostic factors. Full article

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16 pages, 1540 KiB

Open AccessReview

The Invertebrate Immunocyte: A Complex and Versatile Model for Immunological, Developmental, and Environmental Research

by Sandro Sacchi, Davide Malagoli and Nicola Franchi

Cells 2024, 13(24), 2106; https://doi.org/10.3390/cells13242106 - 19 Dec 2024

Abstract

The knowledge of comparative and developmental immunobiology has grown over the years and has been strengthened by the contributions of multi-omics research. High-performance microscopy, flow cytometry, scRNA sequencing, and the increased capacity to handle complex data introduced by machine learning have allowed the [...] Read more.

The knowledge of comparative and developmental immunobiology has grown over the years and has been strengthened by the contributions of multi-omics research. High-performance microscopy, flow cytometry, scRNA sequencing, and the increased capacity to handle complex data introduced by machine learning have allowed the uncovering of aspects of great complexity and diversity in invertebrate immunocytes, i.e., immune-related circulating cells, which until a few years ago could only be described in terms of morphology and basic cellular functions, such as phagocytosis or enzymatic activity. Today, invertebrate immunocytes are recognized as sophisticated biological entities, involved in host defense, stress response, wound healing, organ regeneration, but also in numerous functional aspects of organismal life not directly related to host defense, such as embryonic development, metamorphosis, and tissue homeostasis. The multiple functions of immunocytes do not always fit the description of invertebrate organisms as simplified biological systems compared to those represented by vertebrates. However, precisely the increasing complexity revealed by immunocytes makes invertebrate organisms increasingly suitable models for addressing biologically significant and specific questions, while continuing to present the undeniable advantages associated with their ethical and economic sustainability. Full article

(This article belongs to the Section Cellular Immunology)

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4 pages, 2063 KiB

Open AccessCorrection

Correction: Hazzan et al. Thymic Stromal Lymphopoietin Interferes with the Apoptosis of Human Skin Mast Cells by a Dual Strategy Involving STAT5/Mcl-1 and JNK/Bcl-x_L. Cells 2019, 8, 829

by Tarek Hazzan, Jürgen Eberle, Margitta Worm and Magda Babina

Cells 2024, 13(24), 2105; https://doi.org/10.3390/cells13242105 - 19 Dec 2024

Abstract

Error in Figure 3 [...] Full article

(This article belongs to the Section Cell Signaling)

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13 pages, 2309 KiB

Open AccessArticle

The Formyl Peptid Receptor Ligand Ac2-26 Improves the Integrity of the Blood−Brain Barrier in the Course of Pneumococcal Meningitis

by Johannes Deutloff, Irina Pöhner, Johann Rößler, Markus Kipp, Simone C. Tauber and Lars-Ove Brandenburg

Cells 2024, 13(24), 2104; https://doi.org/10.3390/cells13242104 - 19 Dec 2024

Abstract

Background: The brain is protected from invading pathogens by the blood−brain barrier (BBB) and the innate immune system. Pattern recognition receptors play a crucial role in detecting bacteria and initiating the innate immune response. Among these are G-protein-coupled formyl peptide receptors (FPR), which [...] Read more.

Background: The brain is protected from invading pathogens by the blood−brain barrier (BBB) and the innate immune system. Pattern recognition receptors play a crucial role in detecting bacteria and initiating the innate immune response. Among these are G-protein-coupled formyl peptide receptors (FPR), which are expressed by immune cells in the central nervous system. In this study, we investigated the influence of the FPR ligand Ac2-26 on the integrity of the BBB during pneumococcal meningitis. Methods: Wild-type (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae. Subsequently, different groups of mice were treated with intraperitoneal injections of Ac2-26. The integrity of the BBB was analyzed using various markers through immunohistochemistry and immunofluorescence. Results: The results showed reduced BBB integrity during the course of bacterial meningitis. Treatment with Ac2-26 in WT mice significantly prolonged the maintenance of BBB integrity. However, this effect was not observed in Fpr2-deficient mice. Conclusions: This study extends previous findings on the anti-inflammatory properties of Ac2-26 by demonstrating that Ac2-26 positively affects BBB integrity via FPR2 during pneumococcal meningitis. These findings suggest that further investigation of Ac2-26 and other FPR modulators as potential therapies for Streptococcus pneumoniae-induced meningitis is warranted. Full article

(This article belongs to the Special Issue Advances in the Study of Neuroinflammation)

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12 pages, 3039 KiB

Open AccessReview

Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics: Obstacles and Potential Breakthrough Technologies

by William Taylor and William Mark Erwin

Cells 2024, 13(24), 2103; https://doi.org/10.3390/cells13242103 - 19 Dec 2024

Abstract

Pain and disability secondary to degenerative disc disease continue to burden the healthcare system, creating an urgent need for effective, disease-modifying therapies. Contemporary research has identified potential therapies that include protein-, cellular- and/or matrix-related approaches; however, none have yet achieved a meaningful clinical [...] Read more.

Pain and disability secondary to degenerative disc disease continue to burden the healthcare system, creating an urgent need for effective, disease-modifying therapies. Contemporary research has identified potential therapies that include protein-, cellular- and/or matrix-related approaches; however, none have yet achieved a meaningful clinical impact. The tissue-specific realities of the intervertebral disc create considerable therapeutic challenges due to the disc’s location, compartmentalization, hypovascularization and delicate physiological environment. Furthermore, the imaging modalities currently used in practice are largely unable to accurately identify sources of pain ostensibly discogenic in origin. These obstacles are considerable; however, recent research has begun to shed light on possible breakthrough technologies. Such breakthroughs include revolutionary imaging to better identify tissue sources of pain. Furthermore, novel molecular therapies have been shown to be able to mediate the progression of degenerative disc disease in some large animal studies, and even provide some insight into suppressing the development of tissue sources of discogenic pain. These potential breakthrough technologies have yet to be translated for clinical use. Full article

(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics—Second Edition)

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17 pages, 4485 KiB

Open AccessArticle

Tumor Intrinsic Immunogenicity Suppressor SETDB1 Worsens the Prognosis of Patients with Hepatocellular Carcinoma

by Chang-Qing Yin and Chun-Qing Song

Cells 2024, 13(24), 2102; https://doi.org/10.3390/cells13242102 - 19 Dec 2024

Abstract

Hepatocellular carcinoma (HCC) is clinically distinguished by its covert onset, rapid progression, high recurrence rate, and poor prognosis. Studies have revealed that SETDB1 (SET Domain Bifurcated 1) is a histone H3 methyltransferase located on chromosome 1 and plays a crucial role in carcinogenesis. [...] Read more.

Hepatocellular carcinoma (HCC) is clinically distinguished by its covert onset, rapid progression, high recurrence rate, and poor prognosis. Studies have revealed that SETDB1 (SET Domain Bifurcated 1) is a histone H3 methyltransferase located on chromosome 1 and plays a crucial role in carcinogenesis. Therefore, we aimed to evaluate the clinical significance of SETDB1 expression in HCC. In patients with HCC, elevated levels of SETDB1 correlated with a poorer overall survival (OS) rate, marking it as an independent prognostic factor for HCC, as revealed by both univariate and multivariate Cox analyses. Furthermore, we utilized the SangerBox and TISIDB databases to profile the tumor immune microenvironment in HCC, including scoring the tumor microenvironment and assessing immune cell infiltration. The TIDE algorithm was employed to examine the association between SETDB1 expression and immune responses. Our findings indicated that SETDB1 expression negatively correlated with the majority of immune cells, a wide range of immune cell marker genes, and numerous immune pathways, thereby leading to the reduced effectiveness of immune checkpoint inhibitors. Lastly, both in vivo and ex vivo experiments were conducted to substantiate the role of SETDB1 in HCC tumorigenesis. In conclusion, the upregulation of SETDB1 is associated with a poorer prognosis in HCC patients and inversely correlates with immune cell infiltration, potentially serving as a predictive marker for immunotherapy response. Full article

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32 pages, 5236 KiB

Open AccessReview

Dog Aging: A Comprehensive Review of Molecular, Cellular, and Physiological Processes

by Gabriella Guelfi, Camilla Capaccia, Martina Tedeschi, Antonello Bufalari, Leonardo Leonardi, Beniamino Cenci-Goga and Margherita Maranesi

Cells 2024, 13(24), 2101; https://doi.org/10.3390/cells13242101 - 18 Dec 2024

Abstract

The aging process is a multifactorial biological phenomenon starting at birth and persisting throughout life, characterized by a decline in physiological functions and adaptability. This decline results in the diminished capacity of aging organisms to respond to environmental changes and stressors, leading to [...] Read more.

The aging process is a multifactorial biological phenomenon starting at birth and persisting throughout life, characterized by a decline in physiological functions and adaptability. This decline results in the diminished capacity of aging organisms to respond to environmental changes and stressors, leading to reduced efficiency in metabolic, immune, and hormonal functions. As behavioral flexibility wanes, older individuals face longer recovery times and increased vulnerability to diseases. While early research proposed nine core hallmarks of mammalian aging, recent studies have expanded this framework to twelve key characteristics: epigenetic changes, genomic instability, telomere shortening, loss of proteostasis, altered metabolism, mitochondrial dysfunction, cellular senescence, disrupted intercellular communication, stem cell depletion, immune system dysfunction, accumulation of toxic metabolites, and dysbiosis. Given the growing interest in the aging area, we propose to add a new hallmark: impaired water homeostasis. This potential hallmark could play a critical role in aging processes and might open new directions for future research in the field. This review enhances our understanding of the physiological aspects of aging in dogs, suggesting new clinical intervention strategies to prevent and control issues that may arise from the pathological degeneration of these hallmarks. Full article

(This article belongs to the Special Issue Understanding Aging Mechanisms to Prevent Age-Related Diseases)

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