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Cells
Volume 13
Issue 15
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Cells, Volume 13, Issue 15 (August-1 2024) – 77 articles

Cover Story (view full-size image): ADAR1 is crucial for maintaining smooth muscle and vascular integrity. The deletion of ADAR1 specifically in smooth muscle in mice causes lethality due to extensive hemorrhage and vascular damage. Histological analyses show structural destruction and apoptosis in smooth muscle along with mitochondrial dysfunction. RNA sequencing reveals significant changes in gene expression, such as a reduction in fibrillin-1, which disrupts the interaction between elastin and fibrillin-1. These findings highlight the essential role of ADAR1 in smooth muscle survival and vascular homeostasis. View this paper
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15 pages, 1971 KiB  
Article
RNAseq of Gingival Fibroblasts Exposed to PRF Membrane Lysates and PRF Serum
by Atefe Imani, Layla Panahipour, Hannes Kühtreiber, Michael Mildner and Reinhard Gruber
Cells 2024, 13(15), 1308; https://doi.org/10.3390/cells13151308 - 5 Aug 2024
Viewed by 682
Abstract
Platelet-rich fibrin (PRF) is prepared by spontaneous coagulation of fractionated blood. When squeezed between two plates, PRF is separated into solid PRF membranes and a liquid exudate, the PRF serum. The question arises regarding how much the overall activity remains in the PRF [...] Read more.
Platelet-rich fibrin (PRF) is prepared by spontaneous coagulation of fractionated blood. When squeezed between two plates, PRF is separated into solid PRF membranes and a liquid exudate, the PRF serum. The question arises regarding how much the overall activity remains in the PRF membranes and what is discarded into the PRF serum. To this end, we have exposed gingival fibroblasts to lysates prepared from PRF membranes and PRF serum, followed by bulk RNA sequencing. A total of 268 up- and 136 down-regulated genes in gingival fibroblasts exposed to PRF membrane lysates were significantly regulated under the premise of a minimum log2 with 2.5-fold change and a minus log10 significance level of two, respectively. PRF serum only caused 62 up- and 32 down-regulated genes under these conditions. Among the 46 commonly up-regulated genes were CXCL1, CXCL5, CXCL6, CXCL8, IL33, IL6, and PTGS2/COX2, stanniocalcin-1—all linked to an inflammatory response. PRF membrane lysates further increased chemokines CCL2, CCL7, CXCL2, CXCL3, and IL1R1, IL1RL1, and IL1RN, as well as the paracrine factors IL11, LIF, IGF1, BMP2, BMP6, FGF2, and CCN2/CTGF, and all hyaluronan synthases. On the other hand, PRF serum increased DKK1. The genes commonly down-regulated by PRF membrane lysates and PRF serum included interferon-induced protein with tetratricopeptide repeats (IFIT1, IFIT2, IFIT3) and odd-skipped-related transcription factors (OSR1 and OSR2), as well as FGF18 and GDF15, respectively. Taken together, PRF membrane lysates, compared to PRF serum, cause a more complex response in gingival fibroblasts, but each increased chemokine expression in gingival fibroblasts. Full article
(This article belongs to the Special Issue Oral Tissue Stem Cells in Regenerative Dentistry)
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21 pages, 1926 KiB  
Review
Preserving Genome Integrity: Unveiling the Roles of ESCRT Machinery
by Mattia La Torre, Romina Burla and Isabella Saggio
Cells 2024, 13(15), 1307; https://doi.org/10.3390/cells13151307 - 5 Aug 2024
Viewed by 855
Abstract
The endosomal sorting complex required for transport (ESCRT) machinery is composed of an articulated architecture of proteins that assemble at multiple cellular sites. The ESCRT machinery is involved in pathways that are pivotal for the physiology of the cell, including vesicle transport, cell [...] Read more.
The endosomal sorting complex required for transport (ESCRT) machinery is composed of an articulated architecture of proteins that assemble at multiple cellular sites. The ESCRT machinery is involved in pathways that are pivotal for the physiology of the cell, including vesicle transport, cell division, and membrane repair. The subunits of the ESCRT I complex are mainly responsible for anchoring the machinery to the action site. The ESCRT II subunits function to bridge and recruit the ESCRT III subunits. The latter are responsible for finalizing operations that, independently of the action site, involve the repair and fusion of membrane edges. In this review, we report on the data related to the activity of the ESCRT machinery at two sites: the nuclear membrane and the midbody and the bridge linking cells in the final stages of cytokinesis. In these contexts, the machinery plays a significant role for the protection of genome integrity by contributing to the control of the abscission checkpoint and to nuclear envelope reorganization and correlated resilience. Consistently, several studies show how the dysfunction of the ESCRT machinery causes genome damage and is a codriver of pathologies, such as laminopathies and cancer. Full article
(This article belongs to the Section Cell Proliferation and Division)
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5 pages, 683 KiB  
Editorial
Translating Anti-Inflammatory Strategies for Atherosclerosis: Deep Phenotyping, Next-Generation Drug Targets, and Precision Medicine
by Yaw Asare and Marios K. Georgakis
Cells 2024, 13(15), 1306; https://doi.org/10.3390/cells13151306 - 5 Aug 2024
Viewed by 682
Abstract
Atherosclerosis is the main pathology underlying cardiovascular disease (CVD), including myocardial infarction and ischemic stroke [...] Full article
(This article belongs to the Special Issue Vascular Inflammation and Atherosclerosis: From Basic Mechanisms to Therapeutic Opportunities)
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2 pages, 526 KiB  
Correction
Correction: Bo et al. Atg5 Regulates Selective Autophagy of the Parental Macronucleus during Tetrahymena Sexual Reproduction. Cells 2021, 10, 3071
by Tao Bo, Yu Kang, Ya Liu, Jing Xu and Wei Wang
Cells 2024, 13(15), 1305; https://doi.org/10.3390/cells13151305 - 5 Aug 2024
Viewed by 320
Abstract
In the original publication [...] Full article
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18 pages, 11995 KiB  
Article
The Novel-m0230-3p miRNA Modulates the CSF1/CSF1R/Ras Pathway to Regulate the Cell Tight Junctions and Blood–Testis Barrier in Yak
by Qiu Yan, Qi Wang, Yong Zhang, Ligang Yuan, Junjie Hu and Xingxu Zhao
Cells 2024, 13(15), 1304; https://doi.org/10.3390/cells13151304 - 5 Aug 2024
Viewed by 582
Abstract
The yak (Bos grunniens) is a valuable livestock animal endemic to the Qinghai–Tibet Plateau in China with low reproductive rates. Cryptorchidism is one of the primary causes of infertility in male yaks. Compared with normal testes, the tight junctions (TJs) of Sertoli cells [...] Read more.
The yak (Bos grunniens) is a valuable livestock animal endemic to the Qinghai–Tibet Plateau in China with low reproductive rates. Cryptorchidism is one of the primary causes of infertility in male yaks. Compared with normal testes, the tight junctions (TJs) of Sertoli cells (SCs) and the integrity of the blood–testis barrier (BTB) in cryptorchidism are both disrupted. MicroRNAs are hairpin-derived RNAs of about 19–25 nucleotides in length and are involved in a variety of biological processes. Numerous studies have shown the involvement of microRNAs in the reproductive physiology of yak. In this study, we executed RNA sequencing (RNA-seq) to describe the expression profiles of mRNAs and microRNAs in yaks with normal testes and cryptorchidism to identify differentially expressed genes. GO and KEGG analyses were used to identify the biological processes and signaling pathways which the target genes of the differentially expressed microRNAs primarily engaged. It was found that novel-m0230-3p is an important miRNA that significantly differentiates between cryptorchidism and normal testes, and it is down-regulated in cryptorchidism with p < 0.05. Novel-m0230-3p and its target gene CSF1 both significantly contribute to the regulation of cell adhesion and tight junctions. The binding sites of novel-m0230-3p with CSF1 were validated by a dual luciferase reporter system. Then, mimics and inhibitors of novel-m0230-3p were transfected in vitro into SCs, respectively. A further analysis using qRT-PCR, immunofluorescence (IF), and Western blotting confirmed that the expression of cell adhesion and tight-junction-related proteins Occludin and ZO-1 both showed changes. Specifically, both the mRNA and protein expression levels of Occludin and ZO-1 in SCs decreased after transfection with the novel-m0230-3p mimics, while they increased after transfection with the inhibitors, with p < 0.05. These were achieved via the CSF1/CSF1R/Ras signaling pathway. In summary, our findings indicate a negative miRNA-mRNA regulatory network involving the CSF1/CSF1R/Ras signaling pathway in yak SCs. These results provide new insights into the molecular mechanisms of CSF1 and suggest that novel-m0230-3p and its target protein CSF1 could be used as potential therapeutic targets for yak cryptorchidism. Full article
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16 pages, 6678 KiB  
Article
Enhanced In Vitro Recapitulation of In Vivo Liver Regeneration by Co-Culturing Hepatocyte Organoids with Adipose-Derived Mesenchymal Stem Cells, Alleviating Steatosis and Apoptosis in Acute Alcoholic Liver Injury
by Sun A Ock, Seo-Yeon Kim, Young-Im Kim, Won Seok Ju and Poongyeon Lee
Cells 2024, 13(15), 1303; https://doi.org/10.3390/cells13151303 - 4 Aug 2024
Viewed by 742
Abstract
Hepatocyte organoids (HOs) have superior hepatic functions to cholangiocyte-derived organoids but suffer from shorter lifespans. To counteract this, we co-cultured pig HOs with adipose-derived mesenchymal stem cells (A-MSCs) and performed transcriptome analysis. The results revealed that A-MSCs enhanced the collagen synthesis pathways, which [...] Read more.
Hepatocyte organoids (HOs) have superior hepatic functions to cholangiocyte-derived organoids but suffer from shorter lifespans. To counteract this, we co-cultured pig HOs with adipose-derived mesenchymal stem cells (A-MSCs) and performed transcriptome analysis. The results revealed that A-MSCs enhanced the collagen synthesis pathways, which are crucial for maintaining the three-dimensional structure and extracellular matrix synthesis of the organoids. A-MSCs also increased the expression of liver progenitor cell markers (KRT7, SPP1, LGR5+, and TERT). To explore HOs as a liver disease model, we exposed them to alcohol to create an alcoholic liver injury (ALI) model. The co-culture of HOs with A-MSCs inhibited the apoptosis of hepatocytes and reduced lipid accumulation of HOs. Furthermore, varying ethanol concentrations (0–400 mM) and single-versus-daily exposure to HOs showed that daily exposure significantly increased the level of PLIN2, a lipid storage marker, while decreasing CYP2E1 and increasing CYP1A2 levels, suggesting that CYP1A2 may play a critical role in alcohol detoxification during short-term exposure. Moreover, daily alcohol exposure led to excessive lipid accumulation and nuclear fragmentation in HOs cultured alone. These findings indicate that HOs mimic in vivo liver regeneration, establishing them as a valuable model for studying liver diseases, such as ALI. Full article
(This article belongs to the Special Issue Organoids as an Experimental Tool)
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16 pages, 3166 KiB  
Article
Elevated Salt or Angiotensin II Levels Induce CD38+ Innate Immune Cells in the Presence of Granulocyte-Macrophage Colony Stimulating Factor
by Hannah L. Smith, Bethany L. Goodlett, Shobana Navaneethabalakrishnan and Brett M. Mitchell
Cells 2024, 13(15), 1302; https://doi.org/10.3390/cells13151302 - 4 Aug 2024
Viewed by 708
Abstract
Hypertension (HTN) impacts almost half of adults, predisposing them to cardiovascular disease and renal damage. Salt-sensitive HTN (SSHTN) and angiotensin II (A2)-induced HTN (A2HTN) both involve immune system activation and renal innate immune cell infiltration. Subpopulations of activated [Cluster of differentiation 38 (CD38)] [...] Read more.
Hypertension (HTN) impacts almost half of adults, predisposing them to cardiovascular disease and renal damage. Salt-sensitive HTN (SSHTN) and angiotensin II (A2)-induced HTN (A2HTN) both involve immune system activation and renal innate immune cell infiltration. Subpopulations of activated [Cluster of differentiation 38 (CD38)] innate immune cells, such as macrophages and dendritic cells (DCs), play distinct roles in modulating renal function and blood pressure. It is unknown how these cells become CD38+ or which subtypes are pro-hypertensive. When bone marrow-derived monocytes (BMDMs) were grown in granulocyte-macrophage colony stimulating factor (GM-CSF) and treated with salt or A2, CD38+ macrophages and CD38+ DCs increased. The adoptive transfer of GM-CSF-primed BMDMs into mice with either SSHTN or A2HTN increased renal CD38+ macrophages and CD38+ DCs. Flow cytometry revealed increased renal M1 macrophages and type-2 conventional DCs (cDC2s), along with their CD38+ counterparts, in mice with either SSHTN or A2HTN. These results were replicable in vitro. Either salt or A2 treatment of GM-CSF-primed BMDMs significantly increased bone marrow-derived (BMD)-M1 macrophages, CD38+ BMD-M1 macrophages, BMD-cDC2s, and CD38+ BMD-cDC2s. Overall, these data suggest that GM-CSF is necessary for the salt or A2 induction of CD38+ innate immune cells, and that CD38 distinguishes pro-hypertensive immune cells. Further investigation of CD38+ M1 macrophages and CD38+ cDC2s could provide new therapeutic targets for both SSHTN and A2HTN. Full article
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20 pages, 1311 KiB  
Review
Calcium Deregulation in Neurodegeneration and Neuroinflammation in Parkinson’s Disease: Role of Calcium-Storing Organelles and Sodium–Calcium Exchanger
by Guendalina Bastioli, Silvia Piccirillo, Laura Graciotti, Marianna Carone, Giorgia Sprega, Omayema Taoussi, Alessandra Preziuso and Pasqualina Castaldo
Cells 2024, 13(15), 1301; https://doi.org/10.3390/cells13151301 - 4 Aug 2024
Viewed by 745
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that lacks effective treatment strategies to halt or delay its progression. The homeostasis of Ca2+ ions is crucial for ensuring optimal cellular functions and survival, especially for neuronal cells. In the context of PD, [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that lacks effective treatment strategies to halt or delay its progression. The homeostasis of Ca2+ ions is crucial for ensuring optimal cellular functions and survival, especially for neuronal cells. In the context of PD, the systems regulating cellular Ca2+ are compromised, leading to Ca2+-dependent synaptic dysfunction, impaired neuronal plasticity, and ultimately, neuronal loss. Recent research efforts directed toward understanding the pathology of PD have yielded significant insights, particularly highlighting the close relationship between Ca2+ dysregulation, neuroinflammation, and neurodegeneration. However, the precise mechanisms driving the selective loss of dopaminergic neurons in PD remain elusive. The disruption of Ca2+ homeostasis is a key factor, engaging various neurodegenerative and neuroinflammatory pathways and affecting intracellular organelles that store Ca2+. Specifically, impaired functioning of mitochondria, lysosomes, and the endoplasmic reticulum (ER) in Ca2+ metabolism is believed to contribute to the disease’s pathophysiology. The Na+-Ca2+ exchanger (NCX) is considered an important key regulator of Ca2+ homeostasis in various cell types, including neurons, astrocytes, and microglia. Alterations in NCX activity are associated with neurodegenerative processes in different models of PD. In this review, we will explore the role of Ca2+ dysregulation and neuroinflammation as primary drivers of PD-related neurodegeneration, with an emphasis on the pivotal role of NCX in the pathology of PD. Consequently, NCXs and their interplay with intracellular organelles may emerge as potentially pivotal players in the mechanisms underlying PD neurodegeneration, providing a promising avenue for therapeutic intervention aimed at halting neurodegeneration. Full article
(This article belongs to the Special Issue Calcium Signaling in Immune Cells)
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13 pages, 3095 KiB  
Article
Overexpression of Toxic Poly(Glycine-Alanine) Aggregates in Primary Neuronal Cultures Induces Time-Dependent Autophagic and Synaptic Alterations but Subtle Activity Impairments
by Christina Steffke, Shreya Agarwal, Edor Kabashi and Alberto Catanese
Cells 2024, 13(15), 1300; https://doi.org/10.3390/cells13151300 - 3 Aug 2024
Viewed by 690
Abstract
The pathogenic expansion of the intronic GGGGCC hexanucleotide located in the non-coding region of the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the accumulation of toxic RNA foci and [...] Read more.
The pathogenic expansion of the intronic GGGGCC hexanucleotide located in the non-coding region of the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the accumulation of toxic RNA foci and dipeptide repeats (DPRs), as well as reduced levels of the C9orf72 protein. Thus, both gain and loss of function are coexisting pathogenic aspects linked to C9orf72-ALS/FTD. Synaptic alterations have been largely described in C9orf72 models, but it is still not clear which aspect of the pathology mostly contributes to these impairments. To address this question, we investigated the dynamic changes occurring over time at the synapse upon accumulation of poly(GA), the most abundant DPR. Overexpression of this toxic form induced a drastic loss of synaptic proteins in primary neuron cultures, anticipating autophagic defects. Surprisingly, the dramatic impairment characterizing the synaptic proteome was not fully matched by changes in network properties. In fact, high-density multi-electrode array analysis highlighted only minor reductions in the spike number and firing rate of poly(GA) neurons. Our data show that the toxic gain of function linked to C9orf72 affects the synaptic proteome but exerts only minor effects on the network activity. Full article
(This article belongs to the Special Issue Motor Neuron Diseases: From Molecular Basic Research to Diagnosis and Therapeutics Implications)
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14 pages, 2836 KiB  
Article
Identification of Poliovirus Receptor-like 3 Protein as a Prognostic Factor in Triple-Negative Breast Cancer
by Gian Marco Leone, Katia Mangano, Salvatore Caponnetto, Paolo Fagone and Ferdinando Nicoletti
Cells 2024, 13(15), 1299; https://doi.org/10.3390/cells13151299 - 3 Aug 2024
Viewed by 882
Abstract
Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate [...] Read more.
Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)
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16 pages, 2602 KiB  
Article
MicroRNA Profile of Mouse Adipocyte-Derived Extracellular Vesicles
by Tamás Röszer
Cells 2024, 13(15), 1298; https://doi.org/10.3390/cells13151298 - 1 Aug 2024
Viewed by 635
Abstract
The post-transcriptional control of gene expression is a complex and evolving field in adipocyte biology, with the premise that the delivery of microRNA (miRNA) species to the obese adipose tissue may facilitate weight loss. Cells shed extracellular vesicles (EVs) that may deliver miRNAs [...] Read more.
The post-transcriptional control of gene expression is a complex and evolving field in adipocyte biology, with the premise that the delivery of microRNA (miRNA) species to the obese adipose tissue may facilitate weight loss. Cells shed extracellular vesicles (EVs) that may deliver miRNAs as intercellular messengers. However, we know little about the miRNA profile of EVs secreted by adipocytes during postnatal development. Here, we defined the miRNA cargo of EVs secreted by mouse adipocytes in two distinct phases of development: on postnatal day 6, when adipocytes are lipolytic and thermogenic, and on postnatal day 56, when adipocytes have active lipogenesis. EVs were collected from cell culture supernatants, and their miRNA profile was defined by small RNA sequencing. The most abundant miRNA of mouse adipocyte-derived EVs was mmu-miR-148a-3p. Adipocyte EVs on postnatal day 6 were hallmarked with mmu-miR-98-5p, and some miRNAs were specific to this developmental stage, such as mmu-miR-466i-5p and 12 novel miRNAs. Adipocytes on postnatal day 56 secreted mmu-miR-365-3p, and 16 miRNAs were specific to this developmental stage. The miRNA cargo of adipocyte EVs targeted gene networks of cell proliferation, insulin signaling, interferon response, thermogenesis, and lipogenesis. We provided here a database of miRNAs secreted by developing mouse adipocytes, which may be a tool for further studies on the regulation of gene networks that control mouse adipocyte development. Full article
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3 pages, 877 KiB  
Correction
Correction: Kundu et al. Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer. Cells 2022, 11, 259
by Madhuchhanda Kundu, Sumita Raha, Avik Roy and Kalipada Pahan
Cells 2024, 13(15), 1297; https://doi.org/10.3390/cells13151297 - 1 Aug 2024
Viewed by 388
Abstract
Error in Figures 3 and 9 [...] Full article
(This article belongs to the Collection Advances in Immune Monitoring)
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12 pages, 1931 KiB  
Review
PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases
by Gina M. Gallucci, Colleen M. Hayes, James L. Boyer, Olivier Barbier, David N. Assis and Nisanne S. Ghonem
Cells 2024, 13(15), 1296; https://doi.org/10.3390/cells13151296 - 1 Aug 2024
Viewed by 856
Abstract
Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid [...] Read more.
Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, β/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (β/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease - Volume III)
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23 pages, 9450 KiB  
Article
Neonicotinoid Pesticides Affect Developing Neurons in Experimental Mouse Models and in Human Induced Pluripotent Stem Cell (iPSC)-Derived Neural Cultures and Organoids
by Alessandro Mariani, Davide Comolli, Roberto Fanelli, Gianluigi Forloni and Massimiliano De Paola
Cells 2024, 13(15), 1295; https://doi.org/10.3390/cells13151295 - 31 Jul 2024
Viewed by 617
Abstract
Neonicotinoids are synthetic, nicotine-derived insecticides used worldwide to protect crops and domestic animals from pest insects. The reported evidence shows that they are also able to interact with mammalian nicotine receptors (nAChRs), triggering detrimental responses in cultured neurons. Exposure to high neonicotinoid levels [...] Read more.
Neonicotinoids are synthetic, nicotine-derived insecticides used worldwide to protect crops and domestic animals from pest insects. The reported evidence shows that they are also able to interact with mammalian nicotine receptors (nAChRs), triggering detrimental responses in cultured neurons. Exposure to high neonicotinoid levels during the fetal period induces neurotoxicity in animal models. Considering the persistent exposure to these insecticides and the key role of nAChRs in brain development, their potential neurotoxicity on mammal central nervous system (CNS) needs further investigations. We studied here the neurodevelopmental effects of different generations of neonicotinoids on CNS cells in mouse fetal brain and primary cultures and in neuronal cells and organoids obtained from human induced pluripotent stem cells (iPSC). Neonicotinoids significantly affect neuron viability, with imidacloprid (IMI) inducing relevant alterations in synaptic protein expression, neurofilament structures, and microglia activation in vitro, and in the brain of prenatally exposed mouse fetuses. IMI induces neurotoxic effects also on developing human iPSC-derived neurons and cortical organoids. Collectively, the current findings show that neonicotinoids might induce impairment during neuro/immune-development in mouse and human CNS cells and provide new insights in the characterization of risk for the exposure to this class of pesticides. Full article
(This article belongs to the Section Cells of the Nervous System)
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28 pages, 1193 KiB  
Review
Effects of Angiogenic Factors on the Epithelial-to-Mesenchymal Transition and Their Impact on the Onset and Progression of Oral Squamous Cell Carcinoma: An Overview
by Silvia Pomella, Ombretta Melaiu, Maria Dri, Mirko Martelli, Marco Gargari and Giovanni Barillari
Cells 2024, 13(15), 1294; https://doi.org/10.3390/cells13151294 - 31 Jul 2024
Viewed by 674
Abstract
High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development [...] Read more.
High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels’ formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy. Full article
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17 pages, 1975 KiB  
Review
Sequence of Molecular Events in the Development of Alzheimer’s Disease: Cascade Interactions from Beta-Amyloid to Other Involved Proteins
by Soghra Bagheri, Ali Akbar Saboury and Luciano Saso
Cells 2024, 13(15), 1293; https://doi.org/10.3390/cells13151293 - 31 Jul 2024
Viewed by 805
Abstract
Alzheimer’s disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have [...] Read more.
Alzheimer’s disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women? Full article
(This article belongs to the Special Issue Alzheimer's Disease: Molecular Mechanisms and Novel Treatment Strategies)
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19 pages, 3839 KiB  
Article
Senolytics and Senomorphics Targeting p38MAPK/NF-κB Pathway Protect Endothelial Cells from Oxidative Stress-Mediated Premature Senescence
by Jingyuan Ya and Ulvi Bayraktutan
Cells 2024, 13(15), 1292; https://doi.org/10.3390/cells13151292 - 31 Jul 2024
Viewed by 763
Abstract
Oxidative stress is a prominent causal factor in the premature senescence of microvascular endothelial cells and the ensuing blood–brain barrier (BBB) dysfunction. Through the exposure of an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes [...] Read more.
Oxidative stress is a prominent causal factor in the premature senescence of microvascular endothelial cells and the ensuing blood–brain barrier (BBB) dysfunction. Through the exposure of an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes to H2O2, this study examined whether a specific targeting of the p38MAPK/NF-κB pathway and/or senescent cells could delay oxidative stress-mediated EC senescence and protect the BBB. Enlarged BMECs, displaying higher β-galactosidase activity, γH2AX staining, p16 expression, and impaired tubulogenic capacity, were regarded as senescent. The BBB established with senescent BMECs had reduced transendothelial electrical resistance and increased paracellular flux, which are markers of BBB integrity and function, respectively. Premature senescence disrupted plasma-membrane localization of the tight junction protein, zonula occludens-1, and elevated basement membrane-degrading matrix metalloproteinase-2 activity and pro-inflammatory cytokine release. Inhibition of p38MAPK by BIRB796 and NF-κB by QNZ and the elimination of senescent cells by a combination of dasatinib and quercetin attenuated the effects of H2O2 on senescence markers; suppressed release of the pro-inflammatory cytokines interleukin-8, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; restored tight junctional unity; and improved BBB function. In conclusion, therapeutic approaches that mitigate p38MAPK/NF-κB activity and senescent cell accumulation in the cerebrovasculature may successfully protect BBB from oxidative stress-induced BBB dysfunction. Full article
(This article belongs to the Section Cellular Aging)
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22 pages, 27479 KiB  
Article
CTRP13-Mediated Effects on Endothelial Cell Function and Their Potential Role in Obesity
by Muhammad Aslam, Ling Li, Sina Nürnberger, Bernd Niemann and Susanne Rohrbach
Cells 2024, 13(15), 1291; https://doi.org/10.3390/cells13151291 - 31 Jul 2024
Viewed by 492
Abstract
Background: Obesity, a major component of cardiometabolic syndrome, contributes to the imbalance between pro- and anti-atherosclerotic factors via dysregulation of adipocytokine secretion. Among these adipocytokines, the C1q/TNF-related proteins (CTRPs) play a role in the modulation of atherosclerosis development and progression. Here, we investigated [...] Read more.
Background: Obesity, a major component of cardiometabolic syndrome, contributes to the imbalance between pro- and anti-atherosclerotic factors via dysregulation of adipocytokine secretion. Among these adipocytokines, the C1q/TNF-related proteins (CTRPs) play a role in the modulation of atherosclerosis development and progression. Here, we investigated the vascular effects of CTRP13. Results: CTRP13 is not only expressed in adipose tissue but also in vessels/endothelial cells (ECs) of mice, rats, and humans. Obese individuals (mice, rats, and humans) showed higher vascular CTRP13 expression. Human Umbilical Vein Endothelial Cells (HUVECs), cultured in the presence of serum from obese mice, mimicked this obesity-associated effect on CTRP13 protein expression. Similarly, high glucose conditions and TNF-alpha, but not insulin, resulted in a strong increase in CTRP13 in these cells. Recombinant CTRP13 induced a reduction in EC proliferation via AMPK. In addition, CTRP13 reduced cell cycle progression and increased p53 phosphorylation and p21 protein expression, but reduced Rb phosphorylation, with the effects largely depending on alpha-2 AMPK as suggested by adenoviral overexpression of dominant-negative (DN) or wild-type (WT) alpha 1/alpha 2 AMPK. Conclusion: The present study demonstrates that CTRP13 expression is induced in ECs under diabetic conditions and that CTRP13 possesses significant vaso-modulatory properties which may have an impact on vascular disease progression in patients. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiovascular and Metabolic Diseases)
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15 pages, 1991 KiB  
Article
Culture and Immunomodulation of Equine Muscle-Derived Mesenchymal Stromal Cells: A Comparative Study of Innovative 2D versus 3D Models Using Equine Platelet Lysate
by J. Duysens, H. Graide, A. Niesten, A. Mouithys-Mickalad, G. Deby-Dupont, T. Franck, J. Ceusters and D. Serteyn
Cells 2024, 13(15), 1290; https://doi.org/10.3390/cells13151290 - 31 Jul 2024
Viewed by 515
Abstract
Muscle-derived mesenchymal stromal cells (mdMSCs) hold great promise in regenerative medicine due to their immunomodulatory properties, multipotent differentiation capacity and ease of collection. However, traditional in vitro expansion methods use fetal bovine serum (FBS) and have numerous limitations including ethical concerns, batch-to-batch variability, [...] Read more.
Muscle-derived mesenchymal stromal cells (mdMSCs) hold great promise in regenerative medicine due to their immunomodulatory properties, multipotent differentiation capacity and ease of collection. However, traditional in vitro expansion methods use fetal bovine serum (FBS) and have numerous limitations including ethical concerns, batch-to-batch variability, immunogenicity, xenogenic contamination and regulatory compliance issues. This study investigates the use of 10% equine platelet lysate (ePL) obtained by plasmapheresis as a substitute for FBS in the culture of mdMSCs in innovative 2D and 3D models. Using muscle microbiopsies as the primary cell source in both models showed promising results. Initial investigations indicated that small variations in heparin concentration in 2D cultures strongly influenced medium coagulation with an optimal proliferation observed at final heparin concentrations of 1.44 IU/mL. The two novel models investigated showed that expansion of mdMSCs is achievable. At the end of expansion, the 3D model revealed a higher total number of cells harvested (64.60 ± 5.32 million) compared to the 2D culture (57.20 ± 7.66 million). Trilineage differentiation assays confirmed the multipotency (osteoblasts, chondroblasts and adipocytes) of the mdMSCs generated in both models with no significant difference observed. Immunophenotyping confirmed the expression of the mesenchymal stem cell (MSC) markers CD-90 and CD-44, with low expression of CD-45 and MHCII markers for mdMSCs derived from the two models. The generated mdMSCs also had great immunomodulatory properties. Specific immunological extraction followed by enzymatic detection (SIEFED) analysis demonstrated that mdMSCs from both models inhibited myeloperoxidase (MPO) activity in a strong dose-dependent manner. Moreover, they were also able to reduce reactive oxygen species (ROS) activity, with mdMSCs from the 3D model showing significantly higher dose-dependent inhibition compared to the 2D model. These results highlighted for the first time the feasibility and efficacy of using 10% ePL for mdMSC expansion in novel 2D and 3D approaches and also that mdMSCs have strong immunomodulatory properties that can be exploited to advance the field of regenerative medicine and cell therapy instead of using FBS with all its drawbacks. Full article
(This article belongs to the Collection Stem Cells in Tissue Engineering and Regeneration)
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16 pages, 1100 KiB  
Review
The Role of the MiR-181 Family in Hepatocellular Carcinoma
by Jinbiao Chen, Ken Liu, Mathew A. Vadas, Jennifer R. Gamble and Geoffrey W. McCaughan
Cells 2024, 13(15), 1289; https://doi.org/10.3390/cells13151289 - 31 Jul 2024
Viewed by 687
Abstract
Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs [...] Read more.
Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues—this up-regulation induced epithelial–mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC. Full article
(This article belongs to the Collection MicroRNAs in Cancer: From Molecular Mechanisms to Applications in Diagnostic and Therapeutic Opportunities)
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29 pages, 920 KiB  
Review
The Potential of Metabolomics to Find Proper Biomarkers for Addressing the Neuroprotective Efficacy of Drugs Aimed at Delaying Parkinson’s and Alzheimer’s Disease Progression
by Rafael Franco, Claudia Garrigós, Jaume Lillo and Rafael Rivas-Santisteban
Cells 2024, 13(15), 1288; https://doi.org/10.3390/cells13151288 - 31 Jul 2024
Viewed by 743
Abstract
The first objective is to highlight the lack of tools to measure whether a given intervention affords neuroprotection in patients with Alzheimer’s or Parkinson’s diseases. A second aim is to present the primary outcome measures used in clinical trials in cohorts of patients [...] Read more.
The first objective is to highlight the lack of tools to measure whether a given intervention affords neuroprotection in patients with Alzheimer’s or Parkinson’s diseases. A second aim is to present the primary outcome measures used in clinical trials in cohorts of patients with neurodegenerative diseases. The final aim is to discuss whether metabolomics using body fluids may lead to the discovery of biomarkers of neuroprotection. Information on the primary outcome measures in clinical trials related to Alzheimer’s and Parkinson’s disease registered since 2018 was collected. We analysed the type of measures selected to assess efficacy, not in terms of neuroprotection since, as stated in the aims, there is not yet any marker of neuroprotection. Proteomic approaches using plasma or CSF have been proposed. PET could estimate the extent of lesions, but disease progression does not necessarily correlate with a change in tracer uptake. We propose some alternatives based on considering the metabolome. A new opportunity opens with metabolomics because there have been impressive technological advances that allow the detection, among others, of metabolites related to mitochondrial function and mitochondrial structure in serum and/or cerebrospinal fluid; some of the differentially concentrated metabolites can become reliable biomarkers of neuroprotection. Full article
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25 pages, 7822 KiB  
Article
Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells
by Nicolas Sailliet, Amandine Dupuy, François Brinas, Karine Renaudin, Luc Colas, Clarisse Kerleau, Thi-Van-Ha Nguyen, Cynthia Fourgeux, Jérémie Poschmann, Clément Gosset, Magali Giral, Nicolas Degauque, Hoa Le Mai, Richard Danger and Sophie Brouard
Cells 2024, 13(15), 1287; https://doi.org/10.3390/cells13151287 - 31 Jul 2024
Viewed by 617
Abstract
The aim of our study was to determine whether granzyme B-expressing regulatory B cells (GZMB+ B cells) are enriched in the blood of transplant patients with renal graft tolerance. To achieve this goal, we analysed two single-cell RNA sequencing (scRNAseq) datasets: (1) [...] Read more.
The aim of our study was to determine whether granzyme B-expressing regulatory B cells (GZMB+ B cells) are enriched in the blood of transplant patients with renal graft tolerance. To achieve this goal, we analysed two single-cell RNA sequencing (scRNAseq) datasets: (1) peripheral blood mononuclear cells (PBMCs), including GZMB+ B cells from renal transplant patients, i.e., patients with stable graft function on conventional immunosuppressive treatment (STA, n = 3), drug-free tolerant patients (TOL, n = 3), and patients with antibody-mediated rejection (ABMR, n = 3), and (2) ex-vivo-induced GZMB+ B cells from these groups. In the patient PBMCs, we first showed that natural GZMB+ B cells were enriched in genes specific to Natural Killer (NK) cells (such as NKG7 and KLRD1) and regulatory B cells (such as GZMB, IL10, and CCL4). We performed a pseudotemporal trajectory analysis of natural GZMB+ B cells and showed that they were highly differentiated B cells with a trajectory that is very different from that of conventional memory B cells and linked to the transcription factor KLF13. By specifically analysing GZMB+ natural B cells in TOLs, we found that these cells had a very specific transcriptomic profile associated with a reduction in the expression of HLA molecules, apoptosis, and the inflammatory response (in general) in the blood and that this signature was conserved after ex vivo induction, with the induction of genes associated with migration processes, such as CCR7, CCL3, or CCL4. An analysis of receptor/ligand interactions between these GZMB+/− natural B cells and all of the immune cells present in PBMCs also demonstrated that GZMB+ B cells were the B cells that carried the most ligands and had the most interactions with other immune cells, particularly in tolerant patients. Finally, we showed that these GZMB+ B cells were able to infiltrate the graft under inflammatory conditions, thus suggesting that they can act in locations where immune events occur. Full article
(This article belongs to the Special Issue Immune Functions and Therapeutic Potential of B Lymphocytes in Autoimmune Disorders)
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18 pages, 4874 KiB  
Article
A Novel Liquid Biopsy Method Based on Specific Combinations of Vesicular Markers Allows Us to Discriminate Prostate Cancer from Hyperplasia
by Emanuele Martorana, Gabriele Raciti, Raffaella Giuffrida, Elena Bruno, Vincenzo Ficarra, Giuseppe Mario Ludovico, Nazareno Roberto Suardi, Nunzio Iraci, Loredana Leggio, Benedetta Bussolati, Cristina Grange, Aurelio Lorico, Rosario Leonardi and Stefano Forte
Cells 2024, 13(15), 1286; https://doi.org/10.3390/cells13151286 - 31 Jul 2024
Viewed by 1015
Abstract
Background: Prostate cancer is the second most common cancer in males worldwide, and its incidence is rising. Early detection is crucial for improving the outcomes, but the current screening methods have limitations. While prostate-specific antigen (PSA) testing is the most widely used screening [...] Read more.
Background: Prostate cancer is the second most common cancer in males worldwide, and its incidence is rising. Early detection is crucial for improving the outcomes, but the current screening methods have limitations. While prostate-specific antigen (PSA) testing is the most widely used screening tool, it has poor specificity, leading to a high rate of false positives and unnecessary biopsies. The existing biopsy techniques are invasive and are associated with complications. The liquid biopsy methods that analyze the biomarkers in blood or other bodily fluids offer a non-invasive and more accurate alternative for detecting and characterizing prostate tumors. Methods: Here, we present a novel liquid biopsy method for prostate cancer based on the identification of specific proteins in the extracellular vesicles isolated from the blood of patients with prostate cancer. Results: We observed that a specific combination of sEV proteins is a sensitive indicator of prostate cancer. Indeed, we found that the number of clusters expressed by specific combinations of either intra-vesicular (STAT3 and CyclinD1) or surface proteins (ERBB3, ALK, and CD81) allowed us to significantly discriminate the patients with prostate cancer from the individuals with hyperplasia. Conclusion: This new liquid biopsy method has the potential to improve prostate cancer screening by providing a non-invasive and more accurate diagnostic tool. Full article
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2 pages, 562 KiB  
Correction
Correction: Bellu et al. Smart Nanofibers with Natural Extracts Prevent Senescence Patterning in a Dynamic Cell Culture Model of Human Skin. Cells 2020, 9, 2530
by Emanuela Bellu, Giuseppe Garroni, Sara Cruciani, Francesca Balzano, Diletta Serra, Rosanna Satta, Maria Antonia Montesu, Angela Fadda, Maurizio Mulas, Giorgia Sarais, Pasquale Bandiera, Elena Torreggiani, Fernanda Martini, Mauro Tognon, Carlo Ventura, Jiří Beznoska, Evzen Amler and Margherita Maioli
Cells 2024, 13(15), 1285; https://doi.org/10.3390/cells13151285 - 31 Jul 2024
Viewed by 356
Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)
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23 pages, 2669 KiB  
Review
Nuclear Receptors and the Hidden Language of the Metabolome
by Yujie Chen, Matthew Tom Anderson, Nathaniel Payne, Fabio R. Santori and Natalia B. Ivanova
Cells 2024, 13(15), 1284; https://doi.org/10.3390/cells13151284 - 31 Jul 2024
Viewed by 643
Abstract
Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact [...] Read more.
Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact with their ligands to regulate downstream gene networks, along with the identification of ligands for orphan NHRs, could enable innovative approaches for cellular engineering, disease modeling and regenerative medicine. We review recent discoveries in the identification of physiologic ligands for NHRs. We propose new models of ligand-receptor co-evolution, the emergence of hormonal function and models of regulation of NHR specificity and activity via one-ligand and two-ligand models as well as feedback loops. Lastly, we discuss limitations on the processes for the identification of physiologic NHR ligands and emerging new methodologies that could be used to identify the natural ligands for the remaining 17 orphan NHRs in the human genome. Full article
(This article belongs to the Collection Functions of Nuclear Receptors)
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15 pages, 1224 KiB  
Review
The Need to Identify Novel Markers for Early Renal Injury in Cardiorenal Syndrome
by Anna Lisa, Federico Carbone, Luca Liberale and Fabrizio Montecucco
Cells 2024, 13(15), 1283; https://doi.org/10.3390/cells13151283 - 30 Jul 2024
Cited by 1 | Viewed by 1312
Abstract
The term “Cardiorenal Syndrome” (CRS) refers to the complex interplay between heart and kidney dysfunction. First described by Robert Bright in 1836, CRS was brought to its modern view by Ronco et al. in 2008, who defined it as one organ’s primary dysfunction [...] Read more.
The term “Cardiorenal Syndrome” (CRS) refers to the complex interplay between heart and kidney dysfunction. First described by Robert Bright in 1836, CRS was brought to its modern view by Ronco et al. in 2008, who defined it as one organ’s primary dysfunction leading to secondary dysfunction in the other, a view that led to the distinction of five different types depending on the organ of primary dysfunction and the temporal pattern (acute vs. chronic). Their pathophysiology is intricate, involving various hemodynamic, neurohormonal, and inflammatory processes that result in damage to both organs. While traditional biomarkers have been utilized for diagnosing and prognosticating CRS, they are inadequate for the early detection of acute renal damage. Hence, there is a pressing need to discover new biomarkers to enhance clinical outcomes and treatment approaches. Full article
(This article belongs to the Special Issue Acute Kidney Injury: From Molecular Mechanisms to Diseases)
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18 pages, 850 KiB  
Review
Cell-Based Therapy and Genome Editing as Emerging Therapeutic Approaches to Treat Rheumatoid Arthritis
by Vitaly Chasov, Irina Ganeeva, Ekaterina Zmievskaya, Damir Davletshin, Elvina Gilyazova, Aygul Valiullina and Emil Bulatov
Cells 2024, 13(15), 1282; https://doi.org/10.3390/cells13151282 - 30 Jul 2024
Viewed by 692
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Although much remains unknown about the pathogenesis of RA, there is evidence that impaired immune tolerance and the development of RA are related. And it is precisely the restoration [...] Read more.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Although much remains unknown about the pathogenesis of RA, there is evidence that impaired immune tolerance and the development of RA are related. And it is precisely the restoration of immune tolerance at the site of the inflammation that is the ultimate goal of the treatment of RA. Over the past few decades, significant progress has been made in the treatment of RA, with higher rates of disease remission and improved long-term outcomes. Unfortunately, despite these successes, the proportion of patients with persistent, difficult-to-treat disease remains high, and the task of improving our understanding of the basic mechanisms of disease development and developing new ways to treat RA remains relevant. This review focuses on describing new treatments for RA, including cell therapies and gene editing technologies that have shown potential in preclinical and early clinical trials. In addition, we discuss the opportunities and limitations associated with the use of these new approaches in the treatment of RA. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Treatment of Autoimmune Diseases)
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38 pages, 1881 KiB  
Review
Therapy-Induced Cellular Senescence: Potentiating Tumor Elimination or Driving Cancer Resistance and Recurrence?
by Yue Liu, Isabelle Lomeli and Stephen J. Kron
Cells 2024, 13(15), 1281; https://doi.org/10.3390/cells13151281 - 30 Jul 2024
Viewed by 1094
Abstract
Cellular senescence has been increasingly recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies. While therapy-induced senescence (TIS) has been linked to [...] Read more.
Cellular senescence has been increasingly recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies. While therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis, and normal tissue toxicity, TIS also has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), focusing on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Through the SASP, SnCs can mediate both resistance and response to cancer therapies. To fulfill the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as an antigen source to potentiate anti-tumor immune response. This new perspective suggests treatment approaches based on TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, which may enhance the overall benefits of cancer treatment. Full article
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18 pages, 3802 KiB  
Article
Discovery of Cell Number-Interstitial Fluid Volume (CIF) Ratio Reveals Secretory Autophagy Pathway to Supply eHsp90α for Wound Healing
by Cheng Chang, Xin Tang, Axel H. Schönthal, Mei Chen, David T. Woodley, Yanzhuang Wang, Chengyu Liang and Wei Li
Cells 2024, 13(15), 1280; https://doi.org/10.3390/cells13151280 - 30 Jul 2024
Viewed by 647
Abstract
Cell secretion repairs tissue damage and restores homeostasis throughout adult life. The extracellular heat shock protein-90alpha (eHsp90α) has been reported as an exosome cargo and a potential driver of wound healing. However, neither the mechanism of secretion nor the genetic evidence for eHsp90α [...] Read more.
Cell secretion repairs tissue damage and restores homeostasis throughout adult life. The extracellular heat shock protein-90alpha (eHsp90α) has been reported as an exosome cargo and a potential driver of wound healing. However, neither the mechanism of secretion nor the genetic evidence for eHsp90α in wound healing has been substantiated. Herein, we show that tissue injury causes massive deposition of eHsp90α in tissues and secretion of eHsp90α by cells. Sequential centrifugations of conditioned medium from relevant cell lines revealed the relative distributions of eHsp90α in microvesicle, exosome and trypsin-sensitive supernatant fractions to be approximately <2%, <4% and >95%, respectively. Establishing the cell-number-to-interstitial-fluid-volume (CIF) ratio for the microenvironment of human tissues as 1 × 109 cells: 1 mL interstitial fluid enabled us to predict the corresponding tissue concentrations of eHsp90α in these fractions as 3.74 μg/mL, 5.61 μg/mL and 178 μg/mL. Remarkably, the 178 μg/mL eHsp90α matches the previously reported 100–300 μg/mL of recombinant eHsp90α whose topical application promotes maximum wound healing in animal models. More importantly, we demonstrate that two parallel secretory autophagy-regulating gene families, the autophagy-regulating (AR) genes and the Golgi reassembly-stacking protein (GRASP) genes work together to mediate the secretion of the physiological concentration of eHsp90α to promote wound healing. Thus, utilization of the CIF ratio-based extrapolation method may enable investigators to rapidly predict biomarker targets from cell-conditioned-medium data. Full article
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37 pages, 1284 KiB  
Review
Intratumoral Microbiome: Foe or Friend in Reshaping the Tumor Microenvironment Landscape?
by Athina A. Kyriazi, Makrina Karaglani, Sofia Agelaki and Stavroula Baritaki
Cells 2024, 13(15), 1279; https://doi.org/10.3390/cells13151279 - 30 Jul 2024
Viewed by 845
Abstract
The role of the microbiome in cancer and its crosstalk with the tumor microenvironment (TME) has been extensively studied and characterized. An emerging field in the cancer microbiome research is the concept of the intratumoral microbiome, which refers to the microbiome residing within [...] Read more.
The role of the microbiome in cancer and its crosstalk with the tumor microenvironment (TME) has been extensively studied and characterized. An emerging field in the cancer microbiome research is the concept of the intratumoral microbiome, which refers to the microbiome residing within the tumor. This microbiome primarily originates from the local microbiome of the tumor-bearing tissue or from translocating microbiome from distant sites, such as the gut. Despite the increasing number of studies on intratumoral microbiome, it remains unclear whether it is a driver or a bystander of oncogenesis and tumor progression. This review aims to elucidate the intricate role of the intratumoral microbiome in tumor development by exploring its effects on reshaping the multileveled ecosystem in which tumors thrive, the TME. To dissect the complexity and the multitude of layers within the TME, we distinguish six specialized tumor microenvironments, namely, the immune, metabolic, hypoxic, acidic, mechanical and innervated microenvironments. Accordingly, we attempt to decipher the effects of the intratumoral microbiome on each specialized microenvironment and ultimately decode its tumor-promoting or tumor-suppressive impact. Additionally, we portray the intratumoral microbiome as an orchestrator in the tumor milieu, fine-tuning the responses in distinct, specialized microenvironments and remodeling the TME in a multileveled and multifaceted manner. Full article
(This article belongs to the Special Issue Recent Advances in Tumor Immunological Microenvironment Research)
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