Next Issue
Volume 12, November-2
Previous Issue
Volume 12, October-2
 
 

Cells, Volume 12, Issue 21 (November-1 2023) – 73 articles

Cover Story (view full-size image): The IP3 receptor (IP3R) is a ubiquitously expressed Ca2+-release channel located in the endoplasmic reticulum (ER). Recent work demonstrated that the metabolic enzyme pyruvate kinase M (PKM) 2 interacts with the IP3R, thereby suppressing IP3-induced Ca2+ release. To better understand the physiological role of PKM2 in this process, we developed a PKM2 knockout cell model. These cells, however, overexpress PKM1. In these cells, we investigated cytosolic and mitochondrial Ca2+ handling as well as mitochondrial structure and function. As a second method of investigation, we disrupted the interaction between PKM2 and the IP3R using the D5SD peptide. The latter is derived from the IP3R and mimics its binding site for PKM2. From the obtained results, we propose that besides PKM1, PKM2 and IP3R, at least one other protein participates in the complex. View this paper
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Reader to open them.
Order results
Result details
Section
Select all
Export citation of selected articles as:
21 pages, 23317 KiB  
Article
Correlation of Plasma Membrane Microviscosity and Cell Stiffness Revealed via Fluorescence-Lifetime Imaging and Atomic Force Microscopy
by Yuri M. Efremov, Liubov Shimolina, Alexander Gulin, Nadezhda Ignatova, Margarita Gubina, Marina K. Kuimova, Peter S. Timashev and Marina V. Shirmanova
Cells 2023, 12(21), 2583; https://doi.org/10.3390/cells12212583 - 6 Nov 2023
Cited by 2 | Viewed by 2074
Abstract
The biophysical properties of cells described at the level of whole cells or their membranes have many consequences for their biological behavior. However, our understanding of the relationships between mechanical parameters at the level of cell (stiffness, viscoelasticity) and at the level of [...] Read more.
The biophysical properties of cells described at the level of whole cells or their membranes have many consequences for their biological behavior. However, our understanding of the relationships between mechanical parameters at the level of cell (stiffness, viscoelasticity) and at the level of the plasma membrane (fluidity) remains quite limited, especially in the context of pathologies, such as cancer. Here, we investigated the correlations between cells’ stiffness and viscoelastic parameters, mainly determined via the actin cortex, and plasma membrane microviscosity, mainly determined via its lipid profile, in cancer cells, as these are the keys to their migratory capacity. The mechanical properties of cells were assessed using atomic force microscopy (AFM). The microviscosity of membranes was visualized using fluorescence-lifetime imaging microscopy (FLIM) with the viscosity-sensitive probe BODIPY 2. Measurements were performed for five human colorectal cancer cell lines that have different migratory activity (HT29, Caco-2, HCT116, SW 837, and SW 480) and their chemoresistant counterparts. The actin cytoskeleton and the membrane lipid composition were also analyzed to verify the results. The cell stiffness (Young’s modulus), measured via AFM, correlated well (Pearson r = 0.93) with membrane microviscosity, measured via FLIM, and both metrics were elevated in more motile cells. The associations between stiffness and microviscosity were preserved upon acquisition of chemoresistance to one of two chemotherapeutic drugs. These data clearly indicate that mechanical parameters, determined by two different cellular structures, are interconnected in cells and play a role in their intrinsic migratory potential. Full article
(This article belongs to the Special Issue Advances in Scanning Probe Microscopy in Cell Biology)
Show Figures

Figure 1

15 pages, 4672 KiB  
Article
DAZL Knockout Pigs as Recipients for Spermatogonial Stem Cell Transplantation
by Nathalia L. M. Lara, Taylor Goldsmith, Paula Rodriguez-Villamil, Felipe Ongaratto, Staci Solin, Dennis Webster, Uyanga Ganbaatar, Shane Hodgson, Stanislas M. A. S. Corbière, Alla Bondareva, Daniel F. Carlson and Ina Dobrinski
Cells 2023, 12(21), 2582; https://doi.org/10.3390/cells12212582 - 6 Nov 2023
Viewed by 1265
Abstract
Spermatogonial stem cell (SSC) transplantation into the testis of a germ cell (GC)-depleted surrogate allows transmission of donor genotype via donor-derived sperm produced by the recipient. Transplantation of gene-edited SSCs provides an approach to propagate gene-edited large animal models. DAZL is a conserved [...] Read more.
Spermatogonial stem cell (SSC) transplantation into the testis of a germ cell (GC)-depleted surrogate allows transmission of donor genotype via donor-derived sperm produced by the recipient. Transplantation of gene-edited SSCs provides an approach to propagate gene-edited large animal models. DAZL is a conserved RNA-binding protein important for GC development, and DAZL knockout (KO) causes defects in GC commitment and differentiation. We characterized DAZL-KO pigs as SSC transplantation recipients. While there were GCs in 1-week-old (wko) KO, complete GC depletion was observed by 10 wko. Donor GCs were transplanted into 18 DAZL-KO recipients at 10–13 wko. At sexual maturity, semen and testes were evaluated for transplantation efficiency and spermatogenesis. Approximately 22% of recipient seminiferous tubules contained GCs, including elongated spermatids and proliferating spermatogonia. The ejaculate of 89% of recipients contained sperm, exclusively from donor origin. However, sperm concentration was lower than the wild-type range. Testicular protein expression and serum hormonal levels were comparable between DAZL-KO and wild-type. Intratesticular testosterone and Leydig cell volume were increased, and Leydig cell number decreased in transplanted DAZL-KO testis compared to wild-type. In summary, DAZL-KO pigs support donor-derived spermatogenesis following SSC transplantation, but low spermatogenic efficiency currently limits their use for the production of offspring. Full article
Show Figures

Figure 1

15 pages, 2855 KiB  
Article
Cell-Based Models of ‘Cytokine Release Syndrome’ Endorse CD40L and Granulocyte–Macrophage Colony-Stimulating Factor Knockout in Chimeric Antigen Receptor T Cells as Mitigation Strategy
by Ala Dibas, Manuel Rhiel, Vidisha Bhavesh Patel, Geoffroy Andrieux, Melanie Boerries, Tatjana I. Cornu, Jamal Alzubi and Toni Cathomen
Cells 2023, 12(21), 2581; https://doi.org/10.3390/cells12212581 - 6 Nov 2023
Cited by 4 | Viewed by 2053
Abstract
While chimeric antigen receptor (CAR) T cell therapy has shown promising outcomes among patients with hematologic malignancies, it has also been associated with undesirable side-effects such as cytokine release syndrome (CRS). CRS is triggered by CAR T-cell-based activation of monocytes, which are stimulated [...] Read more.
While chimeric antigen receptor (CAR) T cell therapy has shown promising outcomes among patients with hematologic malignancies, it has also been associated with undesirable side-effects such as cytokine release syndrome (CRS). CRS is triggered by CAR T-cell-based activation of monocytes, which are stimulated via the CD40L–CD40R axis or via uptake of GM-CSF to secrete proinflammatory cytokines. Mouse models have been used to model CRS, but working with them is labor-intensive and they are not amenable to screening approaches. To overcome this challenge, we established two simple cell-based CRS in vitro models that entail the co-culturing of leukemic B cells with CD19-targeting CAR T cells and primary monocytes from the same donor. Upon antigen encounter, CAR T cells upregulated CD40L and released GM-CSF which in turn stimulated the monocytes to secrete IL-6. To endorse these models, we demonstrated that neutralizing antibodies or genetic disruption of the CD40L and/or CSF2 loci in CAR T cells using CRISPR-Cas technology significantly reduced IL-6 secretion by bystander monocytes without affecting the cytolytic activity of the engineered lymphocytes in vitro. Overall, our cell-based models were able to recapitulate CRS in vitro, allowing us to validate mitigation strategies based on antibodies or genome editing. Full article
(This article belongs to the Special Issue CRISPR-CAS9 in Cancer Immunotherapy)
Show Figures

Figure 1

14 pages, 4038 KiB  
Article
G-Protein-Coupled Receptor 91-Dependent Signalling Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidaemic Mice
by Silke Griepke, Mette Trauelsen, Michelle D. Nilsson, Jakob Hansen, Lasse B. Steffensen, Thue W. Schwartz and Daniel F. J. Ketelhuth
Cells 2023, 12(21), 2580; https://doi.org/10.3390/cells12212580 - 6 Nov 2023
Viewed by 1575
Abstract
The TCA cycle intermediate metabolite ‘succinate’ has been proposed as an inflammatory mediator, influencing autoimmunity and allergic reactions, through ligation to its sensing receptor SUCNR1/GPR91. Whether GPR91-mediated signalling influences the chronic inflammatory process of atherosclerosis has never been investigated. The examination of publicly [...] Read more.
The TCA cycle intermediate metabolite ‘succinate’ has been proposed as an inflammatory mediator, influencing autoimmunity and allergic reactions, through ligation to its sensing receptor SUCNR1/GPR91. Whether GPR91-mediated signalling influences the chronic inflammatory process of atherosclerosis has never been investigated. The examination of publicly available datasets revealed that the SUCNR1 gene is expressed in human atherosclerotic plaques, especially in vascular smooth muscle cells. Using GPR91 knockout (Gpr91−/−) and wildtype (WT) littermates, made hyperlipidaemic with the overexpression of the gain-of-function mutated Pcsk9 and Western diet feeding, we showed that the full ablation of GPR91 did not accelerate atherosclerosis—lesions in the aortic arch 2.18 ± 0.48% vs. 1.64 ± 0.31%, and in the aortic roots 10.06 ± 0.91% vs. 10.67 ± 1.53% for Gpr91−/− and WT mice, respectively. In line with this, no differences between groups were observed for macrophage and T-cell infiltration in the plaque, as well as the polarization towards M1- or M2-like macrophages in the aorta, spleen and liver of Gpr91−/− and WT control mice. In conclusion, our study indicates that the global ablation of GPR91 signalling does not influence vascular inflammation or atherogenesis. Full article
Show Figures

Figure 1

20 pages, 4272 KiB  
Review
Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome
by Vincent Le, Gabrielle Abdelmessih, Wendy A. Dailey, Cecille Pinnock, Victoria Jobczyk, Revati Rashingkar, Kimberly A. Drenser and Kenneth P. Mitton
Cells 2023, 12(21), 2579; https://doi.org/10.3390/cells12212579 - 5 Nov 2023
Viewed by 2018
Abstract
Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function, and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early [...] Read more.
Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function, and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway, such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goal of this review is to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genetic Eye Diseases)
Show Figures

Graphical abstract

24 pages, 4965 KiB  
Article
circRNA-miRNA-mRNA Deregulated Network in Ischemic Heart Failure Patients
by Alisia Madè, Alessia Bibi, Jose Manuel Garcia-Manteiga, Anna Sofia Tascini, Santiago Nicolas Piella, Roman Tikhomirov, Christine Voellenkle, Carlo Gaetano, Przemyslaw Leszek, Serenella Castelvecchio, Lorenzo Menicanti, Fabio Martelli and Simona Greco
Cells 2023, 12(21), 2578; https://doi.org/10.3390/cells12212578 - 5 Nov 2023
Cited by 3 | Viewed by 1538
Abstract
Noncoding RNAs (ncRNAs), which include circular RNAs (circRNAs) and microRNAs (miRNAs), regulate the development of cardiovascular diseases (CVD). Notably, circRNAs can interact with miRNAs, influencing their specific mRNA targets’ levels and shaping a competing endogenous RNAs (ceRNA) network. However, these interactions and their [...] Read more.
Noncoding RNAs (ncRNAs), which include circular RNAs (circRNAs) and microRNAs (miRNAs), regulate the development of cardiovascular diseases (CVD). Notably, circRNAs can interact with miRNAs, influencing their specific mRNA targets’ levels and shaping a competing endogenous RNAs (ceRNA) network. However, these interactions and their respective functions remain largely unexplored in ischemic heart failure (IHF). This study is aimed at identifying circRNA-centered ceRNA networks in non-end-stage IHF. Approximately 662 circRNA-miRNA-mRNA interactions were identified in the heart by combining state-of-the-art bioinformatics tools with experimental data. Importantly, KEGG terms of the enriched mRNA indicated CVD-related signaling pathways. A specific network centered on circBPTF was validated experimentally. The levels of let-7a-5p, miR-18a-3p, miR-146b-5p, and miR-196b-5p were enriched in circBPTF pull-down experiments, and circBPTF silencing inhibited the expression of HDAC9 and LRRC17, which are targets of miR-196b-5p. Furthermore, as suggested by the enriched pathway terms of the circBPTF ceRNA network, circBPTF inhibition elicited endothelial cell cycle arrest. circBPTF expression increased in endothelial cells exposed to hypoxia, and its upregulation was confirmed in cardiac samples of 36 end-stage IHF patients compared to healthy controls. In conclusion, circRNAs act as miRNA sponges, regulating the functions of multiple mRNA targets, thus providing a novel vision of HF pathogenesis and laying the theoretical foundation for further experimental studies. Full article
(This article belongs to the Special Issue Non-coding RNAs: Multiple Players in Human Diseases)
Show Figures

Graphical abstract

22 pages, 20134 KiB  
Article
Heavy Metals in Follicular Fluid Affect the Ultrastructure of the Human Mature Cumulus-Oocyte Complex
by Selenia Miglietta, Loredana Cristiano, Ezio Battaglione, Guido Macchiarelli, Stefania Annarita Nottola, Maria Paola De Marco, Flavia Costanzi, Mauro Schimberni, Nicola Colacurci, Donatella Caserta and Giuseppe Familiari
Cells 2023, 12(21), 2577; https://doi.org/10.3390/cells12212577 - 5 Nov 2023
Cited by 1 | Viewed by 1445
Abstract
It is known that exposure to heavy metal such as lead (Pb) and cadmium (Cd) has several adverse effects, particularly on the human reproductive system. Pb and Cd have been associated with infertility in both men and women. In pregnant women, they have [...] Read more.
It is known that exposure to heavy metal such as lead (Pb) and cadmium (Cd) has several adverse effects, particularly on the human reproductive system. Pb and Cd have been associated with infertility in both men and women. In pregnant women, they have been associated with spontaneous abortion, preterm birth, and impairment of the development of the fetus. Since these heavy metals come from both natural and anthropogenic activities and their harmful effects have been observed even at low levels of exposure, exposure to them remains a public health issue, especially for the reproductive system. Given this, the present study aimed to investigate the potential reproductive effects of Pb and Cd levels in the follicular fluid (FF) of infertile women and non-smokers exposed to heavy metals for professional reasons or as a result of living in rural areas near landfills and waste disposal areas in order to correlate the intrafollicular presence of these metals with possible alterations in the ultrastructure of human cumulus-oocyte complexes (COCs), which are probably responsible for infertility. Blood and FF metals were measured using atomic absorption spectrometry. COCs corresponding to each FF analyzed were subjected to ultrastructural analyses using transmission electron microscopy. We demonstrated for the first time that intrafollicular levels of Pb (0.66 µg/dL–0.85 µg/dL) and Cd (0.26 µg/L–0.41 µg/L) could be associated with morphological alterations of both the oocyte and cumulus cells’ (CCs) ultrastructure. Since blood Cd levels (0.54 µg/L–1.87 µg/L) were above the current reference values established by the guidelines of the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA) (0.4 µg/L), whereas blood Pb levels (1.28 µg/dL–3.98 µg/dL) were below the ATSDR reference values (≤5 µg/dL), we believe that these alterations could be due especially to Cd, even if we cannot exclude a possible additional effect of Pb. Our results highlighted that oocytes were affected in maturation and quality, whereas CCs showed scarcely active steroidogenic elements. Regressing CCs, with cytoplasmic alterations, were also numerous. According to Cd’s endocrine-disrupting activity, the poor steroidogenic activity of CCs might correlate with delayed oocyte cytoplasmic maturation. So, we conclude that levels of heavy metals in the blood and the FF might negatively affect fertilization, embryo development, and pregnancy, compromising oocyte competence in fertilization both directly and indirectly, impairing CC steroidogenic activity, and inducing CC apoptosis. Full article
(This article belongs to the Section Reproductive Cells and Development)
Show Figures

Figure 1

31 pages, 5710 KiB  
Review
A Brief Review of Bone Cell Function and Importance
by Veronika Šromová, Dinara Sobola and Pavel Kaspar
Cells 2023, 12(21), 2576; https://doi.org/10.3390/cells12212576 - 5 Nov 2023
Cited by 4 | Viewed by 8223
Abstract
This review focuses on understanding the macroscopic and microscopic characteristics of bone tissue and reviews current knowledge of its physiology. It explores how these features intricately collaborate to maintain the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, which plays a pivotal [...] Read more.
This review focuses on understanding the macroscopic and microscopic characteristics of bone tissue and reviews current knowledge of its physiology. It explores how these features intricately collaborate to maintain the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, which plays a pivotal role in shaping not only our physical framework but also overall health. In this work, a comprehensive exploration of microscopic and macroscopic features of bone tissue is presented. Full article
(This article belongs to the Special Issue Mineralized Tissues Repair and Regeneration 2.0)
Show Figures

Figure 1

19 pages, 1818 KiB  
Article
Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas
by Ankedo Warda, Lech J. P. Staniszewski, Zhela Sabir, Sarah Livingston, Michael Sausedo, Sabeeha Reshi, Eyal Ron, Michael T. Applegate, Dena Haddad, Madleen Khamisi, Pamela A. Marshall, Carl E. Wagner and Peter W. Jurutka
Cells 2023, 12(21), 2575; https://doi.org/10.3390/cells12212575 - 4 Nov 2023
Cited by 1 | Viewed by 1849
Abstract
Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of [...] Read more.
Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR–ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes. Full article
Show Figures

Graphical abstract

20 pages, 8429 KiB  
Article
GRF2 Is Crucial for Cone Photoreceptor Viability and Ribbon Synapse Formation in the Mouse Retina
by David Jimeno, Concepción Lillo, Pedro de la Villa, Nuria Calzada, Eugenio Santos and Alberto Fernández-Medarde
Cells 2023, 12(21), 2574; https://doi.org/10.3390/cells12212574 - 4 Nov 2023
Viewed by 1216
Abstract
Using constitutive GRF1/2 knockout mice, we showed previously that GRF2 is a key regulator of nuclear migration in retinal cone photoreceptors. To evaluate the functional relevance of that cellular process for two putative targets of the GEF activity of GRF2 (RAC1 and CDC42), [...] Read more.
Using constitutive GRF1/2 knockout mice, we showed previously that GRF2 is a key regulator of nuclear migration in retinal cone photoreceptors. To evaluate the functional relevance of that cellular process for two putative targets of the GEF activity of GRF2 (RAC1 and CDC42), here we compared the structural and functional retinal phenotypes resulting from conditional targeting of RAC1 or CDC42 in the cone photoreceptors of constitutive GRF2KO and GRF2WT mice. We observed that single RAC1 disruption did not cause any obvious morphological or physiological changes in the retinas of GRF2WT mice, and did not modify either the phenotypic alterations previously described in the retinal photoreceptor layer of GRF2KO mice. In contrast, the single ablation of CDC42 in the cone photoreceptors of GRF2WT mice resulted in clear alterations of nuclear movement that, unlike those of the GRF2KO retinas, were not accompanied by electrophysiological defects or slow, progressive cone cell degeneration. On the other hand, the concomitant disruption of GRF2 and CDC42 in the cone photoreceptors resulted, somewhat surprisingly, in a normalized pattern of nuclear positioning/movement, similar to that physiologically observed in GRF2WT mice, along with worsened patterns of electrophysiological responses and faster rates of cell death/disappearance than those previously recorded in single GRF2KO cone cells. Interestingly, the increased rates of cone cell apoptosis/death observed in single GRF2KO and double-knockout GRF2KO/CDC42KO retinas correlated with the electron microscopic detection of significant ultrastructural alterations (flattening) of their retinal ribbon synapses that were not otherwise observed at all in single-knockout CDC42KO retinas. Our observations identify GRF2 and CDC42 (but not RAC1) as key regulators of retinal processes controlling cone photoreceptor nuclear positioning and survival, and support the notion of GRF2 loss-of-function mutations as potential drivers of cone retinal dystrophies. Full article
(This article belongs to the Section Tissues and Organs)
Show Figures

Figure 1

30 pages, 2073 KiB  
Review
Capsaicinoids and Their Effects on Cancer: The “Double-Edged Sword” Postulate from the Molecular Scale
by Francisco Luján-Méndez, Octavio Roldán-Padrón, J. Eduardo Castro-Ruíz, Josué López-Martínez and Teresa García-Gasca
Cells 2023, 12(21), 2573; https://doi.org/10.3390/cells12212573 - 4 Nov 2023
Viewed by 2394
Abstract
Capsaicinoids are a unique chemical species resulting from a particular biosynthesis pathway of hot chilies (Capsicum spp.) that gives rise to 22 analogous compounds, all of which are TRPV1 agonists and, therefore, responsible for the pungency of Capsicum fruits. In addition to [...] Read more.
Capsaicinoids are a unique chemical species resulting from a particular biosynthesis pathway of hot chilies (Capsicum spp.) that gives rise to 22 analogous compounds, all of which are TRPV1 agonists and, therefore, responsible for the pungency of Capsicum fruits. In addition to their human consumption, numerous ethnopharmacological uses of chili have emerged throughout history. Today, more than 25 years of basic research accredit a multifaceted bioactivity mainly to capsaicin, highlighting its antitumor properties mediated by cytotoxicity and immunological adjuvancy against at least 74 varieties of cancer, while non-cancer cells tend to have greater tolerance. However, despite the progress regarding the understanding of its mechanisms of action, the benefit and safety of capsaicinoids’ pharmacological use remain subjects of discussion, since capsaicin also promotes epithelial–mesenchymal transition, in an ambivalence that has been referred to as “the double-edge sword”. Here, we update the comparative discussion of relevant reports about capsaicinoids’ bioactivity in a plethora of experimental models of cancer in terms of selectivity, efficacy, and safety. Through an integration of the underlying mechanisms, as well as inherent aspects of cancer biology, we propose mechanistic models regarding the dichotomy of their effects. Finally, we discuss a selection of in vivo evidence concerning capsaicinoids’ immunomodulatory properties against cancer. Full article
(This article belongs to the Special Issue Natural Products in the Treatment of Cancer)
Show Figures

Graphical abstract

17 pages, 3900 KiB  
Article
Adolescent Intermittent Ethanol Drives Modest Neuroinflammation but Does Not Escalate Drinking in Male Rats
by Jessica I. Wooden, Lauren E. Peacoe, Chinchusha Anasooya Shaji, Jennifer K. Melbourne, Cassie M. Chandler, Michael T. Bardo and Kimberly Nixon
Cells 2023, 12(21), 2572; https://doi.org/10.3390/cells12212572 - 4 Nov 2023
Cited by 3 | Viewed by 1776
Abstract
During adolescence, the brain is highly susceptible to alcohol-induced damage and subsequent neuroimmune responses, effects which may enhance development of an alcohol use disorder (AUD). Neuroimmune reactions are implicated in adolescent alcohol exposure escalating adulthood drinking. Therefore, we investigated whether intermittent alcohol exposure [...] Read more.
During adolescence, the brain is highly susceptible to alcohol-induced damage and subsequent neuroimmune responses, effects which may enhance development of an alcohol use disorder (AUD). Neuroimmune reactions are implicated in adolescent alcohol exposure escalating adulthood drinking. Therefore, we investigated whether intermittent alcohol exposure in male, adolescent rats (AIE) escalated adult drinking via two-bottle choice (2BC). We also examined the influence of housing environment across three groups: standard (group-housed with enrichment during 2BC), impoverished (group-housed without enrichment during 2BC), or isolation (single-housed without bedding or enrichment throughout). In the standard group immediately after AIE/saline and after 2BC, we also examined the expression of microglial marker, Iba1, reactive astrocyte marker, vimentin, and neuronal cell death dye, FluoroJade B (FJB). We did not observe an escalation of adulthood drinking following AIE, regardless of housing condition. Further, only a modest neuroimmune response occurred after AIE in the standard group: no significant microglial reactivity or neuronal cell death was apparent using this model, although some astrocyte reactivity was detected in adolescence following AIE that resolved by adulthood. These data suggest that the lack of neuroimmune response in adolescence in this model may underlie the lack of escalation of alcohol drinking, which could not be modified through isolation stress. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
Show Figures

Figure 1

27 pages, 8078 KiB  
Article
Proteomic Analyses of the G Protein-Coupled Estrogen Receptor GPER1 Reveal Constitutive Links to Endoplasmic Reticulum, Glycosylation, Trafficking, and Calcium Signaling
by Maryam Ahmadian Elmi, Nasrin Motamed and Didier Picard
Cells 2023, 12(21), 2571; https://doi.org/10.3390/cells12212571 - 3 Nov 2023
Viewed by 1594
Abstract
The G protein-coupled estrogen receptor 1 (GPER1) has been proposed to mediate rapid responses to the steroid hormone estrogen. However, despite a strong interest in its potential role in cancer, whether it is indeed activated by estrogen and how this works remain controversial. [...] Read more.
The G protein-coupled estrogen receptor 1 (GPER1) has been proposed to mediate rapid responses to the steroid hormone estrogen. However, despite a strong interest in its potential role in cancer, whether it is indeed activated by estrogen and how this works remain controversial. To provide new tools to address these questions, we set out to determine the interactome of exogenously expressed GPER1. The combination of two orthogonal methods, namely APEX2-mediated proximity labeling and immunoprecipitation followed by mass spectrometry, gave us high-confidence results for 73 novel potential GPER1 interactors. We found that this GPER1 interactome is not affected by estrogen, a result that mirrors the constitutive activity of GPER1 in a functional assay with a Rac1 sensor. We specifically validated several hits highlighted by a gene ontology analysis. We demonstrate that CLPTM1 interacts with GPER1 and that PRKCSH and GANAB, the regulatory and catalytic subunits of α-glucosidase II, respectively, associate with CLPTM1 and potentially indirectly with GPER1. An imbalance in CLPTM1 levels induces nuclear association of GPER1, as does the overexpression of PRKCSH. Moreover, we show that the Ca2+ sensor STIM1 interacts with GPER1 and that upon STIM1 overexpression and depletion of Ca2+ stores, GPER1 becomes more nuclear. Thus, these new GPER1 interactors establish interesting connections with membrane protein maturation, trafficking, and calcium signaling. Full article
Show Figures

Graphical abstract

21 pages, 3793 KiB  
Article
Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures
by Kinga Tylek, Ewa Trojan, Monika Leśkiewicz, Imane Ghafir El Idrissi, Enza Lacivita, Marcello Leopoldo and Agnieszka Basta-Kaim
Cells 2023, 12(21), 2570; https://doi.org/10.3390/cells12212570 - 3 Nov 2023
Cited by 1 | Viewed by 960
Abstract
Microglial cells have been demonstrated to be significant resident immune cells that maintain homeostasis under physiological conditions. However, prolonged or excessive microglial activation leads to disturbances in the resolution of inflammation (RoI). Formyl peptide receptor 2 (FPR2) is a crucial player in the [...] Read more.
Microglial cells have been demonstrated to be significant resident immune cells that maintain homeostasis under physiological conditions. However, prolonged or excessive microglial activation leads to disturbances in the resolution of inflammation (RoI). Formyl peptide receptor 2 (FPR2) is a crucial player in the RoI, interacting with various ligands to induce distinct conformational changes and, consequently, diverse biological effects. Due to the poor pharmacokinetic properties of endogenous FPR2 ligands, the aim of our study was to evaluate the pro-resolving effects of a new ureidopropanamide agonist, compound AMS21, in hippocampal organotypic cultures (OHCs) stimulated with lipopolysaccharide (LPS). Moreover, to assess whether AMS21 exerts its action via FPR2 specifically located on microglial cells, we conducted a set of experiments in OHCs depleted of microglial cells using clodronate. We demonstrated that the protective and anti-inflammatory activity of AMS21 manifested as decreased levels of lactate dehydrogenase (LDH), nitric oxide (NO), and proinflammatory cytokines IL-1β and IL-6 release evoked by LPS in OHCs. Moreover, in LPS-stimulated OHCs, AMS21 treatment downregulated NLRP3 inflammasome-related factors (CASP1, NLRP3, PYCARD) and this effect was mediated through FPR2 because it was blocked by the FPR2 antagonist WRW4 pre-treatment. Importantly this beneficial effect of AMS21 was only observed in the presence of microglial FPR2, and absent in OHCs depleted with microglial cells using clodronate. Our results strongly suggest that the compound AMS21 exerts, at nanomolar doses, protective and anti-inflammatory properties and an FPR2 receptor located specifically on microglial cells mediates the anti-inflammatory response of AMS21. Therefore, microglial FPR2 represents a promising target for the enhancement of RoI. Full article
(This article belongs to the Section Cells of the Nervous System)
Show Figures

Figure 1

17 pages, 5898 KiB  
Article
The Adaptive Role of Carotenoids and Anthocyanins in Solanum lycopersicum Pigment Mutants under High Irradiance
by Aleksandr Ashikhmin, Maksim Bolshakov, Pavel Pashkovskiy, Mikhail Vereshchagin, Alexandra Khudyakova, Galina Shirshikova, Anna Kozhevnikova, Anatoliy Kosobryukhov, Vladimir Kreslavski, Vladimir Kuznetsov and Suleyman I. Allakhverdiev
Cells 2023, 12(21), 2569; https://doi.org/10.3390/cells12212569 - 3 Nov 2023
Cited by 2 | Viewed by 1047
Abstract
The effects of high-intensity light on the pigment content, photosynthetic rate, and fluorescence parameters of photosystem II in high-pigment tomato mutants (hp 3005) and low-pigment mutants (lp 3617) were investigated. This study also evaluated the dry weight percentage of low molecular [...] Read more.
The effects of high-intensity light on the pigment content, photosynthetic rate, and fluorescence parameters of photosystem II in high-pigment tomato mutants (hp 3005) and low-pigment mutants (lp 3617) were investigated. This study also evaluated the dry weight percentage of low molecular weight antioxidant capacity, expression patterns of some photoreceptor-regulated genes, and structural aspects of leaf mesophyll cells. The 3005 mutant displayed increased levels of photosynthetic pigments and anthocyanins, whereas the 3617 mutant demonstrated a heightened content of ultraviolet-absorbing pigments. The photosynthetic rate, photosystem II activity, antioxidant capacity, and carotenoid content were most pronounced in the high-pigment mutant after 72 h exposure to intense light. This mutant also exhibited an increase in leaf thickness and water content when exposed to high-intensity light, suggesting superior physiological adaptability and reduced photoinhibition. Our findings indicate that the enhanced adaptability of the high-pigment mutant might be attributed to increased flavonoid and carotenoid contents, leading to augmented expression of key genes associated with pigment synthesis and light regulation. Full article
(This article belongs to the Special Issue Photoreceptor Signaling in Plants under Environmental Stress)
Show Figures

Figure 1

23 pages, 2455 KiB  
Article
The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection
by Georgia Papadopoulou, Stavroula Petroulia, Eirini Karamichali, Alexios Dimitriadis, Dimitrios Marousis, Elisavet Ioannidou, Panagiota Papazafiri, John Koskinas, Pelagia Foka and Urania Georgopoulou
Cells 2023, 12(21), 2568; https://doi.org/10.3390/cells12212568 - 3 Nov 2023
Viewed by 1247
Abstract
Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller [...] Read more.
Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller of critical cellular functions that are essential for HCV propagation. We investigated the putative role of LSD1 in the establishment of HCV infection using genetic engineering and pharmacological inhibition to alter endogenous LSD1 levels. We demonstrated for the first time that HCV replication was inhibited in LSD1-overexpressing cells, while specific HCV proteins differentially fine-tuned endogenous LSD1 expression levels. Electroporation of the full-length HCV genome and subgenomic replicons in LSD1 overexpression enhanced translation and partially restored HCV replication, suggesting that HCV might be inhibited by LSD1 during the early steps of infection. Conversely, the inhibition of LSD1, followed by HCV infection in vitro, increased viral replication. LSD1 was shown to participate in an intriguing antiviral mechanism, where it activates endolysosomal interferon-induced transmembrane protein 3 (IFITM3) via demethylation, leading endocytosed HCV virions to degradation. Our study proposes that HCV-mediated LSD1 oscillations over countless viral life cycles throughout chronic HCV infection may promote epigenetic changes related to HCV-induced hepatocarcinogenesis. Full article
Show Figures

Graphical abstract

13 pages, 2199 KiB  
Commentary
The Evolution of Current Concept of the Reconstructive Ladder in Plastic Surgery: The Emerging Role of Translational Medicine
by Francesco De Francesco, Nicola Zingaretti, Pier Camillo Parodi and Michele Riccio
Cells 2023, 12(21), 2567; https://doi.org/10.3390/cells12212567 - 3 Nov 2023
Cited by 6 | Viewed by 2459
Abstract
Plastic surgeons have used the reconstructive ladder for many decades as a standard directory for complex trauma reconstruction with the goal of repairing body structures and restoring functionality. This consists of different surgical maneuvers, such as secondary intention and direct tissue closure, as [...] Read more.
Plastic surgeons have used the reconstructive ladder for many decades as a standard directory for complex trauma reconstruction with the goal of repairing body structures and restoring functionality. This consists of different surgical maneuvers, such as secondary intention and direct tissue closure, as well as more complex methods such as local tissue transfer and free flap. The reconstructive ladder represents widely known options achievable for tissue reconstruction and wound closure that puts at the bottom rung the simplest methods of reconstruction and strengthens the complexity by moving upward. Regenerative medicine and surgery constitute a quickly spreading area of translational research that can be employed by minimally invasive surgical strategies, with the aim of regenerating cells and tissues in vivo in order to reestablish normal function through the intrinsic potential of cells, in combination with biomaterials and appropriate biochemical stimuli. These translational procedures have the aim of creating an appropriate microenvironment capable of supporting the physiological cellular function to generate the desired cells or tissues and to generate parenchymal, stromal, and vascular components on demand, and above all to produce intelligent materials capable of determining the fate of cells. Smart technologies have been grown that give extra “rungs” on the classic reconstructive ladder to integrate a more holistic, patient-based approach with improved outcomes. This commentary presents the evolution of the traditional concept of the reconstructive ladder in the field of plastic surgery into a new course with the aim of achieving excellent results for soft tissue reconstruction by applying innovative technologies and biologically active molecules for a wide range of surgical diseases. Full article
(This article belongs to the Special Issue New Insights into Adipose-Derived Stem Cells (ADSCs))
Show Figures

Graphical abstract

20 pages, 8205 KiB  
Article
The Small GTPase Rab7 Regulates Antigen Processing in B Cells in a Possible Interplay with Autophagy Machinery
by Marika Runsala, Elina Kuokkanen, Eveliina Uski, Vid Šuštar, Meryem Özge Balci, Johanna Rajala, Vilma Paavola and Pieta K. Mattila
Cells 2023, 12(21), 2566; https://doi.org/10.3390/cells12212566 - 2 Nov 2023
Cited by 1 | Viewed by 1152
Abstract
In B cells, antigen processing and peptide-antigen (pAg) presentation is essential to ignite high-affinity antibody responses with the help of cognate T cells. B cells efficiently internalize and direct specific antigens for processing and loading onto MHCII. This critical step, which enables pAg [...] Read more.
In B cells, antigen processing and peptide-antigen (pAg) presentation is essential to ignite high-affinity antibody responses with the help of cognate T cells. B cells efficiently internalize and direct specific antigens for processing and loading onto MHCII. This critical step, which enables pAg presentation, occurs in MHCII compartments (MIICs) which possess the enzymatic machinery for pAg loading on MHCII. The intracellular transport systems that guide antigen and maintain this unique compartment remain enigmatic. Here, we probed the possible functional role of two known endosomal proteins, the Rab family small GTPases Rab7 and Rab9, that are both reported to colocalize with internalized antigen. As compared to Rab9, we found Rab7 to exhibit a higher overlap with antigen and MIIC components. Rab7 also showed a higher association with antigen degradation. The inhibition of Rab7 drastically decreased pAg presentation. Additionally, we detected the strong colocalization of perinuclearly clustered and presumably MIIC-associated antigen with autophagy protein LC3. When we pharmacologically inhibited autophagy, pAg presentation was inhibited. Together, our data promote Rab7 as an important regulator of antigen processing and, considering the previously reported functions of Rab7 in autophagy, this also raises the possibility of the involvement of autophagy-related machinery in this process. Full article
(This article belongs to the Special Issue Emerging Mechanisms in B Cell Activation)
Show Figures

Figure 1

22 pages, 6147 KiB  
Article
Treating Parkinson’s Disease with Human Bone Marrow Mesenchymal Stem Cell Secretome: A Translational Investigation Using Human Brain Organoids and Different Routes of In Vivo Administration
by Bárbara Mendes-Pinheiro, Jonas Campos, Ana Marote, Carina Soares-Cunha, Sarah L. Nickels, Anna S. Monzel, Jorge R. Cibrão, Eduardo Loureiro-Campos, Sofia C. Serra, Sandra Barata-Antunes, Sara Duarte-Silva, Luísa Pinto, Jens C. Schwamborn and António J. Salgado
Cells 2023, 12(21), 2565; https://doi.org/10.3390/cells12212565 - 2 Nov 2023
Viewed by 1889
Abstract
Parkinson’s disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells [...] Read more.
Parkinson’s disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells (MSCs) are one of the most extensively studied cell sources for regenerative medicine applications, particularly due to the release of soluble factors and vesicles, known as secretome. The main goal of this work was to address the therapeutic potential of the secretome collected from bone-marrow-derived MSCs (BM-MSCs) using different models of the disease. Firstly, we took advantage of an optimized human midbrain-specific organoid system to model PD in vitro using a neurotoxin-induced model through 6-hydroxydopamine (6-OHDA) exposure. In vivo, we evaluated the effects of BM-MSC secretome comparing two different routes of secretome administration: intracerebral injections (a two-site single administration) against multiple systemic administration. The secretome of BM-MSCs was able to protect from dopaminergic neuronal loss, these effects being more evident in vivo. The BM-MSC secretome led to motor function recovery and dopaminergic loss protection; however, multiple systemic administrations resulted in larger therapeutic effects, making this result extremely relevant for potential future clinical applications. Full article
Show Figures

Graphical abstract

20 pages, 10810 KiB  
Article
Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition
by Kyle J. Connolly, Juliette Margaria, Erika Di Biase, Oliver Cooper, Penelope J. Hallett and Ole Isacson
Cells 2023, 12(21), 2564; https://doi.org/10.3390/cells12212564 - 2 Nov 2023
Viewed by 1762
Abstract
Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most [...] Read more.
Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson’s disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers. To investigate functional interactions between brain ApoE and GBA1, in vivo GBA1 inhibition was tested in WT versus ApoE-deficient mice. The experiments demonstrated glycolipid stress caused by GBA1 inhibition in WT mice induced ApoE expression in several brain regions associated with movement and dementia disorders. The absence of ApoE in ApoE-KO mice amplified complement C1q elevations, reactive microgliosis and astrocytosis after glycolipid stress. Mechanistically, GBA1 inhibition triggered increases in cell surface and intracellular lipid transporters ABCA1 and NPC1, respectively. Interestingly, the absence of NPC1 in mice also triggered elevations of brain ApoE levels. These new data show that brain ApoE, GBA1 and NPC1 functions are interconnected in vivo, and that the removal or reduction of ApoE would likely be detrimental to brain function. These results provide important insights into brain ApoE adaptive responses to increased lipid loads. Full article
Show Figures

Figure 1

17 pages, 3366 KiB  
Article
The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation
by Mohamed Abu-Farha, Dhanya Madhu, Prashantha Hebbar, Anwar Mohammad, Arshad Channanath, Sina Kavalakatt, Nada Alam-Eldin, Fatima Alterki, Ibrahim Taher, Osama Alsmadi, Mohammad Shehab, Hossein Arefanian, Rasheed Ahmad, Thangavel Alphonse Thanaraj, Fahd Al-Mulla and Jehad Abubaker
Cells 2023, 12(21), 2563; https://doi.org/10.3390/cells12212563 - 2 Nov 2023
Viewed by 1526
Abstract
Background: Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W [...] Read more.
Background: Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W variant associates with reduced low-density lipoprotein/high-density lipoprotein (LDL/HDL) and increased fasting blood glucose (FBG) in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of the R59W variant on the inflammatory activity of ANGPTL8. Methods: The ANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-κB activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics. Results: The ANGPTL8 R59W variant was associated with increased circulatory levels of tumor necrosis factor alpha (TNFα) and interleukin 7 (IL7). Our in vitro studies using HepG2 cells revealed an increased phosphorylation of key inflammatory proteins of the NF-κB pathway in individuals with the R59W variant as compared to those with the wild type, and TNFα stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-κB p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-κB activity. Conclusion: ANGPTL8 R59W is associated with increased circulatory TNFα, IL7, and NF-κB p65 activity. Weak transient binding of the ANGPTL8 R59W variant explains its regulatory role on the NF-κB pathway and inflammation. Full article
(This article belongs to the Section Cellular Immunology)
Show Figures

Graphical abstract

13 pages, 2842 KiB  
Article
FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres
by Aimee L. Dowling, Stuart Walbridge, Celine Ertekin, Sriya Namagiri, Krystal Camacho, Ashis Chowdhury, Jean-Paul Bryant, Eric Kohut, John D. Heiss, Desmond A. Brown, Sangamesh G. Kumbar and Yeshavanth Kumar Banasavadi-Siddegowda
Cells 2023, 12(21), 2562; https://doi.org/10.3390/cells12212562 - 2 Nov 2023
Viewed by 1149
Abstract
Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the [...] Read more.
Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions, including apoptosis and autophagy. In this study, we tested the role of FKBP38 in glioblastoma tumor biology. Expression of FKBP38 was upregulated in the patient-derived primary glioblastoma neurospheres (GBMNS), compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNSs and increased the caspase 3/7 activity, indicating that FKBP38 is required for the survival of GBMNSs. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed, implying that FKBP38 regulates the self-renewal of GBMNSs. Additionally, the transient knockdown of FKBP38 increased the LC3-II/I ratio, suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNSs is mediated through the JNK/C-Jun–PTEN–AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest that targeting FKBP38 imparts an anti-glioblastoma effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for glioblastoma therapy. Full article
Show Figures

Figure 1

24 pages, 5065 KiB  
Article
Leucine Supplementation Improves Diastolic Function in HFpEF by HDAC4 Inhibition
by Paula Ketilly Nascimento Alves, Antje Schauer, Antje Augstein, Anita Männel, Peggy Barthel, Dirk Joachim, Janet Friedrich, Maria-Elisa Prieto, Anselmo Sigari Moriscot, Axel Linke and Volker Adams
Cells 2023, 12(21), 2561; https://doi.org/10.3390/cells12212561 - 2 Nov 2023
Cited by 1 | Viewed by 1521
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, [...] Read more.
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, no data exist on leucine supplementation on cardiac function in HFpEF. Thus, the current study aimed to investigate the effect of leucine supplementation on myocardial function and key signaling pathways in an established HFpEF rat model. Female ZSF1 rats were randomized into three groups: Control (untreated lean rats), HFpEF (untreated obese rats), and HFpEF_Leu (obese rats receiving standard chow enriched with 3% leucine). Leucine supplementation started at 20 weeks of age after an established HFpEF was confirmed in obese rats. In all animals, cardiac function was assessed by echocardiography at baseline and throughout the experiment. At the age of 32 weeks, hemodynamics were measured invasively, and myocardial tissue was collected for assessment of mitochondrial function and for histological and molecular analyses. Leucine had already improved diastolic function after 4 weeks of treatment. This was accompanied by improved hemodynamics and reduced stiffness, as well as by reduced left ventricular fibrosis and hypertrophy. Cardiac mitochondrial respiratory function was improved by leucine without alteration of the cardiac mitochondrial content. Lastly, leucine supplementation suppressed the expression and nuclear localization of HDAC4 and was associated with Protein kinase A activation. Our data show that leucine supplementation improves diastolic function and decreases remodeling processes in a rat model of HFpEF. Beneficial effects were associated with HDAC4/TGF-β1/Collagenase downregulation and indicate a potential use in the treatment of HFpEF. Full article
Show Figures

Figure 1

35 pages, 8335 KiB  
Review
Mass Spectrometry-Based Proteomic Technology and Its Application to Study Skeletal Muscle Cell Biology
by Paul Dowling, Dieter Swandulla and Kay Ohlendieck
Cells 2023, 12(21), 2560; https://doi.org/10.3390/cells12212560 - 1 Nov 2023
Cited by 4 | Viewed by 2911
Abstract
Voluntary striated muscles are characterized by a highly complex and dynamic proteome that efficiently adapts to changed physiological demands or alters considerably during pathophysiological dysfunction. The skeletal muscle proteome has been extensively studied in relation to myogenesis, fiber type specification, muscle transitions, the [...] Read more.
Voluntary striated muscles are characterized by a highly complex and dynamic proteome that efficiently adapts to changed physiological demands or alters considerably during pathophysiological dysfunction. The skeletal muscle proteome has been extensively studied in relation to myogenesis, fiber type specification, muscle transitions, the effects of physical exercise, disuse atrophy, neuromuscular disorders, muscle co-morbidities and sarcopenia of old age. Since muscle tissue accounts for approximately 40% of body mass in humans, alterations in the skeletal muscle proteome have considerable influence on whole-body physiology. This review outlines the main bioanalytical avenues taken in the proteomic characterization of skeletal muscle tissues, including top-down proteomics focusing on the characterization of intact proteoforms and their post-translational modifications, bottom-up proteomics, which is a peptide-centric method concerned with the large-scale detection of proteins in complex mixtures, and subproteomics that examines the protein composition of distinct subcellular fractions. Mass spectrometric studies over the last two decades have decisively improved our general cell biological understanding of protein diversity and the heterogeneous composition of individual myofibers in skeletal muscles. This detailed proteomic knowledge can now be integrated with findings from other omics-type methodologies to establish a systems biological view of skeletal muscle function. Full article
(This article belongs to the Section Tissues and Organs)
Show Figures

Figure 1

34 pages, 2018 KiB  
Review
Unveiling Mesenchymal Stem Cells’ Regenerative Potential in Clinical Applications: Insights in miRNA and lncRNA Implications
by Maurycy Jankowski, Maryam Farzaneh, Farhoodeh Ghaedrahmati, Milad Shirvaliloo, Arash Moalemnia, Magdalena Kulus, Hanna Ziemak, Mikołaj Chwarzyński, Piotr Dzięgiel, Maciej Zabel, Hanna Piotrowska-Kempisty, Dorota Bukowska, Paweł Antosik, Paul Mozdziak and Bartosz Kempisty
Cells 2023, 12(21), 2559; https://doi.org/10.3390/cells12212559 - 31 Oct 2023
Viewed by 1704
Abstract
It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role [...] Read more.
It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs. Full article
(This article belongs to the Section Stem Cells)
Show Figures

Figure 1

32 pages, 16062 KiB  
Article
Five Inhibitory Receptors Display Distinct Vesicular Distributions in Murine T Cells
by Jiahe Lu, Alisa Veler, Boris Simonetti, Timsse Raj, Po Han Chou, Stephen J. Cross, Alexander M. Phillips, Xiongtao Ruan, Lan Huynh, Andrew W. Dowsey, Dingwei Ye, Robert F. Murphy, Paul Verkade, Peter J. Cullen and Christoph Wülfing
Cells 2023, 12(21), 2558; https://doi.org/10.3390/cells12212558 - 31 Oct 2023
Viewed by 1562
Abstract
T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to a persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3, and TIGIT, as investigated here. These [...] Read more.
T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to a persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3, and TIGIT, as investigated here. These receptors are important as central therapeutic targets in cancer immunotherapy. Inhibitory receptors are not constitutively expressed on the cell surface, but substantial fractions reside in intracellular vesicular structures. It remains unresolved to which extent the subcellular localization of different inhibitory receptors is distinct. Using quantitative imaging of subcellular distributions and plasma membrane insertion as complemented by proximity proteomics and biochemical analysis of the association of the inhibitory receptors with trafficking adaptors, the subcellular distributions of the five inhibitory receptors were discrete. The distribution of CTLA-4 was most distinct, with preferential association with lysosomal-derived vesicles and the sorting nexin 1/2/5/6 transport machinery. With a lack of evidence for the existence of specific vesicle subtypes to explain divergent inhibitory receptor distributions, we suggest that such distributions are driven by divergent trafficking through an overlapping joint set of vesicular structures. This extensive characterization of the subcellular localization of five inhibitory receptors in relation to each other lays the foundation for the molecular investigation of their trafficking and its therapeutic exploitation. Full article
Show Figures

Graphical abstract

18 pages, 3597 KiB  
Article
Attenuating Colorectal Cancer Using Nine Cultivars of Australian Lupin Seeds: Apoptosis Induction Triggered by Mitochondrial Reactive Oxygen Species Generation and Caspases-3/7 Activation
by Kishor Mazumder, Asma Aktar, Sujatha Ramasamy, Biswajit Biswas, Philip G. Kerr and Christopher Blanchard
Cells 2023, 12(21), 2557; https://doi.org/10.3390/cells12212557 - 31 Oct 2023
Viewed by 1758
Abstract
As Australian lupin cultivars are rich sources of polyphenols, dietary fibers, high-quality proteins, and abundant bioactive compounds with significant antioxidant, antidiabetic, and anticancer activities, this research work is aimed at investigating the colon cancer alleviation activity of nine cultivars of lupin seeds on [...] Read more.
As Australian lupin cultivars are rich sources of polyphenols, dietary fibers, high-quality proteins, and abundant bioactive compounds with significant antioxidant, antidiabetic, and anticancer activities, this research work is aimed at investigating the colon cancer alleviation activity of nine cultivars of lupin seeds on HCT116 and HT29 colon carcinoma cell lines through anti-proliferation assay, measurement of apoptosis, and identification of the mechanism of apoptosis. Nine cultivars were pre-screened for anti-proliferation of HCT116 and HT29 cells along with consideration of the impact of heat processing on cancer cell viability. Mandelup and Jurien showed significant inhibition of HCT116 cells, whereas the highest inhibition of HT29 cell proliferation was attained by Jurien and Mandelup. Processing decreased the anti-proliferation activity drastically. Lupin cultivars Mandelup, Barlock, and Jurien (dose: 300 μg/mL) induced early and late apoptosis of colon cancer cells in Annexin V-FITC assay. The mechanism of apoptosis was explored, which involves boosting of caspases-3/7 activation and intracellular reactive oxygen species (ROS) generation in HCT116 cells (Mandelup and Barlock) and HT29 cells (Jurien and Mandelup). Thus, the findings showed that lupin cultivars arrest cell cycles by inducing apoptosis of colorectal carcinoma cells triggered by elevated ROS generation and caspases-3/7 activation. Full article
(This article belongs to the Special Issue The Role of Natural Extracts and Phytochemicals in Cancer Therapy)
Show Figures

Figure 1

17 pages, 1379 KiB  
Review
Regulatory ILC2—Role of IL-10 Producing ILC2 in Asthma
by Nahal Emami Fard, Maria Xiao and Roma Sehmi
Cells 2023, 12(21), 2556; https://doi.org/10.3390/cells12212556 - 31 Oct 2023
Cited by 1 | Viewed by 2185
Abstract
Over the past two decades, a growing body of evidence observations have shown group two innate lymphoid cells (ILC2) to be critical drivers of Type 2 (T2) inflammatory responses associated with allergic inflammatory conditions such as asthma. ILC2 releases copious amounts of pro-inflammatory [...] Read more.
Over the past two decades, a growing body of evidence observations have shown group two innate lymphoid cells (ILC2) to be critical drivers of Type 2 (T2) inflammatory responses associated with allergic inflammatory conditions such as asthma. ILC2 releases copious amounts of pro-inflammatory T2 cytokines—interleukin (IL)-4, IL-5, IL-9, and IL-13. This review provides a comprehensive overview of the newly discovered regulatory subtype of ILC2 described in murine and human mucosal tissue and blood. These KLRG1+ILC2 have the capacity to produce the anti-inflammatory cytokine IL-10. Papers compiled in this review were based on queries of PubMed and Google Scholar for articles published from 2000 to 2023 using keywords “IL-10” and “ILC2”. Studies with topical relevance to IL-10 production by ILC2 were included. ILC2 responds to microenvironmental cues, including retinoic acid (RA), IL-2, IL-4, IL-10, and IL-33, as well as neuropeptide mediators such as neuromedin-U (NMU), prompting a shift towards IL-10 and away from T2 cytokine production. In contrast, TGF-β attenuates IL-10 production by ILC2. Immune regulation provided by IL-10+ILC2s holds potential significance for the management of T2 inflammatory conditions. The observation of context-specific cues that alter the phenotype of ILC warrants examining characteristics of ILC subsets to determine the extent of plasticity or whether the current classification of ILCs requires refinement. Full article
(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms and Therapy of Asthma)
Show Figures

Figure 1

16 pages, 3748 KiB  
Article
Myocardial Mitochondrial DNA Drives Macrophage Inflammatory Response through STING Signaling in Coxsackievirus B3-Induced Viral Myocarditis
by Andong Qin, Zhenke Wen and Sidong Xiong
Cells 2023, 12(21), 2555; https://doi.org/10.3390/cells12212555 - 31 Oct 2023
Viewed by 1274
Abstract
Coxsackievirus B3 (CVB3), a single-stranded positive RNA virus, primarily infects cardiac myocytes and is a major causative pathogen for viral myocarditis (VMC), driving cardiac inflammation and organ dysfunction. However, whether and how myocardial damage is involved in CVB3-induced VMC remains unclear. Herein, we [...] Read more.
Coxsackievirus B3 (CVB3), a single-stranded positive RNA virus, primarily infects cardiac myocytes and is a major causative pathogen for viral myocarditis (VMC), driving cardiac inflammation and organ dysfunction. However, whether and how myocardial damage is involved in CVB3-induced VMC remains unclear. Herein, we demonstrate that the CVB3 infection of cardiac myocytes results in the release of mitochondrial DNA (mtDNA), which functions as an important driver of cardiac macrophage inflammation through the stimulator of interferon genes (STING) dependent mechanism. More specifically, the CVB3 infection of cardiac myocytes promotes the accumulation of extracellular mtDNA. Such myocardial mtDNA is indispensable for CVB3-infected myocytes in that it induces a macrophage inflammatory response. Mechanistically, a CVB3 infection upregulates the expression of the classical DNA sensor STING, which is predominantly localized within cardiac macrophages in VMC murine models. Myocardial mtDNA efficiently triggers STING signaling in those macrophages, resulting in strong NF-kB activation when inducing the inflammatory response. Accordingly, STING-deficient mice are able to resist CVB3-induced cardiac inflammation, exhibiting minimal inflammation with regard to their functional cardiac capacities, and they exhibit higher survival rates. Moreover, our findings pinpoint myocardial mtDNA as a central element driving the cardiac inflammation of CVB3-induced VMC, and we consider the DNA sensor, STING, to be a promising therapeutic target for protecting against RNA viral infections. Full article
Show Figures

Graphical abstract

25 pages, 6902 KiB  
Article
CREB1 Is Involved in miR-134-5p-Mediated Endometrial Stromal Cell Proliferation, Apoptosis, and Autophagy
by Xiaodan Li, Xiaolei Yao, Kang Li, Jiahe Guo, Kaiping Deng, Zhipeng Liu, Fan Yang, Yixuan Fan, Yingnan Yang, Huabin Zhu and Feng Wang
Cells 2023, 12(21), 2554; https://doi.org/10.3390/cells12212554 - 31 Oct 2023
Cited by 1 | Viewed by 1265
Abstract
The successful establishment of endometrial receptivity is a key factor in ensuring the fertility of ewes and their economic benefits. Hu sheep have attracted attention due to their high fecundity and year-round estrus. In this study, we found that in the luteal phase, [...] Read more.
The successful establishment of endometrial receptivity is a key factor in ensuring the fertility of ewes and their economic benefits. Hu sheep have attracted attention due to their high fecundity and year-round estrus. In this study, we found that in the luteal phase, the uterine gland density, uterine coefficient, and number of uterine caruncles of high-fertility Hu sheep were higher than those of low-fertility Hu sheep. Thousands of differentially expressed genes were identified in the endometrium of Hu sheep with different fertility potential using RNA sequencing (RNA-Seq). Several genes involved in endometrial receptivity were screened using bioinformatics analysis. The qRT-PCR analysis further revealed the differential expression of cAMP reactive element binding protein-1 (CREB1) in the Hu sheep endometrium during the estrous cycle. Functionally, our results suggested that CREB1 significantly affected the expression level of endometrial receptivity marker genes, promoted cell proliferation by facilitating the transition from the G1 phase to the S phase, and inhibited cell apoptosis and autophagy. Moreover, we observed a negative linear correlation between miR-134-5p and CREB1 in the endometrium. In addition, CREB1 overexpression prevented the negative effect of miR-134-5p on endometrial stromal cell (ESC) growth. Taken together, these data indicated that CREB1 was regulated by miR-134-5p and may promote the establishment of uterine receptivity by regulating the function of ESCs. Moreover, this study provides new theoretical references for identifying candidate genes associated with fertility. Full article
(This article belongs to the Section Reproductive Cells and Development)
Show Figures

Figure 1

Previous Issue
Back to TopTop