Induced Cell Proliferation Research Articles

DNMT1 prolonged absence is a tunable cellular stress that triggers cell proliferation arrest to protect from major DNA methylation loss

Methylation of cytosine in CpG dinucleotides is an epigenetic modification carried out by DNA-methyltransferases (DNMTs) that contributes to chromatin condensation and structure and, thus, to gene transcription regulation and chromosome stability. DNMT1 maintains the DNA methylation pattern of the genome at each cell cycle by copying it to the newly synthesized DNA strand during the S-phase. DNMT1 pharmacological inhibition as well as genetic knockout and knockdown, leads to passive DNA methylation loss. However, these strategies have been associated with different cell fates, even in the same cell background, suggesting that they can question the interpretation of the obtained results. Using a cell system in which endogenous DNMT1 is fused with an inducible degron and can be rapidly degraded, we found that in non-tumoral RPE-1 cells, DNMT1 loss progressively induced cell proliferation slowing-down and cell cycle arrest at the G1/S transition. The latter is due to p21 activation, which is partly mediated by p53 and leads to a global reduction in DNA methylation. DNMT1 restoration rescues cell proliferation, indicating that its deregulation is sensed as tunable cellular stress.

GPER1 activation by estrogenic compounds in the inflammatory profile of breast cancer cells

Breast cancer (BC) is the most frequent female neoplasm worldwide. Its establishment and development have been related to inflammatory cytokine expression. Steroid hormones such as estradiol (E2) can regulate proinflammatory cytokine secretion through interaction with its nuclear receptors. However, little is known regarding the activation of its membrane estrogen receptor (GPER1) and the inflammatory cytokine environment in BC. We have studied the synthesis and biological effects of molecules analogs to E2 for hormone replacement therapy (HRT), such as pentolame. Nevertheless, its interaction with GPER1 and the modulation of inflammatory cytokines in different BC types has been barely studied and deserves deeper investigation. In this research, the role of GPER1 in the proliferation and modulation of inflammatory cytokines involved in carcinogenesis and metastatic processes in different BC cell lines was assessed by binding to various compounds. To achieve this goal, the presence of GPER1 was identified in different BC cell lines. Subsequently, cell proliferation after exposure to E2, pentolame and GPER1 agonist, G1, was subsequently determined alone or in combination with the GPER1 antagonist, G15. Finally, the pro-inflammatory cytokine secretion derived from the supernatants of BC cells exposed to the previous treatments was also assessed. Interestingly, GPER1 activation or inhibition has significant effects on the cytokine regulation associated with invasion in BC. Notably, pentolame did not induce cell proliferation or increase the proinflammatory cytokine expression compared to E2 in BC cell lines. In addition, pentolame did not induce the presence of the cell adhesion molecule PECAM-1. In contrast, E2 treatment weakly induced the expression of PECAM-1 in MCF-7 and HCC1937 cells, and G1 treatment showed this effect only in MCF-7 cells. The results suggest that GPER1 might be a significant inflammatory modulator with angiogenic-related effects in BC cells. In addition, pentolame might represent an HRT alternative in patients with BC predisposition.

Molecular dynamics simulations of a multicellular model with cell-cell interactions and Hippo signaling pathway.

The transcriptional coactivator Yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) induces cell proliferation through nuclear localization at low cell density. Conversely, at extremely high cell density, the Hippo pathway, which regulates YAP/TAZ, is activated. This activation leads to the translocation of YAP/TAZ into the cytoplasm, resulting in cell cycle arrest. Various cancer cells have several times more YAP/TAZ than normal cells. However, it is not entirely clear whether this several-fold increase in YAP/TAZ alone is sufficient to overcome proliferation inhibition (contact inhibition) under high-density conditions, thereby allowing continuous proliferation. In this study, we construct a three-dimensional (3D) mathematical model of cell proliferation incorporating the Hippo-YAP/TAZ pathway. Herein, a significant innovation in our approach is the introduction of a novel modeling component that inputs cell density, which reflects cell dynamics, into the Hippo pathway and enables the simulation of cell proliferation as the output response. We assume such 3D model with cell-cell interactions by solving reaction and molecular dynamics (MD) equations by applying adhesion and repulsive forces that act between cells and frictional forces acting on each cell. We assume Lennard-Jones (12-6) potential with a softcore character so that each cell secures its exclusive domain. We set cell cycles composed of mitotic and cell growth phases in which cells divide and grow under the influence of cell kinetics. We perform mathematical simulations at various YAP/TAZ levels to investigate the extent of YAP/TAZ increase required for sustained proliferation at high density. The results show that a twofold increase in YAP/TAZ levels of cancer cells was sufficient to evade cell cycle arrest compared to normal cells, enabling cells to continue proliferating even under high-density conditions. Finally, this mathematical model, which incorporates cell-cell interactions and the Hippo-YAP/TAZ pathway, may be applicable for evaluating cancer malignancy based on YAP/TAZ levels, developing drugs to suppress the abnormal proliferation of cancer cells, and determining appropriate drug dosages. The source codes are freely available.

Pim1 is Critical in T-cell-independent B-cell Response and MAPK Activation in B Cells

The Pim family consists of three members that encode a distinct class of highly conserved serine/threonine kinases. In this study, we generated and examined mice with hematopoiesis-specific deletion of Pim1 and bone marrow (BM) chimeric mice with B-cell-specific targeted deletion of Pim1. Pim1 was expressed at all stages of B-cell development and hematopoietic-specific deletion of Pim1 altered B-cell development in BM, spleen and peritoneal. However, Pim1 deficiency did not affect T-cell development. Studies of BM chimeric mice showed that Pim1 is required in a cell-intrinsic manner to maintain normal B-cell development. Pim1 deficiency led to significant changes in B cell antibody responses. Additionally, Pim1 deficiency resulted in reduced B cell receptor (BCR)-induced cell proliferation and cell cycle progression. Examination of the various BCR-activated signaling pathways in Pim1-deficient B cells reveals defective activation of mitogen-activated protein kinases (MAPKs), which are known to regulate genes involved in cell proliferation and survival. qRT-PCR analysis of BCR-engaged B cells from Pim1-deficient B cells revealed reduced expression of cyclin-dependent kinase (CDK) and cyclin genes, including CDK2, CCNB1 and CCNE1. In conclusion, Pim1 plays a crucial role in B-cell development and B cell activation.

PEDF upregulated in Ngfr-positive cells suppresses proliferation of pulmonary artery smooth muscle cells

Abstract Background Pulmonary arterial hypertension (PAH) is a disease with poor prognosis that causes right heart failure due to progressive pulmonary artery remodeling. Although existing pulmonary vasodilators contribute to pulmonary artery reverse remodeling by reducing share stress, the development of therapeutic agents that directly target pulmonary vascular remodeling is desired. Nerve growth factor receptor (Ngfr) is involved in the inflammatory reaction and repair process of damaged tissues. We have previously reported that Ngfr-positive cells are increased in the peripheral blood (PB) of PAH patients and are associated with disease progression. We also found that Ngfr inhibited the pathogenetic progression of pulmonary hypertension in a model of hypoxia-induced pulmonary hypertension. However, it remains unclear how Ngfr positive cells are involved in the pathology of PAH. Purpose In this study, we investigate how Ngfr-positive cells affect the pathogenesis of PAH. Methods & Results To evaluate the localization of Ngfr-positive cells in lung tissue, WT mice (C57BL/6) transplanted with bone marrow (BM) of GFP-Tg mice were kept under hypoxia for 3 weeks to create hypoxia-induced pulmonary hypertension (PH) model. Immunostaining of lung tissue sections indicated that double positive cells (Ngfr+GFP+) were present in the interstitial tissue around the small pulmonary artery. To examine the cellular characteristics of Ngfr-positive cells, RNA sequencing of Ngfr-positive and Ngfr-negative cells in PB was performed. Significantly 78 genes were upregulated in Ngfr-positive cells, including 11 secreted proteins. Among these, we focused on pigment epithelium-derived factor (PEDF), a secreted protein involved in angiogenesis. PEDF mRNA expression was decreased in the lung of Ngfr-KO mice compared to WT mice. We next examined the effect of PEDF on pulmonary artery smooth muscle cells (PASMCs). Platelet-derived growth factor (PDGF)-induced cell proliferation of PASMC was inhibited by PEDF stimulation. Furthermore, PEDF stimulation significantly inhibited PDGF-induced mRNA expressions of TNF and MMP9 in PASMCs. Conclusion In this study, we show that PEDF expression is upregulated in Ngfr-positive cells and that PEDF inhibits PDGF-induced hPASMC proliferation, suggesting that NGFR-positive cells may suppress pulmonary vascular remodeling through PEDF-mediated paracrine effects. PEDF might be a new therapeutic target for PH.

Sericin coats of silk fibres, a degumming waste or future material?

Silk is a fibrous biopolymer with a recorded history in the textile industries for centuries. This fibre is constituted of two different proteins: fibroin and sericin, of which the latter accounting for approximately 20–30 % of the silk mass. Silk sericin (SSER) was previously considered as a waste by-product in silk fibroin extraction. SSER has recently garnered significant scientific interest due to its extensive biological and pharmacological properties. These include antioxidant effects, biocompatibility, low immunogenicity, controlled biodegradability, and the ability to induce cell proliferation. This review covers studies about various aspects of this emerging material, namely, its general morphology, specific structure, molecular weight, features of different layers, and gene sequences. The impact of different extraction methods and the application of extracted SSER based on molecular weight are discussed. Additionally, the characteristic functional groups in the amino acids of sericin facilitate its applications in regenerative medicine, wound healing, drug delivery, textile, environment, and energy, in various forms like hydrogels, films, scaffolds, and conduits. SSER-based materials offer great potentials for multi-functional applications in the upcoming decades, showcasing adaptability for various functional uses and promising future technological advancements.

The TSH Receptor Antibody Reactome Contributes to Retro-Orbital Inflammation.

The thyroid eye disease (TED) of Graves disease is associated with high titers of stimulating TSH receptor antibodies, retro-orbital inflammation, fibroblast release of cytokines and chemokines, and adipogenesis, which in turn leads to proptosis, muscle fibrosis, and dysfunction. Part of this scenario is the induction of fibroblast proliferation and autophagy secondary to synergism between the TSH receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R). While TED is well associated with thyroid-stimulating antibodies to the TSHR, which is also well expressed on fibroblasts, in fact the TSHR reactome has a variety of TSHR antibodies with varying biological activity. Therefore, we have now evaluated the possible role of neutral TSHR antibodies (N-TSHR-mAbs), directed at the hinge region of the TSHR, which do not induce cell proliferation but are known to have effects on multiple proteins in thyroid cells including stress-related signaling molecules. We examined the consequences of an N-TSHR-mAb acting on TSHR-expressing fibroblasts and found marked cell stress, which initiated signaling pathways involving inflammasome activation. This response ended in widespread cell death by pyroptosis through activation of caspase 8 and gasdermin D. Hence, not only can stimulating TSHR autoantibodies influence TED inflammation but the N-TSHR antibodies, representing more of the reactome, may also exaggerate the retro-orbital inflammatory response seen in TED.

WS6 and 5-iodotubercidin small molecules and growth factors; TGF, HGF, and EGF synergistically enhance proliferation of β-like human induced pluripotent stem cells (iPSCs)

ObjectivesIt has been shown that growth factors and small molecules play an essential role in the proliferation of β cells and insulin production. In this study, we investigated the effects of small molecules (WS6 and 5-iodotubercidin) and growth factors (TGFβ, HGF, and EGF) on the proliferation of β-like human ipSCs.MethodsiPSCs derived β cells were treated with small molecules and growth factors. Cytotoxic activity of small molecules and growth factors was determined using MTT assay. Insulin gene expression and secretion were measured by qPCR and ELISA, respectively. The protein expression of insulin was evaluated by western blot as well.ResultsSimltananeous addition of WS6 and Harmine into the culture media increased insulin gene expression compared to treatment by each molecule alone (p < 0.05). It was found that the simultaneous recruitment of EGH, HGF, and TGF-β increased insulin expression compared to treatment by each molecule alone (p < 0.05). Results showed that EGF, HGF, TGF-β growth factors increased insulin gene expression, eventually leading to insulin secretion from β cells (p < 0.05).ConclusionsGrowth factors and small molecules synergistically enhanced the proliferation of β cells and insulin production.

Development and Biocompatibility Assessment of Decellularized Porcine Uterine Extracellular Matrix-Derived Grafts.

Biomaterials derived from biological matrices have been widely investigated due to their great therapeutic potential in regenerative medicine, since they are able to induce cell proliferation, tissue remodeling, and angiogenesis in situ. In this context, highly vascularized and proliferative tissues, such as the uterine wall, present an interesting source to produce acellular matrices that can be used as bioactive materials to induce tissue regeneration. Therefore, this study aimed to establish an optimized protocol to generate decellularized uterine scaffolds (dUT), characterizing their structural, compositional, and biomechanical properties. In addition, in vitro performance and invivo biocompatibility were also evaluated to verify their potential applications for tissue repair. Results showed that the protocol was efficient to promote cell removal, and dUT general structure and extracellular matrix composition remained preserved compared with native tissue. In addition, the scaffolds were cytocompatible, allowing cell growth and survival. In terms of biocompatibility, the matrices did not induce any signs of immune rejection invivo in a model of subcutaneous implantation in immunocompetent rats, demonstrating an indication of tissue integration after 30 days of implantation. In summary, these findings suggest that dUT scaffolds could be explored as a biomaterial for regenerative purposes, which is beyond the studies in the reproductive field.

Grifola frondosa extract as a fetal bovine serum supplement for the culture of bovine muscle satellite cells under low serum conditions

Expensive fetal bovine serum (FBS) is a major obstacle to the production of cultivated meat. However, because FBS substitutes do not sufficiently induce cell proliferation, a good alternative is to reduce the amount of FBS and use ingestible additives to promote cell proliferation. In this study, Grifola frondosa extract (GFE) was used to investigate its potential as an additive to promote myogenesis of bovine muscle satellite cells from Hanwoo cattle under low serum conditions (10 % FBS). GFE treated with 10 % FBS only during the proliferation period not only increased cell proliferation and related biomarkers in a concentration-dependent manner (0.78–12.5 μg/mL), but also increased cell differentiation. Additionally, differentiation was promoted when cells were with GFE treated only during the differentiation period. Especially GFE at 12.5 µg/mL induced significantly higher proliferation and differentiation rates than 20 % FBS medium. In particular, compared to treatment alone in the proliferation or differentiation periods, GFE treatment in both periods contributed to an increase in the differentiation rate and significantly enhanced total protein production. The integration of GFE into cultivated meat production presents a promising approach to reducing FBS dependence, lowering costs, and enhancing scalability, aligning with sustainability and consumer acceptance goals.

Expression of Semaphorin3E/PlexinD1 in human airway smooth muscle cells of patients with COPD.

Semaphorin3E (Sema3E) is a member of axon guidance proteins that have emerged recently as essential regulators of cell migration and proliferation. It binds to PlexinD1 with high affinity and is expressed in different cell types, including immune, cancer, and epithelial cells. Recent work in our lab has revealed a critical immunoregulatory role of Sema3E in experimental allergic asthma; however, its role in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the expression of Sema3E and its receptor, PlexinD1, in the airways of patients with COPD and whether Sema3E regulates airway smooth muscle (ASM) cell proliferation, a key feature of airway remodeling in COPD. We first demonstrate that human ASM cells obtained from COPD express Sema3E and PlexinD1 at both mRNA and protein levels. Also, bronchial sections from patients with COPD displayed immunoreactivity of Sema3E and its receptor PlexinD1, suggestive of functional contribution of Sema3E in airway remodeling. In contrast to ASM cells from healthy donors, Sema3E did not inhibit the platelet-derived growth factor (PDGF) induced cell proliferation in ASM cells of patients with COPD that were consistent with the binding of endogenous Sema3E to its receptors on the cell surface and the expression and release of p61KDa-Sema3E isoform. Our results support the Sema3E-PlexinD1 axis involvement in COPD airway smooth muscle remodeling.NEW & NOTEWORTHY Semaphorin3E (Sema3E), a protein guiding cell movement, is found in various cell types like neural, immune, cancer, and epithelial cells. This study examines Sema3E in chronic obstructive pulmonary disease (COPD) airways. In patients with COPD, airway smooth muscle cells express Sema3E and its receptor PlxD1. Unlike healthy cells, Sema3E does not hinder cell proliferation in COPD, indicating involvement in airway remodeling. These findings highlight the Sema3E-PlxD1 axis in COPD airway changes.

In Vitro Evaluation of Anti-Hemolytic and Cytotoxic Effects of Traditional Mexican Medicinal Plant Extracts on Human Erythrocytes and Cell Cultures.

Plant extracts of fifteen plants of ethnomedicinal use in Mexico were analyzed to provide scientific knowledge of their medicinal properties through the evaluation of different biological activities such as anti-hemolytic, antioxidant, and cytotoxic effects in normal cells. Therefore, methanolic extracts were obtained from each of the plants by the Soxhlet extraction. The hemolytic activity in human erythrocytes was evaluated, as was their potential to protect the erythrocyte membrane against the 2,2'-azobis (2-methylpropionamidine) dihydrochloride (AAPH) and 1,1-diphenyl-2-picryl hydrazyl (DPPH) radicals. Finally, the toxicity of the extracts in normal cell cultures of African green monkey kidney cells (Vero) and peripheral blood mononuclear cells (PBMC) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction method. Most of the extracts showed low hemolytic activity and high anti-hemolytic activity as well as high selectivity indices (SI) and antioxidant effects. Extracts of H. inuloides, J. dioica, and J. spicigera induced cell proliferation of the Vero cells. K. daigremontiana, A. adstringens, S. mexicanum, J. spicigera, L. tridentata, and M. tenuiflora extracts showed PBMC cell proliferation. In the present study, it was observed that the evaluated extracts did not present hemolytic activity, and some presented low toxicity when Vero and PBMC cell cultures were exposed. In conclusion, traditionally used plants possess beneficial health properties, and it is hoped that this study will serve as a basis for understanding the biological effects of traditionally used plants and may complement future studies.

Endoplasmic reticulum stress is involved in mycotoxin zearalenone induced inflammatory response, proliferation, and apoptosis in goat endometrial stromal cells

Zearalenone (ZEA) is an estrogen-like mycotoxin and is considered a secondary metabolite produced by Fusarium fungi, which are widely found in the surrounding environment. ZEA has been found to cause reproductive dysfunction in female and male animals, but the underlying mechanism remains unclear. Therefore, this study examined cell proliferation, cell apoptosis, autophagy protein expression, and some inflammatory cytokines such as IL-1β and IL-8 of goat endometrial stromal cells (ESCs) induced by different concentrations (0, 15, 30, 60, and 90 µM) of ZEA. The apoptosis rate was detected by flow cytometry. Western Blot and ELISA assay were used to identify the ER stress signaling pathway and some inflammatory cytokines. Our results revealed that ZEA induced cell proliferation and inhibited cell apoptosis at low and middle concentrations, while at high concentrations of ZEA, cell apoptosis was induced in ESCs. Additionally, ZEA induced the ER stress protein markers such as ATF6, IRE1α, EIF2α, and ATF4. LC3 as a marker of autophagy was up-regulated at all concentrations of ZEA. Moreover, IL-1β and IL-8 showed down-regulation at a low concentration of ZEA, but middle and high concentrations showed up-regulation. In the present study, Knockdown ERN1 can inhibit autophagy and the main markers of ER stress. These results suggest that the IRE1 pathway can reduce apoptosis protein markers, down activate IRE1, and unfolded protein response branches such as ATF6 and LC3 in ESCs. Additionally, IL-1β and IL-8 achieve up-regulation under knockdown IRE1, which can block ER stress markers.

Chios gum mastic enhance the proliferation and odontogenic differentiation of human dental pulp stem cells.

Dental pulp stem cells (DPSCs) are a type of adult stem cell present in the dental pulp tissue. They possess a higher proliferative capacity than bone marrow mesenchymal stem cells. Their ease of collection from patients makes them well-suited for tissue engineering applications, such as tooth and nerve regeneration. Chios gum mastic (CGM), a resin extracted from the stems and leaves of Pistacia lentiscus var. Chia, has garnered attention for its potential in tissue regeneration. This study aims to confirm alterations in cell proliferation rates and induce differentiation in human DPSCs (hDPSCs) through CGM treatment, a substance known for effectively promoting odontogenic differentiation. Administration of CGM to hDPSC cells was followed by an assessment of cell survival, proliferation, and odontogenic differentiation through protein and gene analysis. The study revealed that hDPSCs exhibited low sensitivity to CGM toxicity. CGM treatment induced cell proliferation by activating cell-cycle proteins through the Wnt/β-catenin pathway. Additionally, the study demonstrated that CGM enhances alkaline phosphatase activation by upregulating the expression of collagen type I, a representative matrix protein of dentin. This activation of markers associated with odontogenic and bone differentiation ultimately facilitated the mineralization of hDPSCs. This study concludes that CGM, as a natural substance, fosters the cell cycle and cell proliferation in hDPSCs. Furthermore, it triggers the transcription of odontogenic and osteogenic markers, thereby facilitating odontogenic differentiation.

HNRNPA2B1 induces cell proliferation and acts as biomarker in breast cancer.

Numerous studies have shown that m6A plays an important regulatory role in the development of tumors. HNRNPA2B1, one of the m6A RNA methylation reading proteins, has been proven to be elevated in human cancers. In this study, we aimed to identify the role of HNRNPA2B1 in breast cancer. HNRNPA2B1 expression was investigated via RT-qPCR and TCGA database in breast cancer. Then, the function of HNRNPA2B1 on cancer cell was measured by CCK8 assays, colony formation and scratch assays. In addition, HNRNPA2B1 expression in BRCA was explored via the Wilcoxon signed-rank test, KruskalWallis test and logistic regression. The association with HNRNPA2B1 expression and survival were considered by KaplanMeier and Cox regression analyses. The biological function of HNRNPA2B1 was analyzed via gene set enrichment analysis (GSEA) and the cluster Profiler R software package. We found that HNRNPA2B1 was highly expressed and induced cell proliferation and migration in breast cancer. Moreover, we observed HNRNPA2B1 induced tumor growth in vivo. In addition, we also found HNRNPA2B1 expression was associated with characteristics and prognosis in breast cancer patients. Our findings suggested that HNRNPA2B1 promoted tumor growth and could function as a new potential molecular marker in breast cancer.

Vitamin D3 Upregulated Protein 1 Deficiency Promotes Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Carcinogenesis in Mice.

VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development in mice. Wild-type (WT) and VDUP1 KO mice were used to investigate the role of VDUP1 in the development of azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced CAC. VDUP1 levels significantly decreased in the colonic tumor and adjacent nontumoral tissues of WT mice after AOM/DSS treatment. Moreover, AOM/DSS-treated VDUP1 KO mice exhibited a worse survival rate, disease activity index, and tumor burden than WT mice. VDUP1 deficiency significantly induced cell proliferation and anti-apoptosis in tumor tissues of VDUP1 KO mice compared to WT littermates. Additionally, mRNA levels of interleukin-6 and tumor necrosis factor-alpha and active forms of signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 were significantly increased in the tumor tissues of VDUP1 KO mice. Overall, this study demonstrated that the loss of VDUP1 promoted AOM/DSS-induced colon tumorigenesis in mice, highlighting the potential of VDUP1-targeting strategies for colon cancer prevention and treatment.

5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase promotes pulmonary arterial smooth muscle cell proliferation via the Ras signaling pathway.

Pulmonary arterial hypertension (PAH) is a debilitating vascular disorder characterized by abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and collagen synthesis, contributing to vascular remodeling and elevated pulmonary vascular resistance. This study investigated the critical role of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) in cell proliferation and collagen synthesis in PASMCs in PAH. Here we show that ATIC levels are significantly increased in the lungs of monocrotaline (MCT)-induced PAH rat model, hypoxia-induced PAH mouse model, and platelet-derived growth factor (PDGF)-stimulated PASMCs. Inhibition of ATIC attenuated PDGF-induced cell proliferation and collagen I synthesis in PASMCs. Conversely, overexpression or knockdown of ATIC causes a significant promotion or inhibition of Ras and ERK activation, cell proliferation, and collagen synthesis in PASMCs. Moreover, ATIC deficiency attenuated Ras activation in the lungs of hypoxia-induced PAH mice. Furthermore, Ras inhibition attenuates ATIC overexpression- and PDGF-induced collagen synthesis and PASMC proliferation. Notably, we identified that transcription factors MYC, early growth response protein 1 (EGR1), and specificity protein 1 (SP1) directly binds to promoters of Atic gene and regulate ATIC expression. These results provide the first evidence that ATIC promotes PASMC proliferation in pulmonary vascular remodeling through the Ras signaling pathway.NEW & NOTEWORTHY Our findings highlight the important role of ATIC in the PASMC proliferation of pulmonary vascular remodeling through its modulation of the Ras signaling pathway and its regulation by transcription factors MYC, EGR1, and SP1. ATIC's modulation of Ras signal pathway represents a novel mechanism contributing to PAH development.

Discovery of fibroblast growth factor 2-derived peptides for enhancing mice skeletal muscle satellite cell proliferation.

Skeletal muscle satellite cells (SCs) are essential for muscle regeneration. Their proliferation and differentiation are influenced by fibroblast growth factor (FGF)-2. In this study, we screened for FGF-2-derived peptides that promote SC proliferation. Utilizing photocleavable peptide array technology, a library of 7-residue peptides was synthesized, and its effect on SC proliferation was examined using a mixture of five peptides. The results showed that peptides 1-5 (136%), 21-25 (136%), 26-30 (141%), 31-35 (159%), 71-75 (135%), 76-80 (144%), and 126-130 (137%) significantly increased SC proliferation. Further experiments revealed that peptide 33, CKNGGFF, enhanced SC proliferation. Furthermore, its extended form, peptide 33-13, CKNGGFFLRIHPD, promoted SC proliferation and increased the percentage of Pax7-positive cells, indicating that SCs were maintained in an undifferentiated state. The addition of FGF-2 and peptide 33-13 further induced cell proliferation but did not increase the percentage of Pax7-positive cells. A proliferation assay using an FGF receptor (FGFR) inhibitor suggested that peptide 33-13 acts through the FGFR-mediated and other pathways. Although further research is necessary to explore the mechanisms of action of these peptides and their potential for in vivo and in vitro use, the high sequence conservation of peptides 33 and 33-13 in FGF-2 across multiple species suggests their broad application prospects in biomedical engineering and biotechnology.

Colorectal cancer and inflammatory bowel diseases share common salivary proteomic pathways

Inflammatory bowels diseases (IBD) are high risk conditions for colorectal cancer (CRC). The discovery of IBD and CRC noninvasive protein/peptide biomarkers using saliva and feces was the aim of this study involving 20 controls, 25 IBD (12 Crohn’s Disease-CD), 37 CRC. By untargeted proteomic (LTQ-Orbitrap/MS), a total of 152 proteins were identified in saliva. Absent in controls, 73 proteins were present in both IBD and CRC, being mainly related to cell-adhesion, cadherin-binding and enzyme activity regulation (g-Profiler). Among the remaining 79 proteins, 14 were highly expressed in CD and 11 in CRC. These proteins clustered in DNA replication/expression and innate/adaptive immunity. In stool, endogenous peptides from 30 different proteins were identified, two being salivary and CD-associated: Basic Proline-rich Protein 1 (PRBs) and Acidic Proline-rich Phosphoprotein. Biological effects of the PRBs-related peptides GQ-15 and GG-17 found in CD stool were evaluated using CRC cell lines. These peptides induced cell proliferation and activated Erk1/2, Akt and p38 pathways. In conclusion, the salivary proteome unveiled DNA stability and immunity clusters shared between IBD and CRC. Salivary PRB-derived peptides, enriched in CD stool, stimulate CRC cell proliferation and the pro-oncogenic RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways suggesting a potential involvement of PRBs in IBD and cancer pathogenesis.

Interleukin-22 Promotes Cell Proliferation to Combat Virus Infection in Human Intestinal Epithelial Cells.

Interferon lambdas (IFN-λs) are crucial to control virus infections at mucosal surfaces. Interleukin-22 (IL-22) was reported to help IFN-λ control rotavirus infection in the intestinal epithelium of mice either by aiding in the induction of interferon-stimulated genes (ISGs) or by increasing cell proliferation thereby clearing virally infected cells. We investigated whether IL-22 and IFN-λs exhibit similar synergistic effects in human intestinal epithelial cells (IECs) models. Our results showed that co-treatment of IL-22 and IFN-λ induced more phosphorylation of STAT1 than either cytokine used alone. However, this increased STAT1 activation did not translate to increased ISGs production or antiviral protection. Transcriptomics analysis revealed that despite sharing a common subunit (IL-10Rb) within their heterodimeric receptors and activating similar STATs, the signaling generated by IL-22 and IFN-λs is independent, with IFN-λ signaling inducing ISGs and IL-22 signaling inducing cell proliferation genes. Using human intestinal organoids, we confirmed that IL-22 increased the size of the organoids through increased cell proliferation and expression of the stem cell marker (OLFM4). These findings suggest that in human intestinal cells, IFN-λs and IL-22 act independently to clear virus infections. IFN-λs induce ISGs to control virus replication and spread, whereas IL-22 increases cell proliferation to eliminate infected cells and repair the damage epithelium. Although these two cytokines do not act synergistically, each plays a key function in the protection of human IECs.