Regulation Of Cell Proliferation Research Articles

Research progress on anti-tumor mechanism of TAOK kinases

Thousand and one amino-acid protein kinases(TAOKs), as a key member of the mitogen-activated protein kinase (MAPK) cascade, has recently attracted widespread attention in the field of anti-cancer research. There are three members of this subfamily: TAOK1, TAOK2, and TAOK3. Studies have shown that members of the TAOK family participate in regulating cell proliferation, apoptosis, migration, and invasion through various pathways, thereby playing an important role in tumorigenesis and progression. This review summarizes the functions of TAOK kinases in tumor cell signal transduction, cell cycle regulation, and the tumor microenvironment, with a particular emphasis on its potential as a target for anti-cancer drugs. Future research will further elucidate the specific mechanisms of action of TAOK kinase in different types of tumors and explore its clinical application prospects.

Causal relationship between circulating glutamine levels and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with a median survival of less than 5 years. In recent years, glutamine has been reported to be involved in the regulation of collagen deposition and cell proliferation in fibroblasts, thereby influencing the progression of IPF. However, the relationships between glutamine and the incidence, progression, and treatment response of IPF remain unclear. Our study aimed to investigate the relationship between circulating glutamine levels and IPF, as well as its potential as a therapeutic target.MethodsWe performed a comprehensive Mendelian Randomization (MR) analysis using the most recent genome-wide association study summary-level data. A total of 32 single nucleotide polymorphisms significantly correlated to glutamine levels were identified as instrumental variables. Eight MR analysis methods, including inverse variance weighted, MR-Egger, weighted median, weighted mode, constrained maximum likelihood, contamination mixture, robust adjusted profile score, and debiased inverse-variance weighted method, were used to assess the relationship between glutamine levels with IPF.ResultsThe inverse variance weighted analysis revealed a significant inverse correlation between glutamine levels and IPF risk (Odds Ratio = 0.750; 95% Confidence Interval : 0.592–0.951; P = 0.017). Sensitivity analyses, including MR-Egger regression and MR-PRESSO global test, confirmed the robustness of our findings, with no evidence of horizontal pleiotropy or heterogeneity.ConclusionOur study provides novel evidence for a causal relationship between lower circulating glutamine levels and increased risk of IPF. This finding may contribute to the early identification of high-risk individuals for IPF, disease monitoring, and development of targeted therapeutic strategies.

Roles and action mechanisms of NRIP1 in pre-eclampsia.

Pre-eclampsia (PE) is characterized by the onset of hypertension and proteinuria during pregnancy. Here, we aimed to explore the functions of nuclear receptor-interacting protein 1 (NRIP1) in PE mice and human placental JEG-3 cells. We evaluated its effects on JEG-3 cell proliferation, apoptosis, invasion, and inflammatory response and regulation of Wnt/β-catenin pathway. NRIP1 levels in human serum and placental tissues, JEG-3 cells, and mouse models were assessed via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. JEG-3 cell growth, apoptosis, migration, and invasion were evaluated via 5-ethynyl-2'-deoxyuridine, flow cytometry, and transwell assays. Levels of the inflammatory factors, matrix metalloproteinase (MMP)-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, were determined via enzyme-linked immunosorbent assay. Wnt/β-catenin pathway was assessed via western blotting and qRT-PCR. Systolic blood pressure and proteinuria were measured using the non-invasive tail cuff method and Coomassie brilliant blue assay, respectively. TdT-mediated dUTP nick-end labeling assay was used to assess cell apoptosis in the placental tissues of PE mice. NRIP1 levels were upregulated in the serum and placental tissues of patients with PE. In vitro experiments revealed that NRIP1-small interfering RNA (siRNA) increased the cell viability, migration, and invasion and reduced the cell apoptosis compared to the control siRNA. Moreover, NRIP1-siRNA activated the Wnt/β-catenin signaling pathway, as indicated by the increased Wnt3a, β-catenin, p-glycogen synthase kinase-3β, c-Myc, and cyclin D1 levels. Levels of the inflammatory factors, IL-6, TNF-α, and MMP-2, were decreased in the NRIP1-siRNA-treated group. Notably, NRIP1 downregulation improved the PE-like symptoms, inhibited the inflammatory responses, and reduced apoptosis in PE mice. This study revealed the crucial roles of NRIP1 in PE. Our findings revealed that NRIP1 downregulation relieved PE symptoms by inhibiting cell proliferation, migration, and invasion via the Wnt/β-catenin pathway, thus providing a novel candidate for PE treatment.

Photoneuroendocrine, circadian and seasonal systems: from photoneuroendocrinology to circadian biology and medicine.

This contribution highlights the scientific development of two intertwined disciplines, photoneuroendocrinology and circadian biology. Photoneuroendocrinology has focused on nonvisual photoreceptors that translate light stimuli into neuroendocrine signals and serve rhythm entrainment. Nonvisual photoreceptors first described in the pineal complex and brain of nonmammalian species are luminance detectors. In the pineal, they control the formation of melatonin, the highly conserved hormone of darkness which is synthesized night by night. Pinealocytes endowed with both photoreceptive and neuroendocrine capacities function as "photoneuroendocrine cells." In adult mammals, nonvisual photoreceptors controlling pineal melatonin biosynthesis and pupillary reflexes are absent from the pineal and brain and occur only in the inner layer of the retina. Encephalic photoreceptors regulate seasonal rhythms, such as the reproductive cycle. They are concentrated in circumventricular organs, the lateral septal organ and the paraventricular organ, and represent cerebrospinal fluid contacting neurons. Nonvisual photoreceptors employ different photopigments such as melanopsin, pinopsin, parapinopsin, neuropsin, and vertebrate ancient opsin. After identification of clock genes and molecular clockwork, circadian biology became cutting-edge research with a focus on rhythm generation. Molecular clockworks tick in every nucleated cell and, as shown in mammals, they drive the expression of more than 3000 genes and are of overall importance for regulation of cell proliferation and metabolism. The mammalian circadian system is hierarchically organized; the central rhythm generator is located in the suprachiasmatic nuclei which entrain peripheral circadian oscillators via multiple neuronal and neuroendocrine pathways. Disrupted molecular clockworks may cause various diseases, and investigations of this interplay will establish a new discipline: circadian medicine.

Phosphatase LHPP confers prostate cancer ferroptosis activation by modulating the AKT-SKP2-ACSL4 pathway

LHPP, a novel, recognized tumor suppressor, exerts a critical influence on the regulation of tumor cell proliferation and survival by modulating various signaling pathways with its phosphatase activity. Here, we unveil a robust correlation between reduced LHPP expression and adverse prognosis in prostate cancer. We demonstrate that LHPP interacts with AKT, thereby dampening AKT phosphorylation and subsequently inhibiting ACSL4 phosphorylation at the T624 site. This interaction impedes phosphorylation-dependent ubiquitination, thwarting SKP2 from recognizing and binding to ACSL4 at the K621 site. As a result, ACSL4 is spared from lysosomal degradation, leading to its accumulation and the promotion of lipid peroxidation, and ferroptosis. Moreover, our findings reveal that Panobinostat, a potent histone-deacetylase inhibitor, intricately regulates LHPP expression at multiple levels through the inhibition of HDAC3. This complex modulation enhances the ferroptosis pathway, offering a novel mechanism for curtailing the growth of prostate tumors and highlighting its significant translational potential for clinical application.

MiR-9-5p regulates Sirt1 involved in testicular development and spermatogenesis in mouse

Testicular development and spermatogenesis are critical for male reproduction, with histone (de)acetylation playing a key role in chromatin remodeling within germ cells. Sirt1, a key histone deacetylase, is implicated in chromatin remodeling, but its expression pattern and specific role in testicular development and spermatogenesis need further study. This study comprehensively analyzed Sirt1 expression in adult and juvenile mouse testicular tissues and across various male germ cells, utilizing RT-qPCR, Western blot, immunofluorescence, and cell transfection. GO and KEGG enrichment analyses were performed to elucidate the biological functions and pathways associated with Sirt1 and its related genes. Multiple miRNA databases were utilized to predict miRNAs targeting Sirt1, and their expression levels were validated using RT-qPCR. Lentiviral transfection was used to knockdown candidate miRNAs to assess their functional roles. The results revealed a significant downregulation of Sirt1 expression in adult mouse testicular tissues compared to juvenile tissues, with pronounced variation across diverse male germ cells. Sirt1 was highly expressed in spermatogonia and mature sperm, but comparatively lower in spermatocytes and spermatids. GO and KEGG enrichment analyses highlighted Sirt1's role in key biological processes, including chromatin organization, regulation of cell proliferation, and energy homeostasis, as well as its association with signaling pathways like cellular senescence, the FoxO signaling pathway, and the AMPK signaling pathway. Bioinformatic analysis and subsequent RT-qPCR validation identified miR-9-5p as a miRNA targeting Sirt1. The expression of miR-9-5p was significantly higher in adult mouse testicular tissues compared to juvenile tissues, inversely correlating with Sirt1 levels. Moreover, the knockdown of miR-9-5p led to a notable increase in Sirt1 mRNA and protein expression. In conclusion, Sirt1 is a key player in mouse testicular development and spermatogenesis. The discovery that miR-9-5p negatively regulates Sirt1 suggests a critical regulatory axis that may govern these processes, providing novel insights into male fertility and potential targets for therapeutic intervention.

The Atypical Dual Specificity Phosphatase DUSP15 Regulates Jak1-Mediated STAT3 Activation.

The signal transducer and activator of transcription 3 (STAT3) protein is a key regulator of cell differentiation, proliferation, and survival in hematopoiesis, immune responses, and other biological systems. STAT3 transcriptional activity is strictly regulated through various mechanisms, such as phosphorylation and dephosphorylation. In this study, we attempted to identify novel phosphatases which regulate STAT3 activity in response to cytokine stimulations. To this end, leukemia inhibitory factor (LIF)/STAT3 dependent phosphatase induction was evaluated in the mouse hepatoma cell line Hepa1-6. After LIF stimulation, the expression of several atypical dual specific phosphatases (aDUSPs) was upregulated in Hepa1-6 cells. Among the LIF-induced aDUSPs, we focused on DUSP15 and clarified its functions in LIF/STAT3 signaling using RNA interference. DUSP15 knockdown decreased LIF-induced Socs3 mRNA expression and STAT3 translocation. Furthermore, loss of DUSP15 reduced the phosphorylation of STAT3 at Tyr705 and Janus family tyrosine kinase 1 (Jak1) at Tyr1034/1035 in response to LIF. The interaction between Jak1 and DUSP15 was observed in LIF-stimulated Hepa1-6 cells. We also demonstrated the suppression of granulocyte colony-stimulating factor (G-CSF)-mediated gp130/STAT3-dependent cell growth of Ba/F-G133 cells via DUSP15 knockdown. Therefore, DUSP15 functions as a positive feedback regulator in the Jak1/STAT3 signaling cascade.

Muscle Atrophy and mRNA-miRNA Network Analysis of Vascular Endothelial Growth Factor (VEGF) in a Mouse Model of Denervation-Induced Disuse.

Skeletal muscle atrophy is frequently caused by the disuse of muscles.It impacts quality of life, especially in aging populations and those with chronic diseases. Understanding the molecular mechanisms underlying muscle atrophy is crucial for developing effective therapies. To investigate the roles of vascular endothelial growth factor (VEGF) and various microRNAs (miRNAs) in muscle atrophy using a mouse model of denervation (DEN)-induced disuse, and to elucidate their interactions and regulatory functions through comprehensive network analysis. The right sciatic nerve of C57BL/6J mice (n=6) was excised to simulate DEN, with the left serving as a sham surgery control (Sham). Following a two-week period, wet muscle weight was measured. Total RNA was extracted from the tibialis anterior muscle for microarray analysis. Significant expression changes were analyzed via Kyoto Encyclopedia of Genes and Genomes (KEGG)pathway analysis and miRNet for miRNAs. Denervated limbs showed a significant reduction in muscle weight. Over 1,000 genes displayed increased expression, while 527 showed reductions to less than half of control levels. VEGF, along with specific miRNAs such as miR-106a-5p, miR-mir20a-5p, mir93-5p and mir17-5p, occupied central regulatory nodes within the gene network. Functional analysis revealed that these molecules are involved in key biological processes including regulation of cell migration, vasculature development, and regulation of endothelial cell proliferation. The increased miRNAswere subjected to further network analysis that revealed significant regulatory interactions with target mRNAs. VEGF and miRNAs play crucial roles in the progression of skeletal muscle atrophy, offering potential targets for therapeutic interventions aimed at reducing atrophy and enhancing muscle regeneration.

Osteogenic potentials in canine mesenchymal stem cells: unraveling the efficacy of polycaprolactone/hydroxyapatite scaffolds in veterinary bone regeneration

BackgroundThe integration of stem cells, signaling molecules, and biomaterial scaffolds is fundamental for the successful engineering of functional bone tissue. Currently, the development of composite scaffolds has emerged as an attractive approach to meet the criteria of ideal scaffolds utilized in bone tissue engineering (BTE) for facilitating bone regeneration in bone defects. Recently, the incorporation of polycaprolactone (PCL) with hydroxyapatite (HA) has been developed as one of the suitable substitutes for BTE applications owing to their promising osteogenic properties. In this study, a three-dimensional (3D) scaffold composed of PCL integrated with HA (PCL/HA) was prepared and assessed for its ability to support osteogenesis in vitro. Furthermore, this scaffold was evaluated explicitly for its efficacy in promoting the proliferation and osteogenic differentiation of canine bone marrow-derived mesenchymal stem cells (cBM-MSCs) to fill the knowledge gap regarding the use of composite scaffolds for BTE in the veterinary orthopedics field.ResultsOur findings indicate that the PCL/HA scaffolds substantially supported the proliferation of cBM-MSCs. Notably, the group subjected to osteogenic induction exhibited a markedly upregulated expression of the osteogenic gene osterix (OSX) compared to the control group. Additionally, the construction of 3D scaffold constructs with differentiated cells and an extracellular matrix (ECM) was successfully imaged using scanning electron microscopy. Elemental analysis using a scanning electron microscope coupled with energy-dispersive X-ray spectroscopy confirmed that these constructs possessed the mineral content of bone-like compositions, particularly the presence of calcium and phosphorus.ConclusionsThis research highlights the synergistic potential of PCL/HA scaffolds in concert with cBM-MSCs, presenting a multidisciplinary approach to scaffold fabrication that effectively regulates cell proliferation and osteogenic differentiation. Future in vivo studies focusing on the repair and regeneration of bone defects are warranted to further explore the regenerative capacity of these constructs, with the ultimate goal of assessing their potential in veterinary clinical applications.

Targeting RSK2 in Cancer Therapy: A Review of Natural Products.

P90 ribosomal S6 kinase 2 (RSK2) is an important member of the RSK family, functioning as a kinase enzyme that targets serine and threonine residues and contributes to regulating cell growth. RSK2 comprises two major functional domains: the N-terminal kinase domain (NTKD) and the C-terminal kinase domain (CTKD). RSK2 is situated at the lower end of the Mitogen-activated protein kinases (MAPK) signaling pathway and is phosphorylated by the direct regulation of Extracellular signal-regulating kinase (ERK). RSK2 has been found to play a pivotal role in regulating cell proliferation, apoptosis, metastasis, and invasion in various cancer cells, including breast cancer and melanoma. Consequently, RSK2 has emerged as a potential target for the development of anti-cancer drugs. Presently, several inhibitors are undergoing clinical trials, such as SL0101. Current inhibitors of RSK2 mainly bind to its NTK or CTK domains and inhibit their activity. Natural products serve as an important resource for drug development and screening and with the potential to identify RSK2 inhibitors. This article discusses how RSK2 influences tumor cell proliferation, prevents apoptosis, arrests the cell cycle process, and promotes cancer metastasis through its regulation of downstream pathways or interaction with other biological molecules. Additionally, the paper also covers recent research progress on RSK2 inhibitors and the mechanisms of action of natural RSK2 inhibitors on tumors. This review emphasizes the significance of RSK2 as a potential therapeutic target in cancer and offers a theoretical basis for the clinical application of RSK2 inhibitors.

The G protein-coupled receptor ADGRG6 maintains mouse growth plate homeostasis through IHH signaling.

The cartilage growth plate is essential for maintaining skeletal growth; however, the mechanisms governing postnatal growth plate homeostasis are still poorly understood. Using approaches of molecular mouse genetics and spatial transcriptomics applied to formalin-fixed, paraffin-embedded tissues, we show that ADGRG6/GPR126, a cartilage-enriched adhesion G protein-coupled receptor (GPCR), is essential for maintaining slow-cycling resting zone cells, appropriate chondrocyte proliferation and differentiation, and growth plate homeostasis in mice. Constitutive ablation of Adgrg6 in osteochondral progenitor cells with Col2a1Cre leads to a shortened resting zone, formation of cell clusters within the proliferative zone, and an elongated hypertrophic growth plate, marked by limited expression of parathyroid hormone-related protein (PTHrP) but increased Indian Hedgehog (IHH) signaling throughout the growth plate. Attenuation of smoothened-dependent hedgehog signaling restored the Adgrg6 deficiency-induced expansion of hypertrophic chondrocytes, confirming that IHH signaling can promote chondrocyte hypertrophy in a PTHrP-independent manner. In contrast, postnatal ablation of Adgrg6 in mature chondrocytes with AcanCreERT2, induced after the formation of the resting zone, does not affect PTHrP expression but causes an overall reduction of growth plate thickness marked by increased cell death specifically in the resting zone cells and a general reduction of chondrocyte proliferation and differentiation. Spatial transcriptomics reveals that ADGRG6 is essential for maintaining chondrocyte homeostasis by regulating osteogenic and catabolic genes in all the zones of the postnatal growth plates, potentially through positive regulation of SOX9 expression. Our findings elucidate the essential role of a cartilage-enriched adhesion GPCR in regulating cell proliferation and hypertrophic differentiation by regulation of PTHrP/IHH signaling, maintenance of slow-cycle resting zone chondrocytes, and safeguarding chondrocyte homeostasis in postnatal mouse growth plates.

RBM3 Inhibits the Cell Cycle of Cutaneous Squamous Cell Carcinoma through the PI3K/AKT Signaling Pathway.

RBM3 is a key RNA-binding protein that has been implicated in various cellular processes, including cell proliferation and cell cycle regulation. However, its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. We aimed to investigate the expression levels of RNA-binding motif protein 3 (RBM3) in patients with cSCC and evaluate its effect on cell ability in cSCC and its underlying regulatory mechanisms. The expression of RBM3 in cSCC tissues and A431 cells was determined via immunohistochemistry and western blotting. Plenti-CMV-RBM3- Puro was used to overexpress RBM3. The effect of RBM3 on the proliferation ability of cSCC cells was evaluated using MTT and colony formation assay. Cell apoptosis and cell cycle were determined using flow cytometry, while the protein expressions of BAX, NF-κB, BCL2, CASPASE 3, CYCLIN B, CYCLIN E, CDK1, phosphorylated (P)-CDK1, CDK2, P-CDK2, ERK, P-ERK, P-AMPK, AKT, P-AKT, MDM2, and P53 were assessed using western blotting. RBM3 expression was significantly downregulated in cSCC tissues and A431 cells. RBM3 overexpression significantly inhibited the cell proliferation and colony formation ability of A431. Notably, RNA-seq results showed that the differentially expressed genes associated with RBM3 were primarily involved in the regulation of the cell cycle, oocyte meiosis, and P53 signaling pathway, as well as the modulation of the MAPK, AMPK, Hippo, mTOR, PI3K/AKT, Wnt, FoxO, and NF-κB signaling pathways. Additionally, our findings demonstrated that overexpression of RBM3 inhibited cell proliferation and induced cell cycle arrest of cSCC through modulation of the PI3K/AKT signaling pathway. This study provides novel insights into the suppressive roles of RBM3 in cell proliferation and the cell cycle in cSCC and highlights its therapeutic potential for cSCC.

SHP2 ablation mitigates osteoarthritic cartilage degeneration by promoting chondrocyte anabolism through SOX9.

Articular cartilage phenotypic homeostasis is crucial for life-long joint function, but the underlying cellular and molecular mechanisms governing chondrocyte stability remain poorly understood. Here, we show that the protein tyrosine phosphatase SHP2 is differentially expressed in articular cartilage (AC) and growth plate cartilage (GPC) and that it negatively regulates cell proliferation and cartilage phenotypic program. Postnatal SHP2 deletion in Prg4+ AC chondrocytes increased articular cellularity and thickness, whereas SHP2 deletion in Acan+ pan-chondrocytes caused excessive GPC chondrocyte proliferation and led to joint malformation post-puberty. These observations were verified in mice and in cultured chondrocytes following treatment with the SHP2 PROTAC inhibitor SHP2D26. Further mechanistic studies indicated that SHP2 negatively regulates SOX9 stability and transcriptional activity by influencing SOX9 phosphorylation and promoting its proteasome degradation. In contrast to published work, SHP2 ablation in chondrocytes did not impact IL-1-evoked inflammation responses, and SHP2's negative regulation of SOX9 could be curtailed by genetic or chemical SHP2 inhibition, suggesting that manipulating SHP2 signaling has translational potential for diseases of cartilage dyshomeostasis.

DDHD2 is involved in the malignant progression of early luminal A breast cancer by changing cell membrane proteins and immune responses functionality

Abstract Background Luminal A breast cancer has the best prognosis of all malignant breast cancer types. In clinical practice, some patients with luminal A breast cancer present with small tumors (usually <20 mm) but with lymph node metastases or even distant organ metastasis. Owing to their insensitivity to chemotherapy and the lack of conclusive clinical evidence, there is a significant gap in research on luminal A breast cancer with high invasiveness. This study aimed to identify genes that drive the invasiveness of luminal A breast cancer and explore the underlying mechanisms. Methods In this study, we first utilized bioinformatics techniques to analyze differentially expressed mRNAs and enrich common functional pathways to identify the target gene DDHD domain containing 2 (DDHD2). We then evaluated the association between DDHD2 expression and patient prognosis, genetic material changes, and transcriptional, translational, and immune responses in luminal A breast cancer. We also conducted experiments at the molecular and cellular levels to validate these biochemical mechanisms. Results The expression of DDHD2 varied between patients with low-grade luminal A breast cancer with and without lymph node metastases. Our findings demonstrated that DDHD2 exerted carcinogenic effects through various pathways by altering cell adhesion and migration, regulating cell proliferation and apoptosis cycles, and suppressing immune responses. Moreover, a pathway through which DDHD2 inhibited immunity was preliminarily verified. Conclusions The results revealed a novel role for DDHD2 in promoting the malignant transformation and invasiveness of luminal A breast cancer. Considering its effects on the tumor microenvironment and tumor-infiltrating immune cells in the epithelial-mesenchymal transition, DDHD2 is proposed as a reliable direction for future immunotherapy and a potential target in luminal A breast cancer immune resistance.

HuR/miR-124-3p/VDR complex bridges lipid metabolism and tumor development in colorectal cancer.

Maintaining a balanced lipid status to prevent lipotoxicity is of paramount importance in various tumors, including colorectal cancer (CRC). HuR, an RNA-binding protein family member, exhibits high expression in many cancers possibly because it regulates cell proliferation, migration, invasion, and lipid metabolism. However, the role of HuR in the regulation of abnormal lipid metabolism in CRC remains unknown. We found that HuR promotes vitamin D receptor (VDR) expression to ensure lipid homeostasis by increasing Triglyceride (TG) and Total Cholesterol (TC) levels in CRC, thus confirming the direct binding of an overexpressed HuR to the CDS and 3'-UTR of Vdr, enhancing its expression. Concurrently, HuR can indirectly affect VDR expression by inhibiting miR-124-3p. HuR can suppress the expression of miR-124-3p, which binds to the 3'-UTR of Vdr, thereby reducing VDR expression. Additionally, a xenograft model demonstrated that targeting HuR inhibits VDR expression, blocking TG and TC formation, and hence mitigating CRC growth. Our findings suggest a regulatory relationship among HuR, miR-124-3p, and VDR in CRC. We propose that the HuR/miR-124-3p/VDR complex governs lipid homeostasis by impacting TG and TC formation in CRC, offering a potential therapeutic target for CRC prevention and treatment.

Deubiquitinase USP10 promotes osteosarcoma autophagy and progression through regulating GSK3β-ULK1 axis

BackgroundDeubiquitinating enzymes (DUBs) are pivotal in maintaining cell homeostasis by regulating substrate protein ubiquitination in both healthy and cancer cells. Ubiquitin-specific protease 10 (USP10) belongs to the DUB family. In this study, we investigated the clinical and pathological significance of USP10 and Unc-51-like autophagy activating kinase 1 (ULK1) in osteosarcoma (OS), as well as the mechanism of USP10 action in ULK1-mediated autophagy and disease progression.ResultsThe analysis of OS and adjacent normal tissues demonstrated that USP10 and ULK1 were significantly overexpressed in OS, and a positive association between their expression and malignant properties was observed. USP10 knockdown in OS cells reduced ULK1 mRNA and protein expression, whereas USP10 overexpression increased ULK1 mRNA and protein expression. In vitro experiments showed that USP10 induced autophagy, cell proliferation, and invasion by enhancing ULK1 expression in OS cell lines. Furthermore, we found that the regulation of ULK1-mediated autophagy, cell proliferation, and invasion in OS by USP10 was dependent on glycogen synthase kinase 3β (GSK3β) activity. Mechanistically, USP10 promoted ULK1 transcription by interacting with and stabilising GSK3β through deubiquitination, which, in turn, increased the activity of the ULK1 promoter, thereby accelerating OS progression. Using a xenograft mouse model, we showed that Spautin-1, a small-molecule inhibitor targeting USP10, significantly reduced OS development, with its anti-tumour activity significantly enhanced when combined with the chemotherapeutic agent cisplatin.ConclusionCollectively, we demonstrated that the USP10-GSK3β-ULK1 axis promoted autophagy, cell proliferation, and invasion in OS. The findings imply that targeting USP10 may offer a promising therapeutic avenue for treating OS.

Occupational exposure to arsenic and leukopenia risk: Toxicological alert.

Arsenic and its inorganic compounds affect numerous organs and systemic functions, such as the nervous and hematopoietic systems, liver, kidneys, and skin. Despite a large number of studies on arsenic toxicity, rare reports have investigated the leukopenia incidence in workers exposed to arsenic. In workplaces, the main source of workers' exposure is the contaminated air by the inorganic arsenic in mines, arsenic or copper smelter industries, and chemical factories. Erythropoiesis inhibition is one of the arsenic effects and it is related to regulatory factor GATA-1. This factor is necessary for the normal differentiation of early erythroid progenitors. JAK-STAT is an important intracellular signal transduction pathway responsible for the mediating normal functions of several cytokines related to cell proliferation and hematopoietic systems development and regulation. Arsenic inactivates JAK-STAT by inhibiting JAK tyrosine kinase and using the IFNγ pathway. The intravascular hemolysis starts after the absorption phase when arsenic binds to the globin of hemoglobin in erythrocytes and is transported into the body, which increases the oxidation of sulfhydryl groups in hemoglobin. So, this article intends to highlight the potential leukopenia risk via inhalation for workers exposed to arsenic and suggests a possible mechanism for this leukopenia through the JAK-signal transducer and activator of transcription (STAT) pathway inhibition.

Unraveling the molecular basis for effective regulation of integrin α5β1 for enhanced therapeutic interventions

Cell attachment to the extracellular matrix significantly impacts the integrity of tissues and human health. The integrin α5β1 is a heterodimer of α5 and β1 subunits and has been identified as a crucial modulator in several human carcinomas. Integrin α5β1 significantly regulates cell proliferation, angiogenesis, inflammation, tumor metastasis, and invasion. This regulatory role of integrin α5β1 in tumor metastasis makes it an appealing target for cancer therapy. The majority of the drugs targeting integrin α5β1 are limited only to clinical trials. In our study, we have performed 94287 compounds screening to determine potential drugs against α5β1 integrin. We have used ATN-161 as a reference and employed combined bioinformatic methodologies, including molecular modelling, virtual screening, MM-GBSA, cell-line cytotoxicity prediction, ADMET, Density Functional Theory (DFT), Non-covalent Interactions (NCI) and molecular simulation, to identify putative integrin α5β1 inhibitors. We found Taxifolin, PD133053, and Acebutolol that possess inhibitory activity against α5β1 integrin and could act as effective drug for the cancer treatment. Taxifolin, PD133053, and Acebutolol exhibited excellent binding to the druggable pocket of integrin α5β1, and also maintained a unique binding mechanism with extra hydrophobic contacts at molecular level. Overall, our study gives new pharmacological candidates that may act as a potential drug against integrin α5β1.

Comprehensive analysis of splicing factor SRs-related gene characteristics: predicting osteosarcoma prognosis and immune regulation status.

To investigate the impact of SRs-related genes on the overall survival and prognosis of osteosarcoma patients through bulk and single-cell RNA-seq transcriptome analysis. In this study, we constructed a prognosis model based on serine/arginine-rich splicing factors (SRs) and predicted the survival of osteosarcoma patients. By analyzing single-cell RNA sequencing data and applying AUCell enrichment analysis, we revealed oncogenic pathways of SRs in osteosarcoma immune cells. Additionally, we described the regulatory role of SRSF7 in pan-cancer. Lasso regression analysis identified 6 key SRs-related genes, and a prognosis prediction model was established. The upregulation of these pathways revealed that SRs promote tumor cell proliferation and survival by regulating related signaling pathways and help tumor cells evade host immune surveillance. Additionally, by grouping single-cell data using AUCell, we found significant differences in T cell expression between high and low-risk groups. The analysis results indicated that the regulatory activity of SRs is closely related to T cell function, particularly in regulating immune responses and promoting immune evasion. Furthermore, SRSF7 regulates cell proliferation and apoptosis. SRs-related genes play a critical regulatory role in osteosarcoma. T cells are key in regulating immune responses and promoting immune evasion through SRs genes. SRSF7 is a significant gene influencing the occurrence and development of osteosarcoma.

Gliomedin drives gastric cancer cell proliferation and migration, correlating with a poor prognosis

Gastric cancer (GC) is a prevalent global malignancy, often diagnosed at advanced stage due to a lack of early symptoms and reliable markers. Previous research has identified gliomedin (GLDN) as a potential predictive marker for poor prognosis in cancer patients. However, the specific relationship between GLDN expression and GC prognosis has been unclear. Using the Tumor-Immune System Interaction Database (TISIDB), we examined GLDN expression in GC tissues and found a positive correlation with advanced clinical stages. Kaplan-Meier Plotter analysis further demonstrated that elevated GLDN levels were closely associated with poor prognosis in GC patients. To explore the functional significance of GLDN in GC, we conducted experiments involving GLDN overexpression and knockdown in GC cell lines, as well as subcutaneous tumor formation in nude mice. Our findings provided compelling evidence that GLDN promotes GC cell proliferation, viability, and migration, significantly enhancing tumor growth in vivo. Mechanistically, RNA-sequencing (RNA-seq) combined with bioinformatics analysis revealed that GLDN influences genes enriched in the p53 signaling pathway. Our data suggest that GLDN likely regulates cell proliferation through the p53-p21-CyclinD/CDK4 signaling axis. In conclusion, our study underscores GLDN's critical role in regulating GC cell proliferation and migration, and proposes its potential as a prognostic marker for GC patients.