Growth Of Cells Research Articles

Upregulation of LY6K induced by FTO-mediated demethylation promotes the tumorigenesis and metastasis of oral squamous cell carcinoma via CAV-1-mediated ERK1/2 signaling activation.

Lymphocyte antigen 6 complex locus K (LY6K) has been demonstrated to play a significant role in cancers and identified as a therapeutic biomarker for head and neck squamous cell carcinoma. However, the role of LY6K in oral squamous cell carcinoma (OSCC) has not been explored. The current study discovered that LY6K was aberrantly upregulated in OSCC cell lines and tissues and that high LY6K expression significantly correlated with poorer survival of OSCC patients. Through stable knockdown of LY6K, we found that the growth, colony formation, migration, and invasion of OSCC cells were substantially suppressed. In addition, tumor growth and lung metastasis in vivo were effectively inhibited by LY6K depletion. Mechanically, LY6K binds with CAV-1 and activates CAV-1-mediated MAPK/ERK signaling to exert its oncogenic effects on OSCC. In addition, LY6K expression in OSCC was discovered to be regulated by FTO-mediated RNA N6-methyladenosine (m6A) modification in an IGF2BP1-dependent manner. Generally, LY6K expression was upregulated by FTO-mediated demethylation in OSCC, which promoted the tumorigenesis and metastasis of OSCC via activating the CAV-1-mediated ERK1/2 signaling pathway.

PPT1 Promotes Growth and Inhibits Ferroptosis of Oral Squamous Cell Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers with poor prognosis in the head and neck. Elucidating molecular mechanisms underlying OSCC occurrence and development is important for the therapy. Dysregulated palmitoylation-related enzymes have been reported in several cancers but OSCC. To explore the role of palmitoyl-protein thioesterase 1 (PPT1) in OSCC. Differentially expressed genes (DEGs) and related protein-protein interaction networks between normal oral epithelial and OSCC tissues were screened and constructed via different online databases. Tumor samples from 70 OSCC patients were evaluated for the relationship between PPT1 expression level and patients'clinic characteristics. The role of PPT1 in OSCC proliferation and metastasis was studied by functional experiments including MTT, colony formation, EdU incorporation and transwell assays. Lentivirus-based constructs were used to manipulate gene expression. FerroOrange probe and malondialdehyde assay were used to determine ferroptosis. Growth of OSCC cells in vivo was investigated by a xenograft mouse model. A total of 555 DEGs were obtained, and topological analysis revealed that PPT1 and GPX4 might play critical roles in OSCC. Increased PPT1 expression was found to be correlated with poor prognosis of OSCC patients. PPT1 effectively promoted the proliferation, migration and invasion while inhibited the ferroptosis of OSCC cells. PPT1 affected the expression of glutathione peroxidase 4 (GPX4). PPT1 promoted growth and inhibited ferroptosis of OSCC cells. PPT1 might be a potential target for OSCC therapy.

Next generation yellow fever vaccine induces an equivalent immune and transcriptomic profile to the current vaccine: observations from a phase I randomised clinical trial

Yellow fever (YF), a mosquito-borne acute viral haemorrhagic illness, is endemic to many tropical and subtropical areas of Africa and Central and South America. Vaccination remains the most effective prevention strategy; however, as repeated outbreaks have exhausted vaccine stockpiles, there is a need for improved YF vaccines to meet global demand. A live-attenuated YF vaccine candidate (referred to as vYF) cloned from a YF-17D vaccine (YF-VAX®) sub-strain, adapted for growth in Vero cells cultured in serum-free media, is in clinical development. We report the innate and adaptive immune responses and the transcriptome profile of selected genes induced by vYF. Healthy adults aged 18-60 years were randomised at a 1:1:1:1 ratio to receive one dose of vYF at 4, 5 or 6 Log CCID50 or YF-VAX (reference vaccine), administered subcutaneously in the upper arm (ClinicalTrials.gov identifier: NCT04142086). Blood/serum samples were obtained at scheduled time points through 180 days (D180) post-vaccination. The surrogate endpoints assessed were: serum cytokine/chemokine concentrations, measured by bead-based Multiplex assay; peripheral blood vYF-specific IgG and IgM memory B cell frequencies, measured by FluoroSpot assay; and expression of genes involved in the immune response to YF-17D vaccination by RT-qPCR. There was no increase in any of the cytokine/chemokine concentrations assessed through D14 following vaccination with vYF or YF-VAX, except for a slight increase in IP-10 (CXCL10) levels. The gene expression profiles and kinetics following vaccination with vYF and YF-VAX were similar, inclusive of innate (antiviral responses [type-1 interferon, IFN signal transduction; interferon-stimulated genes], activated dendritic cells, viral sensing pattern recognition receptors) and adaptive (cell division in stimulated CD4+ T cells, B cell and antibody) immune signatures, which peaked at D7 and D14, respectively. Increases in vYF-specific IgG and IgM memory B cell frequencies at D28 and D180 were similar across the study groups. vYF-induced strong innate and adaptive immune responses comparable to those induced by YF-VAX, with similar transcriptomic and kinetic profiles observed. Sanofi.

Crosstalk of methylation and tamoxifen in breast cancer (Review).

Tamoxifen is a widely used anti‑estrogen drug in the endocrine therapy of breast cancer (BC). It blocks estrogen signaling by competitively binding to estrogen receptor α (ERα), thereby inhibiting the growth of BC cells. However, with the long‑term application of tamoxifen, a subset of patients with BC have shown resistance to tamoxifen, which leads to low overall survival and progression‑free survival. The molecular mechanism of resistance is mainly due to downregulation of ERα expression and abnormal activation of the PI3K/AKT/mTOR signaling pathway. Moreover, the downregulation of targeted gene expression mediated by DNA methylation is an important regulatory mode to control protein expression. In the present review, methylation and tamoxifen are briefly introduced, followed by a focus on the effect of methylation on tamoxifen resistance and sensitivity. Finally, the clinical application of methylation for tamoxifen is described, including its use as a prognostic indicator. Finally, it is hypothesized that when methylation is used in combination with tamoxifen, it could recover the resistance of tamoxifen.

Inhibitory Effect of Tanshinone IIA Extracted from Radix Salviae miltiorrhizae on Melanoma B16F10 Cells

In this study, we investigate the inhibitory effects of Tanshinone IIA on the proliferation and migration of B16F10 melanoma cells and its potential mechanism of action. We cultured B16F10 melanoma cells in vitro and treated them with varying concentrations of tanshinone IIA. The inhibitory effect of tanshinone IIA on B16F10 cells was assessed using the CCK-8 assay, employing methyl thiazolyl tetrazolium. Melanin content was determined by the NaOH cleavage method, while expression levels of melanin-related proteins were analyzed by Western blotting, and migration-related proteins were quantified using ELISA. When the concentration of Tanshinone IIA reached 20 and 40 μg/mL, there was a decrease in the survival rate of B16F10 melanoma cells. The proliferation inhibition rate of B16F10 melanoma cells gradually increased with the duration of drug action and the concentration of Tanshinone IIA. After 48 hours, there was an increase in melanin content. A comparison of melanin synthesis at the three concentrations yielded an F value of 61.820 and P <0.001. The relative expression levels of TYR, TRP-1, TRP-2, and MITF increased when treated with different concentrations of Tanshinone IIA (P < 0.05). MMP-2 and MMP-9 were downregulated when the concentration of Tanshinone IIA was at 40 and 80 μg/mL respectively (P <0.05). In conclusion, our study demonstrated the inhibitory effects of Tanshinone IIA on growth, proliferation, migration, and melanin synthesis in B16F10 melanoma cells. However, further research is needed to elucidate the specific signal transduction pathway activated by Tanshinone IIA.

Groenlandicine enhances cisplatin sensitivity in cisplatin-resistant osteosarcoma cells through the BAX/Bcl-2/Caspase-9/Caspase-3 pathway

Groenlandicine is a protoberberine alkaloid isolated from Coptidis Rhizoma, a widely used traditional Chinese medicine known for its various biological activities. This study aims to validate groenlandicine’s effect on both cisplatin-sensitive and cisplatin-resistant osteosarcoma (OS) cells, along with exploring its potential molecular mechanism.The ligand-based virtual screening (LBVS) method and molecular docking were employed to screen drugs. CCK-8 and FCM were used to measure the effect of groenlandicine on the OS cells transfected by lentivirus with over-expression or low-expression of TOP1. Cell scratch assay, CCK-8, FCM, and the EdU assay were utilized to evaluate the effect of groenlandicine on cisplatin-resistant cells. WB, immunofluorescence, and PCR were conducted to measure the levels of TOP1, Bcl-2, BAX, Caspase-9, and Caspase-3. Additionally, a subcutaneous tumor model was established in nude mice to verify the efficacy of groenlandicine.Groenlandicine reduced the migration and proliferation while promoting apoptosis in OS cells, effectively damaging them. Meanwhile, groenlandicine exhibited weak cytotoxicity in 293T cells. Combination with cisplatin enhanced tumor-killing activity, markedly activating BAX, cleaved-Caspase-3, and cleaved-Caspase-9, while inhibiting the Bcl2 pathway in cisplatin-resistant OS cells. Moreover, the level of TOP1, elevated in cisplatin-resistant OS cells, was down-regulated by groenlandicine both in vitro and in vivo. Animal experiments confirmed that groenlandicine combined with cisplatin suppressed OS growth with lower nephrotoxicity.Groenlandicine induces apoptosis and enhances the sensitivity of drug-resistant OS cells to cisplatin via the BAX/Bcl-2/Caspase-9/Caspase-3 pathway. Groenlandicine inhibits OS cells growth by down-regulating TOP1 level.Therefore, groenlandicine holds promise as a potential agent for reversing cisplatin resistance in OS treatment.

In silico and in vitro evaluation of compounds from Methanol whole extracts of Solanum aculeastrum Dunal berries against benign prostatic hyperplasia and prostate cancer

Background: This study evaluated anti-prostate potentials of compounds from methanol extract of Solanum aculeastrum Dunal berries (MESADB) against benign prostatic hyperplasia (BPH) and prostate cancer (PC). Methods: We used Swiss ADME and pKCSM tools to select drug-like candidates from MESADB. DisGeNET and related databases were used to identify targets for compounds of MESADB, BPH and PC. Molecular roles, biological processes, cellular components involved, and crucial pathways associated with biological processes of gene enrichment were obtained using Gene Ontology (GO) & Kyoto Encyclopedia of Genes and Genomes (KEGG), respectively. Docking was achieved using VINA tool. Antiproliferative and gene expression profiling were determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) bioassay, and RT-qPCR respectively, and data analyzed using Graph Pad Prism (version 8.4). Results: Three ideal drug-like candidates [Undecane; D-Arabinitol; and 9-Oxabicyclo [3.3.1] nonan-2-one,6-hydroxy-] were identified. Key targets included TLR4, PTGS2, STAT3, ESR1, MTOR, SRC, MMP9, HDAC1, AKT1 and EGFR. GO analysis revealed key targets were mainly enriched in 601 biological processes (BP), 53 molecular function (MF) and 24 cellular components (CC) terms (p < 0.05). KEGG analysis presented pathways for cancer, pathway of proteoglycans in cancer, amongst others. Docking revealed [D-Arabinitol; and 9-Oxabicyclo [3.3.1] nonan-2-one,6-hydroxy-] demonstrated high binding affinity with PTGS2 and EGFR. MESADB significantly (p < 0.0001) inhibited growth of DU-145 cells with IC50 value and selectivity index of 5.11μg/ml and 14.84, respectively, while sparing Vero CCL-81 cells. There were significant (p < 0.0001) downregulations of EGFR, PTGS2 and BCL-2, in treated DU-145 cells compared to control. Conclusion: MESADB possesses antiprostate potentials.

Germline mutations in a G protein identify signaling cross-talk in T cells

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.

TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts

BackgroundCardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive.MethodsHeart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35cKO) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin.ResultsTRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-β1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35.ConclusionOur findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling.

Recruitment of the m6A/m6Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48

BackgroundN6-methyladenosine (m6A), the most abundant internal modification on eukaryotic mRNA, and N6, 2′-O-dimethyladenosine (m6Am), are epitranscriptomic marks that function in multiple aspects of posttranscriptional regulation. Fat mass and obesity-associated protein (FTO) can remove both m6A and m6Am; however, little is known about how FTO achieves its substrate selectivity.ResultsHere, we demonstrate that ZBTB48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of ZBTB48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. ZBTB48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2.ConclusionsOur findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which ZBTB48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.

Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.

Myelodysplastic syndrome (MDS) features bone marrow failure and a heightened risk of evolving into acute myeloid leukemia (AML), increasing with age and reducing overall survival. Given the unfavorable outcomes of MDS, alternative treatments are necessary. Glutamine, the most abundant amino acid in the blood, is metabolized first by the enzyme glutaminase (GLS). To investigate whether GLS is involved in the progression of MDS. The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined. We employed GLS inhibitors (CB839, IPN60090) and the BCL2 inhibitor venetoclax, prepared as detailed. MDS and AML cell lines were cultured under standard and modified (hypoxic, glutamine-free) conditions. Viability, proliferation, and caspase activity were assessed with commercial kits. RT-PCR quantified gene expression post-shRNA transfection. Mitochondrial potential, ATP levels, proteasome activity, and metabolic functions were evaluated using specific assays. Statistical analyses (t-tests, ANOVA) validated the findings. The glutamine-free medium inhibited the growth of MDS cells. GLS1 expression was higher in AML cells than in normal control samples (GSE15061), whereas GLS2 expression was not. Treatment of MDS and AML cells for 72 h was inhibited in a dose-dependent manner by GLS inhibitors. Co-treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax and GLS inhibitors increased potency. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax. Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML.

Senolytic effect of triterpenoid complex from Ganoderma lucidum on adriamycin-induced senescent human hepatocellular carcinoma cells model in vitro and in vivo

BackgroundGanoderma lucidum (G. lucidum) is a famous medicinal mushroom that has been reported to prevent and treat a variety of diseases. Different extractions from G. lucidum have been used to manage age-related diseases, including cancer. Nevertheless, the senolytic activity of G. lucidum against senescent cancer cells has not been investigated. Although cellular senescence causes tumor growth inhibition, senescent cells promote the growth of the neighboring tumor cells through paracrine effects. Therefore, the elimination of senescent cells is a new strategy for cancer treatment.MethodsIn this study, senescence was triggered in HCC cells by the chemotherapeutic agent Adriamycin (ADR), and subsequently, cells were treated with TC to assess its senolytic activity.ResultsWe found for the first time that the triterpenoid complex (TC) from G. lucidum had senolytic effect, which could selectively eliminate adriamycin (ADR)-induced senescent cells (SCs) of hepatocellular carcinoma (HCC) cells via caspase-dependent and mitochondrial pathways-mediated apoptosis and reduce the levels of senescence markers, thereby inhibiting the progression of cancers caused by SCs. TC could block autophagy at the late stage in SCs, resulting in a significant activation of TC-induced apoptosis. Furthermore, TC inhibited the senescence-associated secretory phenotype (SASP) in SCs through the inhibition of NF-κB, TFEB, P38, ERK, and mTOR signaling pathways and reducing the number of SCs. Sequential administration of ADR and TC in vivo significantly reduced tumor growth and reversed the toxicity of ADR.ConclusionA triterpenoid complex isolated from G. lucidum may serve as a novel senolytic agent against SCs, and its combination with chemotherapeutic agents may enhance their antitumor efficacy.

Divergent effects of acute and chronic PPT1 inhibition in melanoma

ABSTRACT Macroautophagy/autophagy-lysosome function promotes growth and survival of cancer cells, making them attractive targets for cancer therapy. One intriguing lysosomal target is PPT1 (palmitoyl-protein thioesterase 1). PPT1 inhibitors derived from chloroquine block autophagy, have significant antitumor activity in preclinical models and are being developed for clinical trials. However, the role of PPT1 in tumorigenesis remains poorly understood. Here we report that in melanoma cells, acute siRNA or pharmacological PPT1 inhibition led to increased ferroptosis sensitivity and significant loss of viability, whereas chronic PPT1 knockout using CRISPR-Cas9 produced blunted ferroptosis that led to sustained viability and growth. Each mode of PPT1 inhibition produced lysosome-autophagy inhibition but distinct proteomic changes, demonstrating the complexity of cellular adaptation mechanisms. To determine whether total genetic loss of Ppt1 would affect tumorigenesis in vivo, we developed a Ppt1 conditional knockout mouse model. We then crossed it into the BrafCA, PtenloxP, Tyr:CreERT2 melanoma mouse model to investigate the impact of Ppt1 loss on tumorigenesis. Loss of Ppt1 had no impact on melanoma histology, time to tumor initiation, or survival of tumor-bearing mice. These results suggest that chemical PPT1 inhibitors produce different adaptations than genetic PPT1 inhibition, and additional studies are warranted to fully understand the mechanism of chloroquine derivatives that target PPT1 in cancer.Abbreviations: 4-HT: 4-hydroxytamoxifen; BRAF: B-Raf proto-oncogene, serine/threonine kinase; cKO: conditional knockout; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9; DC661: A specific PPT1 inhibitor; DMSO: dimethyl sulfoxide; Dox; doxycycline hyclate; Easi-CRISPR: efficient additions with ssDNA inserts-CRISPR; GNS561/ezurpimtrostat: A PPT1 inhibitor; Hug: human guide; iCas: inducible CRISPR-Cas9; KO: knockout; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; LDLR: low density lipoprotein receptor; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NT: non-target; PTEN: phosphatase and tensin homolog; PPT1: palmitoyl-protein thioesterase 1; RSL3: RAS-selective lethal small molecule 3; SCRIB/SCRB1: scribble planar cell polarity protein; Tyr:CreERT2: tyrosinase-driven Cre recombinase fused with the tamoxifen-inducible mutant ligand binding domain of the human estrogen receptor; UGCG: UDP-glucose ceramide glucosyltransferase; WT: wild-type.

Seven New Noroleanane Triterpenoids from Mastic and their NO Inhibitory and Cytotoxic Activities.

Mastic is a natural resin produced by Pistacia lentiscus L. (Anacardiaceae) with high medicinal value and have been traditionally used as Uighur imported medicine for centuries. In this study, 16 triterpenoids including seven new norleananetriterpenoids (1-7), along with nine known oleanane triterpenoids (8-16), were isolated from the mastic. Their chemical structures were determined on the basis of extensive spectroscopic analyses (including IR, UV, ESI-HR-MS and NMR spectroscopy) and single-crystal X-ray diffraction. Compounds 4-7, 11, 14 and 16 showed strong inhibitory NO productionin LPS-induced RAW264.7 cells with IC50 values 7.44-9.76 μM, respectively (positive control dexamethasone, 9.93 ± 1.17 μM). Furthermore,compounds 3 and 12 significantly inhibited the growth of SW480 cells, compound 3 showed the most pronounced inhibitory effect with an IC50 of 2.30 ± 0.38 μM.

Cancer-associated fibroblast-derived exosome Leptin promotes malignant biological lineage in pancreatic ductal adenocarcinoma by regulating ABL2 via miR-224-3p

BackgroundCancer-associated fibroblasts, as a major component of the tumor microenvironment, have been shown to exhibit protumorigenic effects in pancreatic ductal adenocarcinoma. Moreover, cancer-associated fibroblasts-derived exosomes have been reported to promote tumor development, but exact mechanisms have not been elucidated. The purpose of this study was to investigate the processes by which exosomes generated from cancer-associated fibroblasts promote tumor growth.Methodstwenty-one patients with pancreatic ductal adenocarcinoma who evaluated preoperatively as potentially surgically resectable without distant metastasis and pathologically examined postoperatively as pancreatic ductal cell carcinoma were included. We determined the expression of Leptin as well as downstream proteins at the clinical and cellular levels. Cancer-associated fibroblast-derived exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. To ascertain the mechanism mediating the action of exosomal Leptin in pancreatic ductal adenocarcinoma, we performed CCK-8 assay, colony formation assays, transwell and wound healing assays in PSN1 cells to evaluate cell proliferation, migration and invasion. Western blotting was used to detect the level of Leptin, ABL2 and exosome markers. qRT-PCR was employed to evaluate miR-224-3p. Cancer-associated fibroblasts markers and exosome uptake were verified by immunofluorescence.ResultsWestern blotting assays show that Leptin is present inside tissues and cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cancer-associated fibroblasts stimulated PSN1 cells growth, migration and invasion in vitro by secreting the exosomal Leptin. Exosomal Leptin could regulate miR-224-3p, which targets negative regulation of ABL2. Inhibiting Leptin significantly limited PSN1 cells growth, migration and invasion. In vitro analyses revealed that miR-224-3p mimics mitigate the inhibitory effect of cancer-associated fibroblasts knockdown of Leptin on PSN1 cells development, but overexpression of ABL2 partly abolished the tumor-promoting phenotype of miR-224-3p mimics.ConclusionOur results revealed that cancer-associated fibroblasts mediate pancreatic ductal adenocarcinoma development by regulating the miR-224-3p/ABL2 molecular axis through the secretion of the exosomal Leptin.

Identifying Potential Diagnostic and Therapeutic Targets for Infantile Hemangioma Using WGCNA and Machine Learning Algorithms.

Infantile hemangioma (IH) is the most common benign vascular tumor during infancy and childhood and is characterized by abnormal vascular development. It is the most common vascular tumor and its related mechanisms and treatments remain a problem. IH-related biomarkers have been identified using transcriptome analysis and can be used to predict clinical outcomes. This study aimed to identify the key target genes for IH treatment and explore their possible roles in the IH pathophysiology. Gene records were acquired from the Gene Expression Omnibus database. Utilizing integrated weighted gene co-expression network examination, gene clusters were determined. Single-sample gene set enrichment analysis was performed to gauge immune infiltration. Essential genes were identified via Random Forest and Least Absolute Selection and Shrinkage Operator analyses. Ultimately, a set of five pivotal genes associated with the ailment was identified (NETO2, IDO1, KDR, MEG3, and TMSB15A). A nomogram for predicting IH diagnosis was constructed based on hub genes. The calibration curve showed valid agreement between the prediction and conclusion that the key genes in the model were clinically significant. Neuropilin and Tolloid-like 2 (NETO2) are closely associated with tumor development. The role value of NETO2 expression levels increased in hemangioma-derived endothelial cells (HemECs). After silencing NETO2, the growth and migration of cancer cells were significantly restrained. This study revealed the critical role of NETO2 in IH development, suggesting that targeting NETO2 may be effective in improving the therapeutic outcome of IH.

Preclinical Evaluation of STI-8811, a Novel Antibody Drug Conjugate Targeting BCMA for the Treatment of Multiple Myeloma.

Treatment for patients with Multiple Myeloma (MM) has experienced rapid development and improvement in recent years, however, patients continue to experience relapse and MM remains largely incurable. B cell maturation antigen (BCMA) has been widely recognized as a promising target for treatment of MM due to its exclusive expression in B cell linage cells and its critical role in the growth and survival of malignant plasma cells. Here, we introduce STI-8811, a BCMA-targeting antibody drug conjugate linked to an auristatin-derived duostatin payload via an enzymatically cleavable peptide linker, using our proprietary C-lock technology. STI-8811 exhibits target specific binding activity and rapid internalization, leading to G2/M cell cycle arrest, caspase 3/7 activation and apoptosis in BCMA-expressing tumor cells in vitro. Soluble BCMA (sBCMA) is shed by MM cells into the blood and increases with disease progression, competing for ADC binding and reducing its efficacy. We report enhanced cytotoxic activity in the presence of high levels of sBCMA compared to a belantamab mafodotin biosimilar (J6M0-mcMMAF). STI-8811 demonstrated greater in vivo activity than J6M0-mcMMAF in solid and disseminated multiple myeloma models, including tumor models with low BCMA expression and/or in large solid tumors representing soft tissue plasmacytomas. In Cynomolgus monkeys, STI-8811 was well tolerated, with toxicities consistent with other BCMA targeting ADCs with auristatin payloads in clinical studies. STI-8811 has the potential to outperform current clinical candidates with lower toxicity and higher activity under conditions found in patients with advanced disease.

3D-printed polycaprolactone-magnetic nanoparticles composite multifunctional scaffolds for bone tissue regeneration and hyperthermia treatment

Cancer management after tumor resection is characterized by two critical needs: (i) rehabilitation of the resected tissue and (ii) preventing post-surgical tumor recurrence by destroying any residual tumors. The state of the art in literature is limited because it tackles these two major priorities individually, it achieves tissue regeneration via autologous grafting and prevents tumor recurrence through chemotherapy. In this paper, extrusion 3D printing has been employed to manufacture composite multi-functional scaffolds with polycaprolactone (PCL) as a polymeric matrix and magnetic nanoparticles (MNPs) in a 0 to 50 wt% ratio, that would aid in bone regeneration and cancer management via magnetic hyperthermia treatment. The fabricated scaffolds were evaluated for their mechanical, magnetic and thermal characteristics. The Young’s modulus of the scaffolds increased multi-fold with increasing concentration of MNPs added to PCL (26.88±9.02 MPa for pure PCL to 229.06±37.05 MPa for PCL/50 wt% MNP scaffolds). PCL/MNP scaffolds displayed a directly proportional correlation between MNP concentration and saturation magnetization. While the in vitro tests showed a statistically significant cell growth of human Mesenchymal Stem Cells (hMSCs) over 7 days for all MNP concentrations, only the 50% MNP scaffold showed an increase in temperature over 41oC when subjected to an alternating magnetic field making it suitable for the hyperthermia treatment. On application of alternating magnetic fields to PCL and PCL/50 wt% MNP scaffolds, there was an increase in hMSCs proliferation and decrease in Bone cancer cells proliferation, thus proving the potential to be used as a multi-functional scaffold for post-surgical bone cancer management.  

Mechanistic Insight into Anticancer Prowess of Piper Species and their Bioactive Compounds: A Review

Southern Asia boasts a diverse array of Piper species, renowned for their antimicrobial, antioxidant, and anti-inflammatory properties. These plants, also native to the American tropics, have played a significant role in traditional medicine and culinary practices. Notably, Piper longum L., P. nigrum L., and P. betle L. are recognized for their bioactive compounds, particularly alkaloids, which contribute to their beneficial properties. In recent decades, there has been increased focus on studying these plants for their potential anticancer effects, encompassing both direct cytotoxic effects and indirect modulation of the tumor microenvironment. Major scientific literature databases were consulted using appropriate keywords to present a comprehensive and proportionate analysis of the anticancer potential of the three species, including valuable insights into their therapeutic perspectives, molecular mechanisms, and broader applications in cancer treatment. Numerous pharmacological trials on the bioactive components and extracts have underscored their clinical significance, revealing multifaceted actions such as antiproliferative effects, antiangiogenic properties, immunomodulation, antimetastatic activity, induction of apoptosis, and modulation of various signaling pathways in both malignant and non-malignant disorders. Among the explored compounds, piperine and piperlongumine, prominent alkaloids within the Piper genus, have demonstrated notable efficacy in restricting the growth of cancer cells and tumors. This article emphasizes the biomedical and pharmacological findings related to the anticancer properties of the three Piper species, with a focus on their mechanism of action. These insights could open avenues for future clinical scenarios and therapeutic utilization of bioactive substances and extracts derived from these species.

Helicobacter pylori induce circ_0046854 to regulate microRNA-511-3p/CSF1 axis and enhance the resistance of gastric cancer to cisplatin.

Helicobacter pylori (HP) is considered a major risk factor for gastric cancer (GC) and during this process, cytotoxin‑associated gene A (CagA) plays in essence. The study mainly focused on the molecular mechanism of circular RNA 0046854 (circ_0046854) in HP-induced GC. Clinically, 56 cases of GC and normal tissues were collected, and the GC tissues were divided into HP-negative GC tissues (HP-) and 33 HP-positive GC tissues (HP+). Tissue expression of circ_0046854, microRNA (miR)-511-3p and colony-stimulating factor 1 (CSF1) was tested. BGC-823/Cisplatin (DDP) resistant strain was induced and cell growth and DDP resistance were detected after HP infection. In vivo experiments were performed using a mouse xenograft model. The relationship between circ_0046854, miR-511-3p and CSF1 was confirmed. GC tissues especially HP+ cancer tissues expressed high circ_0046854 and CSF1 and low miR-511-3p. HP-induced circ_0046854 expression in GC cells through CagA. Inhibition of circ_0046854 or miR-511-3p elevation inhibited the growth and DDP resistance in GC cells. Circ_0046854 acted as a sponge for miR-511-3p, which targeted CSF1. Restoring CSF1 could abolish the inhibitory effect of miR-511-3p overexpression on CagA+ HP-induced GC progression in vitro. Circ_0046854 silencing repressed tumor growth and aggrandized the inhibiting effects of DDP on tumorigenesis in vivo. Circ_0046854/miR-511-3p/CSF1 axis may be involved in the development of HP-induced GC, thus providing new ideas for studying the mechanism of HP-related gastric diseases.