Phase Arrest Research Articles

Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma.

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.

CDT1, transcriptionally regulated by E2F2, promotes lung adenocarcinoma progression

CDT1, a gene that shows excessive expression in various malignancies, functions as a pivotal regulator of replication licensing. In this study, we observed a positive correlation in expression between CDT1 and E2F2 among patients with lung adenocarcinoma (LUAD). Our findings substantiated that E2F2 directly interacted with the promoter region of CDT1, as confirmed by ChIP-qPCR assays, and depletion of E2F2 resulted in a downregulation of CDT1 expression in LUAD cell lines by gene interference technology. Furthermore, we identified an upregulation of CDT1 mRNA level in Chinese LUAD samples. Notably, in the loss-of-function assays, depletion of CDT1 in LUAD cell lines inhibited cell proliferation, migration, and invasion. Concurrently, it promoted cell apoptosis and induced G0/G1 phase arrest using MTT, flow cytometry, and Transwell assays, reinforcing its role as an oncogene.Furthermore, enhanced tumor ablation was determined in a CDT1-downregulated LUAD tumor-bearing nude mouse model. Collectively, our results strongly suggest that E2F2 positively regulates CDT1 expression and actively participates in the progression of lung adenocarcinoma, thereby providing valuable insights into identifying novel therapeutic targets for LUAD treatment.

Plant Extract-Mediated Synthesis of Silver Nanoparticles and Their Anticancer Potentials

Five plant extracts (Ardisia argentea, Aegiceras corniculatum, Polycarpaea corymbosa, Maesa perlaria, and Schima wallichii) were utilized as reducing agents in the synthesis of silver nanoparticles (AgNPs) through a green route. As the reducing power and total content of phenolic compounds in the extract increased, the absorbance of the surface plasmon resonance of the resulting AgNPs also increased. The characteristic surface plasmon resonance was clearly observed at 400∼500 nm. The AgNPs were spherical, as shown by field emission transmission electron microscopy images, with an average size between 10.4±0.3 nm and 22.2±0.8 nm. The cytotoxicity in A549 (lung cancer) and HeLa (cervical cancer) cells increased in a dose-dependent manner. Specifically, at the highest dose, the AgNPs synthesized with the A. corniculatum extract exhibited the highest cytotoxicity and induced high levels of reactive oxygen species (ROS). Interestingly, it was observed that smaller AgNPs tended to generate higher levels of ROS. Cell death was clearly observed in the treatment with the AgNPs. A G2/M phase arrest occurred in cell cycle analysis, which induced cell death. The results obtained herein support the potential of natural product-mediated synthesis of AgNPs as a promising anticancer nanomedicine.

Marine derived macrolide bryostatin 4 inhibits the TGF-β signaling pathway against acute erythroleukemia.

Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) with an extremely poor prognosis when treated with available drugs. Therefore, new investigational agents capable of inducing remission are urgently required. Bioinformatics analysis, western blot and qRT-PCR were used to reveal the potential biological mechanism of bryostatin 4 (B4), an antineoplastic macrolide derived from the marine bryozoan Bugula neritina. Then, in vivo experiments were conducted to evaluate the role of transforming growth factor (TGF)-β signaling in the progression of AEL. Our results revealed that the proliferation of K562 cells and TF-1 cells was significantly inhibited by B4 at IC50 values of 37 nM and 52 nM, respectively. B4 inhibited TGF-β signaling and its downstream pathway targets, particularly the phosphorylation of Smad2, Smad3, Ras, C-RAF, ERK1/2, and MEK. B4 also played an important role in cell invasion and migration in K562 cells and TF-1 cells by reducing the protein levels of the mesenchymal cell marker vimentin. Moreover, Flow cytometry and western blot analyses demonstrated that B4 induced apoptosis and initiated G0/G1 phase arrest by modulating mitochondrial dysfunction and cyclin-dependent kinase (CDK) expression. These findings indicated that B4 could inhibit the proliferation, migration, invasion, and TGF-β signaling pathways of AEL cells, thus suggesting that B4 possesses therapeutic potential as a treatment for AEL.

Synthetic Benzylic Diselenides and Disulfides: Potential Anticancer Activities via Modulation of the ROS-dependent Akt/β-Catenin Signaling Pathway.

The natural and synthetic organodiselenides have garnered much research attention due to their chemotherapeutic and chemopreventive activities. Herein, we describe the synthesis of a series of benzylic diselenides, which were synthesized by coupling the in situ generated disodium diselenide with the corresponding benzylic halides. The diselenides were evaluated for their anticancer activities in the highly aggressive triple-negative breast cancer cells. Preliminary anti-proliferative activities indicated 4-cyano-substituted diselenide 7 to be most potent with an IC50 value of 1.9 ± 0.3 μM. Detailed mechanistic investigations showed that diselenide 7 induces apoptosis and causes G1 phase arrest of the cell cycle. It exhibits anticancer activity by suppressing the Akt/β-catenin signaling pathway. Further control experiments with LiCl (inhibitor of GSK-3β) revealed that down-regulation of β-catenin was promoted by GSK-3β-induced phosphorylation of β-catenin and its subsequent proteasomal degradation. Moreover, the intracellular ROS was found to act as an upstream mediator for the inactivation of the Akt/β-catenin signaling pathway. The present study describing the efficient anticancer activity of a synthetic benzylic diselenide towards triple-negative breast cancer cells through the modulation of ROS-dependent Akt/β-catenin signaling pathway would certainly be helpful in the future towards the development of small-molecule organoselenium compounds for the treatment of cancer.

Traditional Chinese medicine combined with chemotherapy in the treatment of advanced non-small cell lung cancer: key drug screening and mechanism analysis.

In the course of clinical treatment for anti-tumor, the combination of traditional Chinese medicine (TCM) and other treatment schemes can reduce toxicity and increase efficiency. The purpose of this paper is to find out the key TCM and effective components for the treatment of non-small cell lung cancer (NSCLC) and analyze its therapeutic mechanism by analyzing the prescription of TCM combined with chemotherapy for NSCLC. Firstly, the prescriptions of TCM in the randomized controlled trials combined with chemotherapy for NSCLC were collected, and the core TCM was screened by frequency statistics, association rule analysis, and cluster analysis. Then, the intersection targets of the potential effects of NSCLC and core Chinese medicine were collected, and PPI analysis and enrichment analysis were performed on the intersection targets to screen the core targets, components, and pathways. The core components were verified by molecular docking and cell experiments. In this study, 269 prescriptions were collected, among which the frequency of medication for Astragalus membranaceus (HQ, in Chinese), Wolfiporia cocos (FL, in Chinese), and Atractylodes macrocephala (BZ, in Chinese) was over 100. Association rule analysis showed that they were highly correlated and clustered into the same category in cluster analysis. Their core components were quercetin, kaempferol, and isorhamnetin. The molecular docking results of the core components with the core targets AKT1 and EGFR obtained by PPI network analysis showed that they could bind stably. KEGG analysis screened 110 pathways including PI3K-Akt; the results of CCK-8 showed that quercetin, kaempferol, and isorhamnetin could effectively inhibit the proliferation of A549 cells, and isorhamnetin had the best inhibitory effect. Isorhamnetin can inhibit the migration and invasion of A549 cells, induce apoptosis and G1 phase arrest, and decrease the expression of P-PI3K and P-AKT in A549 cells. In a word, the key TCM for the treatment of NSCLC includes HQ, FL, and BZ. and its key components quercetin, kaempferol, and isorhamnetin have potential therapeutic effects on NSCLC according to the research results.

Reversible acetylation of HDAC8 regulates cell cycle

HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.

Integrated metabolomics and proteomics analyses to reveal anticancer mechanism of hemp oil extract in colorectal cancer

Cannabis sativa L., with a rich history in Chinese folk medicine, includes hemp strains that offer substantial economic and medical benefits due to their non-addictive properties. Hemp has demonstrated various pharmaceutical activities, including anti-inflammatory, antioxidant, and anti-tumor effects. This study explores the potential of hemp oil extract (HOE) in treating colorectal cancer (CRC). Despite its promise, the specific anticancer mechanisms of HOE have not been well understood. To elucidate these mechanisms, we employed mass spectrometry-based metabolomics and proteomics to investigate the global effects of HOE on CRC cells. Additionally, bioinformatics approaches, including bulk RNA-seq and single-cell RNA-seq, were used to identify gene expression differences and cellular heterogeneity. The results were validated using flow cytometry, western blotting, and immunohistochemistry. Our findings reveal that HOE induces significant alterations in purine metabolism pathways, down-regulates c-MYC, and inhibits the expression of cell cycle-related proteins such as CCND1, CDK4, and CDK6, leading to cell cycle arrest in the G1 phase. This comprehensive analysis demonstrates that HOE effectively blocks the cell cycle in the G1 phase, thereby inhibiting colorectal cancer cell proliferation. These findings provide experimental evidence supporting the potential therapeutic use of hemp in medicine.

O-Sialoglycoprotein Endopeptidase Deficiency Impairs Proteostasis and Induces Autophagy in Human Embryonic Stem Cells.

The OSGEP gene encodes O-sialoglycoprotein endopeptidase, a catalytic unit of the highly conserved KEOPS complex (Kinase, Endopeptidase, and Other Proteins of small Size) that regulates the second biosynthetic step in the formation of N-6-threonylcarbamoyladenosine (t6A). Mutations in KEOPS cause Galloway-Mowat syndrome (GAMOS), whose cellular function in mammals and underlying molecular mechanisms are not well understood. In this study, we utilized lentivirus-mediated OSGEP knockdown to generate OSGEP-deficient human embryonic stem cells (hESCs). OSGEP-knockdown hESCs exhibited reduced stemness factor expression and G2/M phase arrest, indicating a potential role of OSGEP in the regulation of hESC fate. Additionally, OSGEP silencing led to enhanced protein synthesis and increased aggregation of proteins, which further induced inappropriate autophagy, as evidenced by the altered expression of P62 and the conversion of LC3-I to LC3-II. The above findings shed light on the potential involvement of OSGEP in regulating pluripotency and differentiation in hESCs while simultaneously highlighting its crucial role in maintaining proteostasis and autophagy, which may have implications for human disease.

Natural Compound-Rhein and PROTACs Unleash Potent VEGFR-2 Degraders.

VEGFR-2 is a prominent therapeutic target in antitumor drug research to block tumor angiogenesis. This study focused on the synthesis and optimization of PROTACs based on the natural product rhein, resulting in the successful synthesis of 15 distinct molecules. In A549 cells, D9 exhibited remarkable antitumor efficacy with an IC50 of 5.88±0.50 μM, which was 15-fold higher compared to rhein (IC50=88.45±2.77 μM). An in-depth study of the effect of D9 on the degradation of VEGFR-2 revealed that D9 was able to induce the degradation of VEGFR-2 in A549 cells in a time-dependent manner. The observed effect was reversible, contingent upon the proteasome and ubiquitination system, and demonstrably linked to CRBN. Further experiments revealed that D9 induced apoptosis in A549 cells and led to cell cycle arrest in the G1 phase. Molecular docking simulations validated the binding mode of D9 to VEGFR, establishing the potential of D9 to bind to VEGFR-2 in its natural state. In summary, this study confirms the feasibility of natural product-bound PROTAC technology for the development of a new generation of VEGFR-2 degraders, offering a novel trajectory for the future development of pharmacological agents targeting VEGFR-2.

L-2-Hydroxyglutarate contributes to tumor radioresistance through regulating the hypoxia-inducible factor-1α signaling pathway.

l-2-Hydroxyglutarate (l-2-HG) has been regarded as a tumor metabolite, and it plays a crucial role in adaptation of tumor cells to hypoxic conditions. However, the role of l-2-HG in tumor radioresistance and the underlying mechanism have not yet been revealed. Here, we found that l-2-HG exhibited to have radioresistance effect on U87 human glioblastoma cells, which could reduce DNA damage and apoptosis caused by irradiation, promote cell proliferation and migration, and impair G2/M phase arrest. Mechanistically, l-2-HG upregulated the protein level of hypoxia-inducible factor-1α (HIF-1α) and the expression levels of HIF-1α downstream target genes. The knockdown ofl-2-hydroxyglutarate dehydrogenase(L2HGDH) gene promoted the tumor growth and proliferation of U87 cells in nude mice by increasing HIF-1α expression level in vivo. In addition, the low expression level of L2HGDH gene was correlated with the short survival of patients with glioma or kidney cancer. In conclusion, our study revealed the role and mechanism of l-2-HG in tumor radioresistance and may provide a new perspective for overcoming tumor radioresistance and broaden our comprehension of the role of metabolites in tumor microenvironment.

Baitouweng decoction suppresses growth of esophageal carcinoma cells through miR-495-3p/BUB1/STAT3 axis.

Esophageal carcinoma (EC) is one of the most prevalent cancers in human populations worldwide. Baitouweng decoction is one of the most important Chinese medicine formulas, with the potential to treat cancer. To investigate the role and mechanism of Baitouweng decoction on EC cells. Differentially expressed genes (DEGs) in EC tissues and normal tissues were screened by the cDNA microarray technique and by bioinformatics methods. The target genes of microRNAs were predicted based on the TargetScan database and verified by dual luciferase gene reporter assay. We used Baitouweng decoction to intervene EC cells, and detected the activity of EC9706 and KYSE150 cells by the MTT method. Cell cycle and apoptosis were measured by flow cytometry. The expression of BUB1 mRNA and miR-495-3p was measured by qRT-PCR. The protein levels of BUB1, STAT3, p-STAT3, CCNB1, CDK1, Bax, Caspase3, and Caspase9 were measured by Western blot analysis. The migration and invasion abilities of the cells were measured by wound-healing assay and Transwell invasion assay, respectively. DEGs identified are involved in biological processes, signaling pathways, and network construction, which are mainly related to mitosis. BUB1 was the key hub gene, and it is also a target gene of miR-495-3p. Baitouweng decoction could upregulate miR-495-3p and inhibit BUB1 expression. In vitro experiments showed that Baitouweng decoction significantly inhibited the migration and invasion of EC cells and induced apoptosis and G2/M phase arrest. After treatment with Baitouweng decoction, the expression of Bax, Caspase 3, and Caspase 9 in EC cells increased significantly, while the expression of BUB1, CCNB1, and CDK1 decreased significantly. Moreover, the STAT3 signaling pathway may play an important role in this process. Baitouweng decoction has a significant inhibitory effect on EC cell growth. BUB1 is a potential therapeutic target for EC. Further analysis showed that Baitouweng decoction may inhibit the growth of EC cells by upregulating miR-495-3p targeting the BUB1-mediated STAT3 signal pathway.

Spinosad blocks CHRNA5 mediated EGFR signaling pathway activation to inhibit lung adenocarcinoma proliferation

Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, with high incidence and low survival rates. Nicotinic acetylcholine receptors play an important role in the progression of LUAD. In this study, a screening of 17 nicotinic acetylcholine receptor allosteric agents revealed that spinosad effectively suppressed the proliferation of LUAD cells. The experiments demonstrated that spinosad induced cell cycle arrest in the G1 phase and stimulated apoptosis, thereby impeding the growth of LUAD and enhancing the responsiveness to gefitinib in vitro and vivo. Mechanistic insights obtained through transcriptome sequencing, Co-IP, and protein immunoblots indicated that spinosad disrupted the interaction between CHRNA5 and EGFR, thereby inhibiting the formation of downstream complexes and activation of the EGFR signaling pathway. The supplementation of exogenous acetylcholine showed to mitigate the inhibition of LUAD cell proliferation induced by spinosad. This study elucidates the therapeutic effects and mechanisms of spinosad in LUAD, and offers a theoretical and experimental foundation for novel LUAD treatments.

Dual Inhibition of PI3 Kinase and MAP Kinase Signaling Pathways in Intrahepatic Cholangiocellular Carcinoma Cell Lines Leads to Proliferation Arrest but Not Apoptosis.

Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly, intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation, such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and the results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed additive effects of the dual inhibition of the two pathways, in accordance with the inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1 phase arrest but not apoptosis or cell death (measured by cleaved caspase-3, AIFM1 regulation, sub-G0/G1 phase). We conclude that the dual inhibition of the MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block the proliferation of ICC cell lines in vitro; however, potential clinical applications must be critically examined, as a proliferation block could also induce resistance to standard therapies.

Anlotinib destabilizes PAX3-FOXO1 to induce rhabdomyosarcoma cell death via upregulating NEK2

BackgroundRhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children and adolescents, in which PAX3-FOXO1 fusion gene positive patients have very poor prognosis. PAX3-FOXO1 has been identified as an independent prognostic predictor in RMS, with no currently available targeted therapeutic intervention. The novel tyrosine kinase inhibitor anlotinib exhibits a wide range of anticancer effects in multiple types of cancers; however, there have been no relevant studies regarding its application in RMS. Materials and methodsWe investigated the effects of PAX3-FOXO1 on the therapeutic efficacy of anlotinib using the CCK-8 assay, flow cytometry, invasion assay, wound healing assay, western blotting, quantitative polymerase chain reaction(qPCR), and xenograft experiments. RNA-seq and co-immunoprecipitation assays were conducted to determine the specific mechanism by which anlotinib regulates PAX3-FOXO1 expression. ResultsAnlotinib effectively inhibited RMS cell proliferation and promoted apoptosis and G2/M phase arrest while impeding tumor growth in vivo. Downregulation of PAX3-FOXO1 enhances the antitumor effects of anlotinib. Anlotinib upregulates protein kinase NEK2 and increases the degradation of PAX3-FOXO1 via the ubiquitin-proteasome pathway, leading to a reduction in PAX3-FOXO1 protein levels. ConclusionAnlotinib effectively inhibited the malignant progression of RMS and promoted degradation of the fusion protein PAX3-FOXO1. Anlotinib could be a targeted therapeutic approach to treat PAX3-FOXO1 fusion-positive RMS.

Synthesis and comparative analysis of the cytotoxicity and mitochondrial effects of triphenylphosphonium and F16 maslinic and corosolic acid hybrid derivatives

The cytotoxic profile and antiproliferative and mitochondrial effects of triterpene acid conjugates with mitochondriotropic lipophilic triphenylphosphonium (TPP+) and F16 cations were evaluated. Maslinic and corosolic acids chosen as the investigation objects were synthesized from commercially available oleanolic and ursolic acids. Study of the cytotoxic activity of TPP+ and F16 triterpenoid derivatives against six tumor cell lines demonstrated a comparable synergistic effect in the anticancer activity, which was most pronounced in the case of MCF-7 mammary adenocarcinoma cells and Jurkat and THP-1 leukemia cells. The corosolic and maslinic acid hybrid derivatives caused changes in the progression of tumor cell cycle phases when present in much lower doses than their natural triterpene acid precursors. The treatment of tumor cell lines with the conjugates resulted in the cell cycle arrest in the G1 phase and increase in the cell population in the subG1 phase. The cationic derivatives of the acids were markedly superior to their precursors as inducers of hyperproduction of reactive oxygen species and more effectively decreased the mitochondrial potential in isolated rat liver mitochondria. We concluded that the observed cytotoxic effect of TPP+ and F16 triterpenoid conjugates is attributable to the ability of these compounds to initiate mitochondrial dysfunctions. Their cytotoxicity, antiproliferative action, and mitochondrial effects depend little on the type of cationic groups used.

Effect and mechanism of resveratrol on ferroptosis mediated by p53/SLC7A11 in oral squamous cell carcinoma

ObjectiveResveratrol (Res) is a natural phytoestrogen with antitumor activity. This study sought to investigate the role of Res in ferroptosis in oral squamous cell carcinoma (OSCC).MethodsNormal human oral keratinocyte (HOK)/oral OSCC (CAL-27/SCC-9) cell lines were treated with different doses of Res. Res toxicity was determined by MTT assay, with half maximal inhibitory concentration values of Res on CAL-27 and SCC-9 cells calculated. Cell viability/colony formation efficiency/migration/invasion/cycle were assessed by CCK-8/colony formation assay/transwell assay/flow cytometry. The expression of p53 protein in the nucleus and cytoplasm, glutathione peroxidase 4 (GPX4) expression, and SLC7A11 messenger RNA (mRNA) and protein expression levels were determined by Western blot and RT-qPCR. Fe2+ content, reactive oxygen species (ROS) level, reduced glutathione (GSH), and lactate dehydrogenase (LDH) release were assessed.ResultsMedium- to low-dose Res had no toxic effect on HOK cells, while high-dose Res markedly reduced HOK cell viability. Res significantly suppressed the viability of OSCC cells (CAL-27 and SCC-9). Res inhibited OSCC cell colony formation/migration/invasion, and induced G1 phase arrest. Res caused the translocation of p53 protein to the nucleus, obviously increased Fe2+ content, ROS level and LDH release, decreased GSH content and GPX4 protein expression, and induced ferroptosis. Down-regulation of p53 partially reversed the inhibitory effects of Res on CAL-27 cell malignant behaviors. Res inhibited SLC7A11 transcription by promoting p53 entry into the nucleus. SLC7A11 overexpression negated the the regulatory effects of p53 knockout on the role of Res in OSCC cell malignant behaviors and ferroptosis.ConclusionRes accelerated ferroptosis and inhibited malignant behaviors in OSCC cells by regulating p53/SLC7A11.

Exploring allocryptopine as a neuroprotective agent against oxidative stress-induced neural apoptosis via Akt/GSK-3β/tau pathway modulation

Alzheimer’s disease (AD) is characterized by neuronal loss due to hyperphosphorylated proteins induced by oxidative stress. AD remains a formidable challenge in the medical field, as current treatments focusing on single biomarkers have yielded limited success. Hence, there’s a burgeoning interest in investigating novel compounds that can target mechanisms, offering alternative therapeutic approaches. The aim of this study is to investigate the effects of allocryptopine, an isoquinoline alkaloid, on mechanisms related to AD in order to develop alternative treatment strategies. In this study, the in vitro AD cell model was obtained by inducing nerve growth factor (NGF)-differentiated PC12 (dPC12) cells to oxidative stress with H2O2, and also the effect mechanism of different allocryptopine concentrations on the in vitro AD cell model was studied. The treatments’ antioxidative effects at the ROS level and their regulation of the cell cycle were assessed through flow cytometry, while their anti-apoptotic effects were evaluated using both flow cytometry and qRT-PCR. Additionally, the phosphorylation levels of Akt, GSK-3β, and tau proteins were analyzed via western blot, and the interactions between Akt, GSK-3β, CDK5 proteins, and allocryptopine were demonstrated through molecular docking. Our study’s conclusive results revealed that allocryptopine effectively suppressed intracellular ROS levels, while simultaneously enhancing the Akt/GSK-3β signaling pathway by increasing p-Akt and p-GSK-3β proteins. This mechanism played a critical role in inhibiting neural cell apoptosis and preventing tau hyperphosphorylation. Moreover, allocryptopine demonstrated its ability to regulate the G1/S cell cycle progression, leading to cell cycle arrest in the G1 phase, and facilitating cellular repair mechanisms, potentially contributing to the suppression of neural apoptosis. The in silico results of allocryptopine were shown to docking with the cyclin-dependent kinase 5 (CDK 5) playing a role in tau phosphorylation Akt and GSK-3β from target proteins. Therefore, the in silico study results supported the in vitro results. The results showed that allocryptopine can protect dPC12 cells from oxidative stress-induced apoptosis and hyperphosphorylation of the tau protein by regulating the Akt/GSK-3β signaling pathway. Based on these findings, it can be suggested that allocryptopine, with its ability to target biomarkers and its significant effects on AD-associated mechanisms, holds promise as a potential candidate for drug development in the treatment of AD. Further research and clinical trials are recommended in the future.

HOXC4 promotes proliferation of pancreatic cancer cells by increasing LDHA-mediated glycolysis.

Homeobox C4 (HOXC4) is a member of homeobox family and acts as a transcription factor in regulating morphological development. The current study aimed to determine its role in pancreatic cancer (PC). Bioinformatics analysis was employed to assess the expression and clinical significance of HOXC4 in PC, while the expression of HOXC4 was further confirmed in PC tissues through quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The impact of HOXC4 on PC cell proliferation was evaluated using various assays including Cell Counting Kit-8, colony formation, apoptosis detection, cell cycle analysis, and subcutaneous tumorigenesis. Extracellular acidification rate, glucose uptake, and lactate production measurements were detected to examine the impact of HOXC4 on glycolysis. The relationship between HOXC4 and lactate dehydrogenase A (LDHA) was investigated using CHIP assay, luciferase reporter assay, and western blot. Notably, there was a substantial increase in HOXC4 expression in PC, and patients with elevated HOXC4 levels exhibited shorter survival durations. HOXC4 knockdown resulted in significantly reduced proliferation and colony formation in PC cells, accompanied by increased apoptosis and G1 phase arrest. The overexpression of HOXC4 resulted in contrasting effects. In vivo, the proliferation of PC cells was diminished upon the knockdown of HOXC4. HOXC4 exhibited an increase in LDHA expression by binding to its promoter. The suppressive effects of HOXC4 knockdown on PC cells were counteracted upon the restoration of LDHA. In conclusion, HOXC4 promoted the proliferation of PC cells by increasing LDHA-mediated glycolysis. HOXC4 can act as a target for PC therapy.

Mechanisms of Cancerprotective Effects of Phytosterols. Literature Review

Cancer is recognized as the second leading cause of mortality in the Russian Federation. Prolonging the life of oncology patients involves treatment with toxic drugs, causing multiple side effects. Today, scientists around the world are striving to find non-toxic drugs. The present study explores phytosterols. Phytosterols refer to a class of steroids widely distributed in plants as an essential component of plant cell membranes. They include stigmasterol, beta-sitosterol, and campesterol. Stigmasterol has been found to increase the expression of proapoptotic genes (Bax, p53) and decrease the expression of the antiapoptotic gene Bcl-2 in HepG2 liver cancer cells. Stigmasterol is able to induce cell arrest in G0-G1 phase (stationary phase), resulting in fewer cells in the G2/M phase (division phase). It induces apoptosis and protective autophagy in gastric cancer cells while inhibiting the Akt/mTOR signaling pathway. β-sitosterol exhibits growth inhibitory and cytotoxic effects against a number of established cancer cell lines in vitro and in vivo, and remains free from acute/subacute toxic effects. β-sitosterol is widely used to treat chronic prostate diseases. In 2020, spendings on dietary supplements rich in beta-sitosterol accounted for $24 827 065 in the USA. Campesterol induces cell apoptosis via the mitochondrial pathway. It appears cytotoxic to U937 hepatocellular cancer cells. Campesterol induces cell apoptosis and activates proapoptotic signaling in ovarian cancer cell lines of a person. The present literature review demonstrates that specific substances in this group, beta-sitosterol, stigmasterol, and campesterol, provide pronounced antitumor effects.