Induced Cell Apoptosis Research Articles

Single-cell transcriptome profiling of m6A regulator-mediated methylation modification patterns in elderly acute myeloid leukemia patients

Millions of people worldwide die of acute myeloid leukaemia (AML) each year. Although N6-methyladenosine (m6A) modification has been reported to regulate the pathogenicity of AML, the mechanisms by which m6A induces dysfunctional hematopoietic differentiation in elderly AML patients remain elusive. This study elucidates the mechanisms of the m6A landscape and the specific roles of m6A regulators in hematopoietic cells of elderly AML patients. Notably, fat mass and obesity-associated protein (FTO) was found to be upregulated in hematopoietic stem cells (HSCs), myeloid cells, and T-cells, where it inhibits their differentiation via the WNT signaling pathway. Additionally, elevated YT521-B homology domain family proteins 2 (YTHDF2) expression in erythrocytes was observed to negatively regulate differentiation through oxidative phosphorylation, resulting in leukocyte activation. Moreover, IGF2BP2 was significantly upregulated in myeloid cells, contributing to an aberrant chromosomal region and disrupted oxidative phosphorylation. m6A regulators were shown to induce abnormal cell-cell communication within hematopoietic cells, mediating ligand-receptor interactions across various cell types through the HMGB1-mediated pathway, thereby promoting AML progression. External validation was conducted using an independent single-cell RNA sequencing (scRNA-Seq) dataset. The THP-1 and MV411 cell lines were utilized to corroborate the m6A regulator profile; in vitro experiments involving short hairpin RNA (shRNA) targeting FTO demonstrated inhibition of cell proliferation, migration, and oxidative phosphorylation, alongside induction of cell cycle arrest and apoptosis. In summary, these findings suggest that the upregulation of m6A regulators in HSCs, erythrocytes, myeloid cells, and T-cells may contribute to the malignant differentiation observed in AML patients. This research provides novel insights into the pathogenesis of AML in elderly patients and identifies potential therapeutic targets.

Metal Doping Enabling Defective CoMo-Layered Double Hydroxide Nanosheets as Highly Efficient Photosensitizers for NIR-II Photodynamic Cancer Therapy.

Photodynamic therapy (PDT) is attracting widespread attention as a promising strategy for tumor treatment. However, the efficacy of PDT is severely limited by the insufficient tissue penetration depth of the light source and low reactive oxygen species (ROS) generation efficiency. Herein, the metal doping strategy is reported to construct a series of defect-rich M-doped amorphous CoMo-layered double hydroxide (a-M-CoMo-LDH, M = Mn, Cu, Al, Ni, Mg, Zn) photosensitizers (PSs) for NIR-II PDT. Especially, M-doped CoMo-LDH nanosheets are synthesized through a simple hydrothermal method and then etched by acid treatment to prepare defect-rich a-M-CoMo-LDH nanosheets. Under NIR-II 1270 nm laser irradiation, the defect-rich a-Zn-CoMo-LDH nanosheets exhibit the optimal PDT performance compared with other a-M-CoMo-LDH nanosheets, and also possess much higher ROS production activity (3.9 times) than that of the pristine a-CoMo-LDH, with a singlet oxygen quantum yield up to 1.86, which is the highest among all the reported PSs. After polyethylene glycol (PEG) modification, the a-Zn-CoMo-LDH-PEG nanosheets can function as an effective inorganic PS for PDT, effectively inducing cell apoptosis in vitro and eradicating tumors in vivo. Notably, transcriptome sequencing analysis and further molecular validation highlight the critical role of the apoptotic/p53/AMPK/oxidative phosphorylation signaling pathways in a-Zn-CoMo-LDH-PEG-induced cancer cell apoptosis.

Antiproliferative Activity of Antioxidants-Rich Extracts from Olea europaea L. Leaves and Oil Against Six Cancerous Human Cell Lines

ABSTRACT The present work aims to study the cytotoxic effect of the methanolic extract of leaves and oil of three olive cultivars: Manzanillo, Picual and Koronieki. Against six cancer cell lines, namely MCF-7 and MDA (breast cancer), HepG2 (liver cancer), PC3 (prostate cancer), Caco-2 (colon cancer), and A549 (lung cancer) using the MTT method. The results obtained showed that Manzanillo leaf methanolic extract (LMME) and Manzanillo oil (OMME) gave the highest cytotoxicity with the lowest IC50 against Caco2 and A549 cell lines. To explain this result, the mechanism of action was studied at the chemical, cellular and molecular levels. The chemical composition analysis of LMME and OMME was performed by GC-MAS. Furthermore, phytochemical analysis was performed. In addition to cell cycle analysis and apoptosis induction, the gene expression of three apoptotic genes was measured. The total phenolic contents (TPC) and total flavonoid contents (TFC) of (LMME) were greater than that of (OMME). Both LMME and OMME had arrested cell cycle at G1 phase for each of Caco2 and A549 cells. LMME and OMME induce up regulation of Casp3 and BAX genes and down regulation of Bcl-2 gene. These results indicated that, LMME and OMME had anti-proliferation effect against Caco2 and A549 cells through induction of apoptosis pathway. Further detailed studies are needed to examine the effect of each fraction of whole extract.

Nimotuzumab and irinotecan synergistically induce ROS-mediated apoptosis by endoplasmic reticulum stress and mitochondrial-mediated pathway in cervical cancer.

Irinotecan (CPT-11), a chemotherapeutic agent used to treat several types of cancer, induces cytotoxic effects on healthy cells. The epidermal growth factor receptor (EGFR) plays a crucial role in various forms of cancer. Nimotuzumab (NmAb), a monoclonal antibody that targets the EGFR, is utilized in some countries to treat malignancies that have an overexpression of EGFR. Yet, there is a lack of literature on the potential anticancer properties of the CPT-11 and NmAb combination on in vitro human cervical cancer cells. This study investigates the apoptosis mode of the CPT-11 and NmAb combination on cervical HeLa cancer cells. The Annexin V/propidium iodide staining examination demonstrated that the combination of CPT-11 and NmAb resulted in a decrease in the number of viable cells and more potent induction of cell apoptosis than the effects of CPT-11 or NmAb alone in HeLa cells. Furthermore, the combined treatment resulted in elevated levels of reactive oxygen species (ROS) and Ca2+ compared to the treatment with CPT-11 or NmAb alone. Cells that were pretreated with N-acetyl-l-cysteine, a substance that scavenges ROS, and then treated with CPT-11, NmAb, or a combination of CPT-11 and NmAb exhibited higher numbers of viable cells compared to those treated with CPT-11 or NmAb alone. The combination of CPT-11 and NmAb resulted in significantly higher caspase-3, -8, and -9 activity levels than CPT-11 or NmAb alone, as measured by flow cytometer assay. The combination of CPT-11 and NmAb in HeLa cells resulted in elevated endoplasmic reticulum stress-, mitochondria-, and caspase-mediated proteins compared to treatment with CPT-11 or NmAb alone. According to these observations, NmAb enhances the effectiveness of CPT-11 in fighting cancer by stimulating cell death in the HeLa cells. Therefore, NmAb has the potential to improve the efficacy of CPT-11 as a future cervical cancer treatment in humans.

The Effects of Phenylpropanoid and Aurone Compounds on Cell Cycle Modulation and Apoptosis Induction in 4T1 Breast Cancer Cells

The Effects of Phenylpropanoid and Aurone Compounds on Cell Cycle Modulation and Apoptosis Induction in 4T1 Breast Cancer Cells

Styryl dyes for viscosity measurement and detection of pathological processes in mitochondria of living cells using fluorescence lifetime imaging microscopy, a critical study

In the present work, two molecular rotors based on styryl dyes were synthesized and investigated. Both dyes showed significant sensitivity to the viscosity of the medium. Due to their significant positive charge, they efficiently accumulated in mitochondria of living cells. Binding to mitochondria resulted in increased fluorescence intensity and fluorescence lifetime of the dyes, allowing them to be visualized without washing off the unbound dye. We have also shown that the fluorescence lifetime of the studied molecular rotors is determined not only by the viscosity of the medium, but also by interactions with cell components such as proteins and nucleic acids. The present work clearly shows that these interactions do not allow a reliable estimation of viscosity in cell organelles using the synthesized dyes. This compromises the results of previous viscosity studies using molecular rotors at least of the styryl type. Nevertheless, induction of cell apoptosis by benzylviologen led to an increase in brightness and fluorescence lifetime of the dyes, which can be caused by both changes in viscosity and changes in the expression profile of proteins localized in mitochondria and interacting with the dyes. Thus, the obtained styryl dyes, like previously published homologous compounds, cannot be used for viscosity measurements, but can be used for identification of pathological states of the cell.

TRIM16 and PRC1 Are Involved in Pancreatic Cancer Progression and Targeted by Delphinidin.

Pancreatic cancer (PC) is the leading cause of cancer-related death worldwide, and new biomarkers, therapeutic targets, and candidate drugs are needed. In this work, three PC-related microarray datasets (GSE183795, GSE28735, and GSE62452) were analyzed. The differentially expressed genes (DEGs) of PC were obtained with the limma package in R. Weighted gene co-expression network analysis (WGCNA) and machine learning approaches were used to screen the hub genes. Kaplan-Meier plotter and receiver operating characteristic (ROC) curve analysis were utilized to assess the diagnostic efficacy of the hub genes. The binding ability between natural bioactive ingredients and hub proteins was evaluated by molecular docking and molecular dynamics simulation. CCK-8, flow cytometry, transwell, and western blot assays were used to analyze the viability, apoptosis, cell cycle progression, invasion, and pathway change of PC cells. Additionally, a nude mice model was used to evaluate the aggressive properties of PC cells invivo. In this study, a total of 988 DEGs were identified, which were mainly enriched in cell adhesion and PI3K-Akt signaling pathway, and two core genes TRIM16 and PRC1 were further identified. The overall survival of patients with high expression of TRIM16 and PRC1 was shorter. Delphinidin (Del) had good binding affinity with both TRIM16 and PRC1, and Del could inhibit the viability, invasion, and metastasis of PC cells and induce cell apoptosis and G0/G1 phase arrest. In addition, Del could promote the activation of p53 and inhibit the activation of the PI3K/AKT signaling pathway in PC cells. In summary, TRIM16 and PRC1 are identified as prognostic biomarkers and therapeutic targets for PC, and Del has good binding affinity with them and may be a potential therapeutic agent for PC.

A highly branched glucomannan from the fruiting body of Schizophyllum commune: Structural characteristics and antitumor properties analysis

In this study, a highly branched glucomannan (SCP-1) from Schizophyllum commune fruiting body with good solubility was isolated, and its structural characteristics and antitumor properties were analyzed. The monosaccharides of SCP-1 were fucose, glucosamine hydrochloride, galactose, glucose and mannose with a relative molar ratio of 14:6:210:593:177, and the molecular weight (Mw) of SCP-1 was 15.1 kDa. SCP-1 showed a rough and dense surface, and it was aggregated to particles in distilled water, though it might have triple-helix conformation. The main backbone chain of SCP-1 was →[3)-β-D-Glcp-(1]3→3)-β-D-Glcp-(1→2)-α-D-Manp-(1→2)-α-D-Manp-(1→3)-α-D-Glcp-(1→ and three sides chains including α-D-Glcp-(1→[6)-β-D-Glcp-(1]2→, α-D-Glcp-(1→3)-α-D-Manp-(1→ and α-D-Glcp-(1→[6)-α-D-Galp-(1]3→ were linked with 1,6-glycosidic bond, which was significantly different with the schizophyllan isolated from the mycelia of S. commune. SCP-1 could significantly inhibit the growth of A549 cells, the inhibition rate reached 41.62 % and the percentage of cells in S phase increased from 27.17 % to 56.40 % (400 μg/mL, 48 h). Moreover, SCP-1 could induce cell apoptosis and the total apoptosis rate reached 28.13 %. SCP-1 exerted apoptosis inducing effect probably by reducing the expression ratio of Bcl-2/Bax and the p-PI3K, p-Akt and p-mTOR expression level. The results showed that SCP-1 might have the potential to act as an antitumor agent for lung cancer therapy.

Protopanaxadiol triggers G0/G1 cell cycle arrest and apoptosis in human cervical cancer HeLa cells through the PPER pathway

Protopanaxadiol (PPD) is considered to be the most active pharmacological element in ginseng and has been widely studied for its anticancer effects. However, the detailed anticancer mechanism of this compound in cervical cancer (CC) HeLa cells has yet to be thoroughly understood. In this research, we discovered that PPD effectively inhibits CC HeLa cell proliferation and cause morphological changes, with an IC50 measured at 34.18 μM. Based on mRNA-seq analysis, we revealed the mechanism by which PPD inhibits HeLa cell proliferation. The results from Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated significant enrichment of DGEs in the cell cycle and protein processing in the endoplasmic reticulum (PPER) pathway. By inducing DNA damage, PPD resulted in G0/G1 phase cell cycle arrest, inhibited Bcl-2 to cause ROS production, upregulated cytochrome c (Cyto-c) expression, thereby further reducing mitochondrial membrane potential (Δψm), activated the caspase family, and induced cell apoptosis. In addition, PPD promoted Ca2+ leakage, downregulated the PPER pathway (PERK, ATF6, and IRE1α), increased Chop expression levels, and mediated programmed cell death. These observations imply that PPD can induce apoptosis in HeLa cells, highlighting its potential as a novel natural therapeutic for cervical cancer.

GCRV-II major outer capsid protein VP4 promotes cell apoptosis by VDAC2-mediated calcium pathway facilitation

Grass Carp Reovirus (GCRV) is widely concerned because of its widespread prevalence and high mortality to grass carp (Ctenopharyngodon idellus). Viral protein 4 (VP4) is an important major outer capsid protein of GCRV and is involved in the regulation of cell cycle and cycle of GCRV replication. However, the elaborate function of VP4 remains to be explicated. To understand its function, we screened the transcriptome of Ctenopharyngodon idellus kidney (CIK) cells transfected with VP4 and found that VP4 may be involved in regulation of ion transmembrane transporter activity and calcium signaling pathway. It was observed through transmission electron microscopy and confocal microscopy. VP4 causes endoplasmic reticulum (ER) stress and leads to abnormal Calcium ions (Ca2+) concentration in cells. Also, VP4 promoted the loss of mitochondrial membrane potential, which allowed a large amount of Ca2+ to enter mitochondria and led to mitochondrial damage and apoptosis. In this transcriptome, we found that voltage-dependent anion channel 2 (VDAC2) was significantly upregulated. Moreover, the results also showed that the expression of C.idellus voltage-dependent anion channel 2 (CiVDAC2) and the degree of cell apoptosis were increased along with the increase of VP4 transfection. In contrast, knockdown of CiVDAC2 can reduce the concentration of Ca2+ and the occurrence of apoptosis caused by VP4 transfection. In conclusion, the results demonstrated that VP4 can induce cell apoptosis through VDAC2-mediated calcium pathway facilitation. This study provides some insights for the prevention and treatment of GCRV infection in grass carp.

Research Progress on the Anticancer Activity of Plant Polysaccharides.

Tumor is a serious threat to human health, with extremely high morbidity and mortality rates. However, tumor treatment is challenging, and the development of antitumor drugs has always been a significant research focus. Plant polysaccharides are known to possess various biological activities. They have many pharmacological properties such as immunomodulation, antitumor, antiviral, antioxidative, antithrombotic, and antiradiation effects, reduction of blood pressure and blood sugar levels, and protection from liver injury. Among these effects, the antitumor effect of plant polysaccharides has been widely studied. Plant polysaccharides can inhibit tumor proliferation and growth by inhibiting tumor cell invasion and metastasis, inducing cell apoptosis, affecting the cell cycle, and regulating the tumor microenvironment. They also have the characteristics of safety, high efficiency, and low toxicity, which can alleviate, to a certain extent, the adverse reactions caused by traditional tumor treatment methods such as surgery, radiotherapy, and chemotherapy. Therefore, this paper systematically summarizes the direct antitumor effects of plant polysaccharides, their regulatory effects on the tumor microenvironment, and intervening many common high-incidence tumors in other ways. It also provides data support for the administration of plant polysaccharides in modern tumor drug therapy, enabling the identification of new targets and development of new drugs for tumor therapy.

Chlorhexidine Dihydrochloride Shows Anti-tumor Effects in Desmoid Tumors and Colorectal Cancer.

Desmoid tumors (DTs), or aggressive fibromatosis, are rare neoplasms arising from connective tissue, frequently exhibiting local invasiveness. The limited treatment options and high recurrence rates of DTs highlight the need for novel therapeutic strategies. This study investigated the efficacy of chlorhexidine dihydrochloride (CD) in inhibiting the growth of DTs and colorectal cancer (CRC). A mouse model with Apc mutations, specifically Apc1638N/+, was generated to study DTs. DT cells (Apc1638N+) (DTA) were collected from the mice for in vitro experiments. DTA were treated with CD, along with a CRC cell line (HCT-116), and tumor organoids derived from Apc1638N/+ mice. The effects of CD were assessed through cell viability assay (WST assay), colony formation assay, and cell migration assay. We tested the induction of cell apoptosis through caspase 3/7 activity assays and immunoblot analysis of cleaved-caspase 3 and cleaved-PARP1. Additionally, CD was tested for its anti-tumor efficacy using an in vivo CRC xenograft model with the HCT-116 cell line. CD significantly inhibited the viability, migration, and colony formation of DTA and CRC cells. It remarkably decreased the tumor growth in organoids derived from intestinal tumor cells in the Apc1638N/+ mouse model. Furthermore, CD showed anti-tumor effects in an in vivo CRC xenograft model using the HCT-116 cell line. CD represents a promising therapeutic strategy for treating both DTs and CRC.

Assessing the stereoselective bioactivity and biotoxicity of penthiopyrad in soil environment for efficacy improvement and hazard reduction

Penthiopyrad, a chiral pesticide, has been widely used in agricultural production. However, systematic evaluation of stereoselective bioactivity and biotoxicity of penthiopyrad in soil environment is insufficient. In this study, the stereoselective bioactivity of penthiopyrad against three soil-borne disease pathogens and its stereoselective biotoxicity to soil non-target organisms were investigated. The present results showed that the bioactivities of S-penthiopyrad were 546, 76 and 1.1-fold higher than those of R-penthiopyrad due to their different interaction modes with SDH in different target pathogens. S-penthiopyrad was more persistent in the soil environment and had stronger bioaccumulation than R-penthiopyrad. The accumulation of penthiopyrad in earthworms induced the response of detoxification system, resulting in the significant increases in the activity of detoxifying enzymes, such as GST, CarE, and CYP450. Additionally, both S-penthiopyrad and R-penthiopyrad induced cell apoptosis, intestinal damage and differentially expressed genes in earthworms, especially S-penthiopyrad. Furthermore, S-penthiopyrad has stronger binding capacity with COL6A and ACE proteins, while R-penthiopyrad has stronger binding capacity with CYP450 family proteins, which may be the main reason for the differences in biotoxicity between PEN enantiomers. Considering the differences in bioactivity and biotoxicity of penthiopyrad enantiomers, as well as the modes of action of pesticides on target and non-target organisms, S-penthiopyrad has greater potential for future development.

METTL14 Promotes Lipopolysaccharide-Induced Myocardial Damage via m6A-Dependent Stabilization of TRPM7 mRNA.

Sepsis-induced myocardial injury (SIMI) is a vital pathological component of severe sepsis and septic shock. As a prevalent internal mRNA modification in eukaryotic cells, N6-methyladenosine (m6A) modification is implicated in sepsis and immune disorders. Methyltransferase-like 14 (METTL14), a core subunit of the methyltransferase complex that catalyzes messenger RNA m6A modification, is involved in the regulation of human cardiomyocyte cell line (AC16) injury. This study aimed to explore the role and mechanism of METTL14 in lipopolysaccharide (LPS) -induced myocardial injury.Cell viability and apoptosis were analyzed via 3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and TdT-mediated dUTP nick-end labeling (TUNEL) assay. The Tumor necrosis factor alpha (TNF-α) and Interleukin-1beta (IL-1β) levels were analyzed via Enzyme linked immunosorbent assay (ELISA). Caspase-3 activity, reactive oxygen species activity, malondialdehyde level, and glutathione level were assessed using special assay kits. The levels of transient receptor potential melastatin 7 (TRPM7) and METTL14 mRNA were determined via Real-time quantitative polymerase chain reaction (RT-qPCR). Meanwhile, the protein levels of TRPM7, METTL14, phospho-p65 (p-p65), total p65 (p65), p-IκBα, and total IκBα (IκBα) were examined via western blot assay.LPS treatment repressed AC16 cell viability and induced cell apoptosis, inflammatory response, oxidative stress, and ferroptosis in vitro. METTL14 and TRPM7 were upregulated in LPS-treated AC16 cells. At the molecular level, METTL14 could increase the stability of TRPM7 mRNA via m6A methylation. Moreover, METTL14 deficiency could abolish LPS-triggered AC16 cell injury and ferroptosis via TRPM7 regulation.METTL14 knockdown reversed LPS-caused myocardial cell damage mainly by regulating the stability of TRPM7 mRNA, providing a novel therapeutic target for septic cardiomyopathy treatment.

Cytotoxic activity of silver nanoparticles prepared by eco-friendly synthesis using Lythrum salicaria extract on breast cancer cells.

Metal nanoparticles (NPs) have widely been investigated due to their several applications in therapeutic activities. The current investigation highlights the cytotoxic effects of the eco-friendly phytosynthesis route for silver nanoparticles using Lythrum salicaria (L. salicaria) extract (AgNPs-LS). The change in color from colorless to brown confirmed the reduction of silver ions to AgNPs. x-ray diffraction (XRD) analysis demonstrated high crystallinity. The surface morphology of AgNPs-LS was spherical, and their average sizes were 50nm. energy-dispersive x-ray analysis (EDAX) confirmed that silver was the predominant component, indicating the involvement of L. salicaria plant extract in the green synthesis process. In vitro dimethyl thiazolyl tetrazolium bromide (MTT) assay showed significant cytotoxicity of AgNPs-LS against MCF7 cells, with an IC50 of 113µg mL- 1. In contrast, AgNPs-LS showed minimal cytotoxicity to HEK293 cells (IC50: 254µg mL- 1), demonstrating a higher sensitivity of cancer cells to AgNPs-LS. Moreover, AgNPs-LS resulted in MCF7 cells producing reactive oxygen species (ROS) and undergoing cell cycle arrest at the G2/M phase, serving as barriers to the proliferation of cancer cells. Annexin V fluorescein isothiocyanate (FITC) assays and fluorescence microscopy confirmed the induction of apoptosis in MCF7 cells by AgNPs-LS. Gene expression analysis revealed upregulated pro-apoptotic genes (Bax, p53, caspase-3, and caspase-9) and downregulated an anti-apoptotic gene (Bcl2) in michigan cancer foundation7 (MCF7) cells treated with AgNPs-LS. These results indicate that AgNPs-LS induced apoptosis via the intrinsic pathway (mitochondrial-mediated mechanism) and involved p53-dependent regulation. The current study results implied that AgNPs-LS fabricated by a bio-green approach could be helpful to the future of nanomedicine.

Honokiol-loaded PLGA-PEG nanoparticles with solubility in water for infusion treatment of solid cancer

This study aimed to investigate honokiol-loaded PLGA-PEG nanoparticles with good stability in water for infusion treatment. The characteristics of this nanoparticle-based delivery system were analyzed in a previous study. Additionally, fourier transform infrared spectroscopy confirmed the successful loading of honokiol into PLGA-PEG nanoparticles, revealing characteristic chemical shifts. In vitro drug release studies demonstrated sustained release over 72 h, with lower release rates compared to free honokiol. Cytotoxicity assays on A549 and 3LL lung cancer cells showed that the IC50 values for the nanoparticles were significantly lower than those for free honokiol, with values of 8.76 ± 1.51 μg/ml and 7.46 ± 0.53 μg/ml for the nanoparticles, compared to 12.03 ± 1.07 μg/ml and 10.51 ± 1.27 μg/ml for free honokiol, respectively. Apoptosis induction in cancer cells was demonstrated, emphasizing the potential therapeutic benefits. In vivo studies using a murine carcinoma model showed higher concentrations of honokiol in tumor tissues and major organs with the nanoparticle formulation. Tumor growth inhibition was significantly greater in the nanoparticle-treated group, achieving an inhibition ratio (IR) of 85.32 %, compared to 65.99 % for free honokiol. Hematological and biochemical analyses and histopathological examination indicated no significant adverse effects. The study suggests that honokiol-loaded PLGA-PEG nanoparticles covered by carboxyl (COOH) groups (Nano-HK), with good solubility in water, enhance the delivery and therapeutic efficacy of honokiol, providing a promising avenue for cancer treatment.

Molecular mechanisms of apoptosis induction in KG1a leukemia cells by the Ginkgo biloba extract (EGb)

Molecular mechanisms of apoptosis induction in KG1a leukemia cells by the Ginkgo biloba extract (EGb)

USP5-dependent HDAC1 promotes cisplatin resistance and the malignant progression of non-small cell lung cancer by regulating RILP acetylation levels.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with cisplatin (DDP) resistance being a significant challenge in its treatment. Histone deacetylase 1 (HDAC1) has been implicated in the regulation of NSCLC progression; however, its role in the resistance of NSCLC to DDP remains unclear. The mRNA levels of HDAC1, ubiquitin specific peptidase 5 (USP5), and Rab interacting lysosomal protein (RILP) were analyzed by quantitative real-time polymerase chain reaction. The protein expression of HDAC1, multidrug resistance protein 1 (MRP1) and RILP was detected by western blotting assay or immunohistochemistry assay. The IC50 value of DDP was determined using a cell counting kit-8 assay, while cell proliferation, apoptosis, and invasion were assessed using 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, and trans well invasion assay, respectively. Cancer stem-like cell properties were analyzed by a sphere formation assay. The interaction between USP5 andHDAC1 was investigated using MG132 assay and co-immunoprecipitation (Co-IP).RILP acetylation was analyzed by a Co-IP assay. A xenograft mouse model assay was employed to study the in vivo effects of HDAC1 silencing on DDP sensitivity. HDAC1 expression was upregulated in DDP-resistant NSCLC tissues and cells. Silencing HDAC1 enhanced the sensitivity of NSCLC cells to DDP, inhibited cell proliferation, invasion, and the formation of microspheres and induced cell apoptosis. USP5 was found to deubiquitinate and stabilize HDAC1 in DDP-resistant NSCLC cells. Moreover, HDAC1 overexpression reversed the effects induced by USP5 silencing. HDAC1 also sensitized Rab-interacting lysosomal protein (RILP) acetylation in DDP-resistant NSCLC cells, and RILP upregulation counteracted the effects of HDAC1 overexpression in DDP-resistant NSCLC cells. HDAC1 silencing also improved the sensitivity of tumors to DDP in vivo. USP5-dependentstabilization of HDAC1 contributed to cisplatin resistance and the malignancy of NSCLC by diminishing the levels of RILP acetylation, which suggested that targeting the HDAC1-USP5axis might represent a novel therapeutic strategy for overcoming DDP resistance in NSCLC patients.

Functionalization of ZIF-8 Nanoparticles for Efficient Delivery of 4-Aminoantipyrine and Apoptosis Induction in Breast Cancer Cells

Functionalization of ZIF-8 Nanoparticles for Efficient Delivery of 4-Aminoantipyrine and Apoptosis Induction in Breast Cancer Cells

Free Cholesterol-Induced Liver Injury in Non-Alcoholic Fatty Liver Disease: Mechanisms and a Therapeutic Intervention Using Dihydrotanshinone I.

Build-up of free cholesterol (FC) substantially contributes to the development and severity of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the specific mechanism by which FC induces liver injury in NAFLD and propose a novel therapeutic approach using dihydrotanshinone I (DhT). Rather than cholesterol ester (CE), we observed elevated levels of total cholesterol, FC, and alanine transaminase (ALT) in NAFLD patients and high-cholesterol diet-induced NAFLD mice compared to those in healthy controls. The FC level demonstrated a positive correlation with the ALT level in both patients and mice. Mechanistic studies revealed that FC elevated reactive oxygen species level, impaired the function of lysosomes, and disrupted lipophagy process, consequently inducing cell apoptosis. We then found that DhT protected mice on an HCD diet, independent of gut microbiota. DhT functioned as a potent ligand for peroxisome proliferator-activated receptor α (PPARα), stimulating its transcriptional function and enhancing catalase expression to lower reactive oxygen species (ROS) level. Notably, the protective effect of DhT was nullified in mice with hepatic PPARα knockdown. Thus, these findings are the first to report the detrimental role of FC in NAFLD, which could lead to the development of new treatment strategies for NAFLD by leveraging the therapeutic potential of DhT and PPARα pathway.