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Photodynamic therapy (PDT) is a promising cancer treatment. This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]-10,15,20-triphenyl-porphyrin (DTP) mediated PDT (DTP-PDT). Cell viability, reactive oxygen species (ROS), and apoptosis were measured with a Cell Counting Kit-8 assay, DCFH-DA fluorescent probe, and Hoechst staining, respectively. Cell apoptosis- and autophagy-related proteins were examined using western blotting. RNA sequencing was used to screen differentially expressed mRNAs (DERs), and bioinformatic analysis was performed to identify the major biological events after DTP-PDT. Our results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 cells. The ROS scavenger N-acetyl-L-cysteine (NAC) and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced cytotoxicity. DTP-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2, which could also be inhibited by NAC or SB203580. The level of LC3B-II, a marker of autophagy, was increased by DTP-PDT. A total of 3496 DERs were obtained after DTP-PDT. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes, the nuclear lumen, protein binding, cell cycle, protein targeting to the endoplasmic reticulum, and ribosomal DNA replication. Disease Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle checkpoints. Protein-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting genes. Therefore, DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy, partly through ROS and the P38 MAPK signaling pathway. Genes associated with the cell cycle, ribosomes, DNA replication, and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 Chen et al.)

JS-K as an exogenous NO donor could release NO after activation by glutathione S-transferases (GSTs). The present study explores the effects of JS-K on MAPK pathway in HepG2 and Bel-7402 cells. JS-K significantly prompted apoptosis and SB203580 (a p38 inhibitor) and SP600125 (a JNK inhibitor) prior to JS-K could partly reverse apoptosis and activation of cleaved-caspase-3 and cleaved PARP. However, U0126 (a MEK inhibitor) strengthened the cell apoptosis and the expressions of cleaved-caspase-3 and cleaved PARP. JS-K caused phosphorylation of p38 MAPK and JNK but attenuated phosphorylation of ERK, which were reversed by Carboxy-PTIO (a NO scavenger). Meanwhile, the phosphorylation of HSP27, c-JUN and ATF-2 were activated in JS-K-treated cells. SB203580 and SP600125 could attenuate phosphorylation of p38 MAPK and JNK, respectively. The phosphorylation in downstream substrates of p38 MAPK and JNK was also abolished by SB203580 and SP600125 in JS-K-treated cells. Additionally, JS-K decreased phosphorylation of c-Raf, which subsequently caused a decrease of MEK1/2 phosphorylation. Several downstream targets of ERK1/2 including p90RSK and transcription factors (e.g., Elk-1, c-Myc and c-Fos) were inhibited. U0126 potentiated JS-K-induced inhibitory effect of Raf/MEK/ERK pathway. The same results were also observed in the downstream substrates of ERK1/2 including p90RSK, Elk-1, c-Myc and c-Fos. Moreover, Carboxy-PTIO abolished the inhibitory effect of Raf/MEK/ERK pathway triggered by JS-K. Finally, JS-K significantly suppressed the growth of rat primary hepatic carcinoma via MAPK pathway in vivo. Taken together, JS-K can induce hepatocellular carcinoma cells apoptosis through its activation of JNK and p38 MAPK and inactivation of Raf/MEK/ERK signaling pathways.

Background: PABA/NO, O 2 -{2,4-dinitro-5-[4-(N-methylamino) benzoyloxy] phenyl} 1-(N, N-dimethylamino) diazen-1-ium-1,2-diolate, is a diazeniumdiolate-based NO-donor prodrug that releases exogenous nitric oxide at high concentrations to induce apoptosis in many tumor cell lines., Purpose: This study aimed to determine the effects of PABA/NO on hepatocellular carcinoma proliferation and apoptosis induction both in vitro and in vivo experiments., Results: PABA/NO dramatically inhibited the growth of Bel-7402 hepatocellular carcinoma cells and significantly induced apoptosis in a concentration-dependent manner, accompanied by down-regulation of Bcl-2 and Bcl-xL, up-regulation of Bax and Bad, release of Cyt c and activation of cleaved-caspase-9/3 and cleaved-PARP, which were related to suppressing PI3K/AKT/mTOR and MEK/ERK signaling pathways. LY294002 (a PI3K inhibitor) and U0126 (an ERK inhibitor) prior to PABA/NO were found to synergistically enhance PABA/NO-induced apoptosis. Carboxy-PTIO as a NO scavenger obviously attenuated PABA/NO-induced apoptosis. Additionally, H22 tumor-bearing mice experiments demonstrated that PABA/NO exerted good anti-tumor effects via reducing tumor volume, tumor weight and decreasing the expression of CD34. Furthermore, PABA/NO treatment strongly inhibited the phosphorylation of PI3K/AKT/mTOR and MEK/ERK signaling pathways in H22 hepatocellular carcinoma tissues., Conclusions: PABA/NO induced apoptosis through inhibition of PI3K/Akt/mTOR and MEK/ERK pathway in hepatocellular carcinoma cells.

JS-K, (O 2 -(2, 4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen 1-ium-1, 2-diolate), is a novel diazeniumdiolate-based nitric oxide donor prodrug. The present study investigated the relationship between reactive oxygen species (ROS) elevation, Ca 2+ overload and mitochondrial disruption in JS-K-induced apoptosis. JS-K could significantly inhibit cell growth and induce apoptosis in a dose-dependent manner. Meanwhile, JS-K caused the accumulation of ROS, overload of Ca 2+ , decrease of mitochondrial membrane potential, release of cytochrome c (Cyt c) from mitochondria to the cytoplasm, increase of Bax-to-Bcl-2 ratio and activation of caspase- 9/3. NAC (an antioxidant) or BAPTA (an intracellular Ca 2+ chelator) could partially reverse the above events, while BAPTA had little effect on the levels of ROS. Furthermore, pre-treatment with Carboxy-PTIO (a NO scavenger) significantly blocked the increasing of ROS, cytosolic Ca 2+ and reversed the loss of mitochondrial membrane potential in JS-K-induced apoptosis. Taken together, the results suggested that NO released from JS-K could significantly induce HepG2 cell apoptosis through a ROS/Ca 2+ /caspase-mediated mitochondrial pathway., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Protein phosphatase 2A (PP2A) is an important enzyme within various signal transduction pathways. The present study was investigated PP2A mediates JS-K-induced apoptosis by affecting Bcl-2 family protein. JS-K showed diverse inhibitory effects in five HCC cell lines, especially HepG2 cells. JS-K caused a dose- and time-dependent reduction in cell viability and increased in levels of LDH release. Meanwhile, JS-K- induced apoptosis was characterized by mitochondrial membrane potential reduction, Hoechst 33342 + /PI + dual staining, release of cytochrome c (Cyt c), and activation of cleaved caspase-9/3. Moreover, JS-K-treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C), decrease of anti-apoptotic Bcl-2 family-protein expression including p-Bcl-2 (Ser70), Bcl-2, Bcl-xL, and Mcl-1 as well as the increase of pro-apoptosis Bcl-2 family-protein including Bim, Bad, Bax, and Bak. Furthermore, JS-K caused a marked increase of intracellular NO levels while pre-treatment with Carboxy-PTIO (a NO scavenger) reduced the cytotoxicity effects and the apoptosis rate. Meanwhile, pre-treatment with Carboxy-PTIO attenuated the JS-K-induced up-regulation of PP2A, Cyt c, and cleaved-caspase-9/3 activation. The silencing PP2A-C by siRNA could abolish the activation of PP2A-C, down-regulation of anti-apoptotic Bcl-2 family-protein (p-Bcl-2, Bcl-2, Bcl-xL, and Mcl-1), increase of pro-apoptosis Bcl-2 family-protein (Bim, Bad, Bax, and Bak) and apoptotic-related protein (Cyt c, cleaved caspase-9/3) that were caused by JS-K in HepG2 cells. In addition, pre-treatment with OA (a PP2A inhibitor) also attenuated the above effects induced by JS-K. In summary, NO release from JS-K induces apoptosis through PP2A activation, which contributed to the regulation of Bcl-2 family proteins., (© 2018 Wiley Periodicals, Inc.)

Background: JS-K is a nitric oxide (NO) donor and could generate intracellularly high levels of NO. The study explores PP2A as a tumor suppressor is a major determinant mediating JS-K-caused apoptosis in human hepatocellular carcinoma (HCC) cells., Methods: The human HCC cell lines (PLC5, Huh-7, Bel-7402, SMMC-7721 and HepG2) were used to assess effects of JS-K on cell viability, apoptosis induction and PP2A activation. Effects of JS-K on cell morphology, mitochondrial membrane potential, apoptosis and NO levels were determined in HCC cells expressing PP2A. Simultaneously, the expression of PP2A family including PP2A-A(α/β), PP2A-B55, PP2A-C(α/β) and the substrates of PP2A, such as β-catenin, c-Myc and p-Bcl-2 (Ser70) were detected in sensitive HCC cells. Furthermore, the role of NO in mediating the expression of PP2A was further validated with Z-VAD-FMK (a caspase inhibitor), Carboxy-PTIO (a NO scavenger), okadaic acid (OA, a PP2A inhibitor) and FTY720 (a PP2A agonist) in JS-K treated cells. In addition, the genetic manuplation of PP2A including overexpression and knockdown have been also performed in JS-K treated cells. Moreover, the rat model of primary hepatic carcinoma was established with diethylnitrosamine for 16 weeks to verify the anti-tumor effects of JS-K in vivo. Immunohistochemical and Western blot analysis were used to determine the expression of proteins in rat primary hepatic carcinoma tissues., Results: JS-K significantly inhibited cell proliferation, increased apoptosis rate and activated PP2A activity in five HCC cells viability, especially SMMC7721 and HepG2 cells. It was characterized by loss of mitochondrial membrane potential, significant externalization of phosphatidylserine, nuclear morphological changes. Moreover, JS-K enhanced Bax-to-Bcl-2 ratio, released cytochrome c (Cyt c) from mitochondria, activated cleaved-caspase-9/3 and the cleavage of PARP, and decreased the expression of X-linked inhibitor of apoptosis protein (XIAP). Both Z-VAD-FMK and Carboxy-PTIO suppressed the activation of cleaved-caspase-9/3 and of cleaved-PARP in JS-K-treated sensitive HCC cells. Simultaneously, JS-K treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C) but not PP2A-A and PP2A-B55, which subsequently inactivated and dephosphorylated the PP2A substrates including β-catenin, c-Myc, and p-Bcl-2 (Ser70). However, silencing PP2A-C could abolish both the activation of PP2A-C and down-regulation of β-catenin, c-Myc and p-Bcl-2 (Ser70) in sensitive HCC cells. Conversely, PP2A overexpression could enhance the effects of JS-K on activation of PP2A and down-regulation of β-catenin, c-Myc and p-Bcl-2 (Ser70). In addition, adding okadaic acid (OA), a PP2A inhibitor, abolished the effects of JS-K on apoptosis induction, PP2A activation and the substrates of PP2A dephosphorylation; FTY720, a PP2A agonist, enhanced the effects of JS-K including apoptosis induction, PP2A activation and the substrates of PP2A dephosphorylation. The mice exhibited a lower number and smaller tumor nodules in response to JS-K-treated group. A marked increase in the number of hepatocytes with PCNA-positive nuclei (proliferating cells) was evident in DEN group and tended to decrease with JS-K treatment. Furthermore, JS-K treatment could induce PP2A activation and the substrates of PP2A inactivation such as β-catenin, c-Myc and p-Bcl-2(Ser70) in DEN-induced hepatocarcinogenesis., Conclusions: High levels of NO released from JS-K induces a caspase-dependent apoptosis through PP2A activation.

The Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway has been shown to play an important role in hematopoiesis, and hematopoietic cells are sensitive targets for benzene-induced hematotoxicity. We therefore hypothesized that dysregulation of the Akt/GSK-3β/β-catenin signaling was associated with benzene-induced hematotoxicity. Here, we showed that hydroquinone (HQ), a major metabolite of benzene in humans, significantly inhibited cell viability and colony formation while inducing apoptosis of human bone marrow mononuclear cells in vitro. Interestingly, we found that HQ inhibited the Akt affected β-catenin signaling by activation of GSK-3β, resulting in downregulation of β-catenin and its targets Cyclin D1 and Survivin. HQ blocked nuclear translocation of β-catenin and lymphoid enhancer-binding factor 1 (LEF-1), and importantly, HQ also reduced the interaction of β-catenin and LEF-1 in the nucleus. As expected, blockage of GSK-3β activity with a GSK-3β inhibitor lithium chloride (LiCl) or activation of Akt signaling with an Akt agonist insulin-like growth factor-1 (IGF-1) could inhibit HQ-induced activation of GSK-3β as well as hematotoxicity. Taken together, our results suggest that HQ-induced hematotoxicity in bone marrow mononuclear cells is associated with dysregulation of Akt/GSK-3β/β-catenin signaling due to the dissociation of β-catenin/LEF-1 complex, and LiCl and IGF-1 may be two potential agents to ameliorate HQ-induced hematotoxicity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Segetoside I is a plant-derived bisdesmosidic saponin from Vaccaria segetalis (Neck) with reported anticancer activities. This development has raised an interest in the therapeutic potential of segetoside I. Here, we report the in vitro and in vivo antitumor activities of segetoside I against some selected cancer cell lines (HepG2, human hepatoma; H22, mouse hepatoma; MCF-7, breast cancer; U251, gliocoma; BGC, HGC & SGC, gastric cancinoma; Lovo-1,colon cancer). MTT bioassay analysis showed that HepG2 cells were the most sensitive to segetoside I compared with other cancer cell lines, with lower toxicity in healthy mouse embryonic fibroblast cells. Segetoside I pretreatment of HepG2 resulted in apoptotic induction, dose-dependent DNA fragmentation, inhibition of cell migration, up-regulation of Bax and down-regulation of Bcl-2, which indicated that an apoptotic signaling event could have been initiated. The segetoside I also suppressed hepato-tumour growth in mice with virtually no cytotoxicity and prolonged animal survival, making it a strong oncology drug agent. These findings showed that segetoside I exhibited its antitumor activity via apoptotic induction and significantly support the possible application of the antitumor agent as a potential chemotherapeutic candidate worthy of further investigations., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

5-Fluorouracil (5-FU)-based chemotherapy as a first-line treatment is quite limited, because of its inefficiency and clinical resistance to it. The search for chemosensitizers that could augment its efficiency and overcome the drug resistance to 5-FU has kindled great interest among scientists. Selenocystine (SeC), a naturally occurring selenoamino acid, displayed broad-spectrum anticancer activity in our previous studies. This study demonstrates that SeC acts as an effective enhancer of 5-FU-induced apoptosis in A375 human melanoma cells through induction of mitochondria-mediated apoptosis with the involvement of DNA damage-mediated p53 phosphorylation and ERK inactivation. Pretreatment of the cells with SeC significantly enhanced 5-FU-induced loss of mitochondrial membrane potential (∆ψm) by regulating the expression levels of Bcl-2 family proteins. SeC and 5-FU in combination also triggered cell oxidative stress through regulation of the intracellular redox system and led to DNA damage and inactivation of ERK and AKT. Moreover, inhibitors of ERK and AKT effectively enhanced the apoptotic cell death induced by the combined treatment. However, pretreatment of the cells with glutathione reversed the apoptosis induced by SeC and 5-FU and recovered the expression of ERK and AKT inactivation, which revealed the important role of reactive oxygen species in cell apoptosis and regulation of ERK and AKT pathways. Taken together, our results suggest that a strategy of using SeC and 5-FU in combination could be a highly efficient way to achieve anticancer synergism., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The olfactory system is an unusual tissue in which olfactory receptor neurons (ORNs) are continuously replaced throughout the life of mammals. Clearance of the apoptotic ORNs corpses is a fundamental process serving important functions in the regulation of olfactory nerve turnover and regeneration. However, little is known about the underlying mechanisms. Olfactory ensheathing cells (OECs) are a unique type of glial cells that wrap olfactory axons and support their continual regeneration from the olfactory epithelium to the bulb. In the present study, OECs were identified to exist in two different states, resting and reactive, in which resting OECs could be activated by LPS stimulation and functioned as phagocytes for cleaning apoptotic ORNs corpses. Confocal analysis revealed that dead ORNs debris were engulfed by OECs and co-localized with lysosome associated membrane protein 1. Moreover, phosphatidylserine (PS) receptor was identified to express on OECs, which allowed OECs to recognize apoptotic ORNs by binding to PS. Importantly, engulfment of olfactory nerve debris by OECs was found in olfactory mucosa under normal turnover and was significantly increased in the animal model of olfactory bulbectomy, while little phagocytosis by Iba-1-positive microglia/macrophages was observed. Together, these results implicate OEC as a primary innate immunocyte in the olfactory pathway, and suggest a cellular and molecular mechanism by which ORNs corpses are removed during olfactory nerve turnover and regeneration., (Copyright © 2013 Wiley Periodicals, Inc.)

Background & Aims: Expression of osteopontin correlates with tumor progression and metastasis. The mechanisms by which osteopontin promotes tumor cell survival remain unclear. Here we used short-hairpin RNA-mediated gene silencing to investigate the antitumor effects by osteopontin depletion in hepatocellular carcinoma (HCC)., Methods: We applied polyethylenimine nanoparticles to deliver a short-hairpin RNA for depletion of osteopontin expression in HCC cells. Tumorigenicity and metastatic potentials of HCC cells were studied in vitro and in nude mice. Nuclear factor-kappaB (NF-kappaB) activation was analyzed by gel shift assay and luciferase analysis. The expressions of integrins were examined by real-time reverse-transcription polymerase chain reaction. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and mitochondrial membrane potential analysis., Results: Down-regulation of osteopontin inhibited HCC cell growth, anchorage-independent growth, adhesion with fibronectin and invasion through extracellular matrix in vitro, and suppressed tumorigenicity and lung metastasis in nude mice. Osteopontin silencing resulted in suppression of alphav, beta1, and beta3 integrin expressions, blockade of NF-kappaB activation, inhibition of Bcl-2/Bcl-xL and XIAP expressions, increase of Bax expression, and induction of a mitochondria-mediated apoptosis. Furthermore, down-regulation of osteopontin inhibited drug-induced NF-kappaB activation and sensitized HCC cells to chemotherapeutic agents in vitro, which led to complete regression of HCC xenografts in nude mice., Conclusions: Osteopontin may facilitate tumorigenesis and metastasis through prevention of tumor cells from apoptosis. RNA interference-mediated depletion of osteopontin may be a promising strategy for the treatment of HCC by sensitizing the chemotherapeutic drugs.

Reactive oxygen species (ROS) and cellular oxidant stress have long been associated with cancer. Here, we show that TIP30, also called CC3, regulates p53 mRNA stability and induces apoptosis by sensing of intracellular oxidative stress in human hepatocellular carcinoma (HCC) cells. Introduction of TIP30 induced more cell death in HepG2 cells with a high level of intracellular ROS than that in normal liver cell line, HL7702, which had low level of intracellular ROS. Treatment with an antioxidant agent attenuated TIP30-induced cell death in HepG2 cells, whereas oxidant H(2)O(2) augmented TIP30-induced cell death in HL7702 cells. The conformation of TIP30 was altered with the formation of an intermolecular disulfide bridge under oxidative stress. TIP30 greatly enhanced p53 expression and its transcriptional activity under oxidative stress, which was probably through stabilization of p53 mRNA. TIP30 induced apoptosis and mitochondrial dysfunction were blocked by silencing of p53 expression. The nuclear import of mRNA-binding protein HuR was blocked upon TIP30 introduction, which might be due to the interruption of the association of HuR with importin beta2. The elevated cytoplasmic HuR bound to p53 mRNA 3'-untranslated region, resulting in prolonged half-life of p53 mRNA. Our results suggest that TIP30 is involved in cellular oxidative stress surveillance and induces apoptosis through stabilization of p53 mRNA in HCC cells.

Background: Programmed cell death ligand‐1 (PD‐L1) is a promising target for immune checkpoint blockade therapy in breast cancer. However, the preoperative evaluation of PD‐L1 expression in breast cancer is rarely explored. Purpose: To determine the ability of radiomics signatures based on preoperative dynamic contrast‐enhanced (DCE) MRI to evaluate PD‐L1 expression in breast cancer. Study Type: Retrospective. Population: 196 primary breast cancer patients with preoperative MRI and postoperative pathological evaluation of PD‐L1 expression, divided into training (n = 137, 28 PD‐L1‐positive) and test cohorts (n = 59, 12 PD‐L1‐positive). Field Strength/Sequence: 3.0T; volume imaging for breast assessment DCE sequence. Assessment: Radiomics features were extracted from the first phase of DCE‐MRI by using the minimum redundancy maximum relevance method and least absolute shrinkage and selection operator algorithm. Three radiomics signatures were constructed based on the intratumoral, peritumoral, and combined intra‐ and peritumoral regions. The performance of the signatures was assessed using area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, and accuracy. Statistical Tests: Univariable and multivariable logistic regression analysis, t‐tests, chi‐square tests, Fisher exact test or Yates correction, ROC analysis, and one‐way analysis of variance. P < 0.05 was considered significant. Results: In the test cohort, the combined radiomics signature (AUC, 0.853) exhibited superior performance compared to the intratumoral (AUC, 0.816; P = 0.528) and peritumoral radiomics signatures (AUC, 0.846; P = 0.905) in PD‐L1 status evaluation, although the differences did not reach statistical significance. Data Conclusion: Intratumoral and peritumoral radiomics signatures based on preoperative breast MRI showed some potential accuracy for the non‐invasive evaluation of PD‐L1 status in breast cancer. Level of Evidence: 4 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

The Brucella type IV secretion system (T4SS) can promote the intracellular survival and reproduction of Brucella. T4SS secretes effector proteins to act on cellular signaling pathways to inhibit the host's innate immune response and cause a chronic, persistent Brucella infection. Brucella can survive in host cells for a long time by inhibiting macrophage apoptosis and avoiding immune recognition. The effector protein, BspF, secreted by T4SS, can regulate host secretory transport and accelerate the intracellular replication of Brucella. BspF has an acetyltransferase domain of the GNAT (GCN5-related N-acetyltransferases) family, and in our previous crotonylation proteomics data, we have found that BspF has crotonyl transferase activity and crotonylation regulation of host cell protein in the proteomics data. Here, we found that BspF attenuates the crotonylation modification of the interacting protein p53, which reduces the p53 expression through the GNAT domain. BspF can inhibit the transcription and protein expression of downstream apoptotic genes, thereby inhibiting host cell apoptosis. Additionally, the Brucella ΔbspF mutant stain promotes apoptosis and reduces the survival rate of Brucella in the cells. In conclusion, we identified that the T4SS effector protein BspF can regulate host cell apoptosis to assist Brucella in its long-term survival by attenuating crotonylation modification of p53 and decreasing p53 expression. Our findings reveal a unique mechanism of elucidating how Brucella regulates host cell apoptosis and promotes its proliferation through the secretion of effector proteins. [ABSTRACT FROM AUTHOR]

Breast cancer is a highly harmful malignant tumor, which poses a great threat to women's body and mind, and the mortality rate ranks second among all women's diseases. The incidence rate accounts for 7-10% of various malignant tumors in the whole body, second only to uterine cancer in women, and has become the main cause of threatening women's health. Advanced breast cancer is often considered an incurable disease. The family of heterogeneous nuclear ribonucleoprotein complexes is composed of about 20 hnRNP proteins with molecular weights ranging from 32 to 120 kDa, and they are named according to their molecular weights. Among them, hnRNPA2 and hnRNPB1 are the two most important members of the hnRNP family, both derived from the same gene on chromosome 7p15. Therefore, research to understand the molecular mechanism and process of breast cancer progression has an important role in promoting the current medical research on breast cancer treatment methods. Therefore, studying the mechanism of tumorigenesis is the key to tumor prevention and treatment. Therefore, this paper proposes that A2/B1 promotes the stability of NRF2 mRNA and inhibits ferroptosis and cell proliferation in breast cancer cells. The article mainly introduces the disease diagnosis method based on artificial neural network and its neural network algorithm. In the experimental part, the activity of hnRNP A2/B1 on cancer cells is deeply studied. The results show that the absorbance of the MTT method increases continuously with the extension of the culture time, and the maximum reaches 1.2. This fully shows that its absorption capacity is very strong, especially after 24 hours, the absorption rate rises from 0.6 to 0.9, which shows that 24 hours is the best absorption time. And it can also be found that hnRNPA2/B1 has a significant inhibitory effect on breast cancer cells; it can reduce the effect on breast cancer cell cycle and apoptosis. [ABSTRACT FROM AUTHOR]

Purpose. This study aimed to explore the function and molecular mechanism of long noncoding RNA Small Nucleolar RNA Host Gene 1 (SNHG1) in the development of hypopharyngeal squamous cell carcinoma (HSCC). Methods. Human HSCC cell line FaDu was used in this study. Cell viability and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. Cell migration and invasion were measured by Transwell assay. The expression of PARP6, XRCC6, β-catenin, and EMT-related proteins (E-cadherin and N-cadherin) were determined using western blotting. Moreover, the regulatory relationship between SNHG1 and PARP6 was investigated. Furthermore, the effects of the SNHG1/PARP6 axis on tumorigenicity were explored in vivo. Results. Suppression of SNHG1 suppressed the viability, migration, and invasion but promoted apoptosis of FaDu cells in vitro (P < 0.01). PARP6 is a target of SNHG1, which was upregulated by SNHG1 knockdown in FaDu cells (P < 0.01). SNHG1 suppression and RARP6 overexpression inhibited FaDu cell proliferation, migration, and invasion (P < 0.05). SNHG1 suppression and RARP6 overexpression also inhibited tumorigenicity of HSCC in vivo. Furthermore, the protein expression of E-cadherin was significantly increased and that of N-cadherin, β-catenin, and XRCC6 was dramatically decreased in HSCC after SNHG1 suppression or/and RARP6 overexpression both in vitro and in vivo (P < 0.01). Conclusions. SNHG1 silencing inhibits HSCC malignant progression via upregulating PARP6. XRCC6/β-catenin/EMT axis may be a possible downstream mechanism of the SNHG1/PARP6 axis in HSCC. SNHG1/PARP6 can be used as a promising target for the treatment of HSCC. [ABSTRACT FROM AUTHOR]

Dysfunction of histone acetylation inhibits topoisomerase IIα (Topo IIα), which is implicated in benzene-induced hematotoxicity in patients with chronic benzene exposure. Whether histone deacetylase (HDAC) inhibitors can relieve benzene-induced hematotoxicity remains unclear. Here we showed that hydroquinone, a main metabolite of benzene, increased the HDAC activity, decreased the Topo IIα expression and induced apoptosis in human bone marrow mononuclear cells in vitro, and treatment with two HDAC inhibitors, namely trichostatin A (TSA) or a mixture of ribosome-inactivating proteins MCP30, almost completely reversed these effects. We further established a benzene poisoning murine model by inhaling benzene vapor in a container and found that benzene poisoning decreased the expression and activity of Topo IIα, and impaired acetylation of histone H4 and H3. The analysis of regulatory factors of Topo IIα promoter found that benzene poisoning decreased the mRNA levels of SP1 and C-MYB, and increased the mRNA level of SP3. Both TSA and MCP30 significantly enhanced the acetylation of histone H3 and H4 in Topo IIα promoter and increased the expression and activity of Topo IIα in benzene poisoning mice, which contributed to relieve the symptoms of hematotoxicity. Thus, treatment with HDAC inhibitors represents an attractive approach to reduce benzene-induced hematotoxicity. [ABSTRACT FROM AUTHOR]

Novel pyrrolopyridone BET degraders were designed and synthesized based on the binding mode between the pyrrolopyridone BET inhibitor with the BRD4 protein. The potent degraders on MV-4-11 cells were discovered through structure-activity relationship study. Modification of warhead on pyrrolopyridone BET degraders significantly regulates BRD4 isoform (long and short) protein degradation, which induces differential cell cycle arrest and apoptosis on MV-4-11 cells. Docking study revealed that the fine structural modification of BET degraders may bind with the BD domain of BRD4 protein to engage various surface areas that bind with CRBN. Two class of degraders possessing modulated degradation of BRD4 short isoform were developed by changing the warhead and induced different biological response on cell cycle and apoptosis. [Display omitted] • Two class of pyrrolopyridone BRD4 degraders 7f and 13i were synthesized. • Fine structural modifications selectively adjusted BRD4 S degradation. • Different cell cycle and apoptosis response were induced by 7f and 13i. [ABSTRACT FROM AUTHOR]

According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan -HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines. A series of pyrrolopyridone derivatives were designed and synthesized for their HDAC1/6 and BRD4(BD1/BD2) inhibitory activity and selectivity. Lead compounds with potent selective HDAC and BRD4 dual inhibitions were achieved based on SARs and the first HDAC6/BRD4(BD2) dual inhibitor was discovered. Image 1 • Novel pyrrolopyridone-based HDAC/BRD4 dual inhibitors were synthesized. • Lead compounds with both potent enzymatic and cellular activities were evaluated. • HDAC isoforms and BRD4 bromodomain of lead compounds were investigated. • The first HDAC6/BRD4(BD2) dual inhibitor was discovered. [ABSTRACT FROM AUTHOR]