Copper oxide nanoparticles (CuO NPs) are widely used as catalysts or semiconductors in material fields. Recent studies have suggested that CuO NPs have adverse genotoxicity and cytotoxicity effects ...on various cells. However, little is known about the toxicity of CuO NPs following exposure to murine lungs. The purpose of this fundamental research was to investigate whether CuO NPs could induce epithelial cell injury, pulmonary inflammation, and eventually fibrosis in C57BL/6 mice. Our studies showed that CuO NPs aggravated pulmonary inflammation in a dose-dependent manner. CuO NPs induced apoptosis of epithelial cells as indicated by TUNEL staining, flow cytometry and western blot analysis, which was partially caused by increased reactive oxygen species (ROS). In addition, CuO NPs exposure promoted collagen accumulation and expression of the progressive fibrosis marker α-SMA in the lung tissues, indicating that CuO NP inhalation could induce pulmonary fibrosis in C57BL/6 mice. All data provide novel evidence that there is an urgent need to prevent the adverse effects of CuO NPs in the human respiratory system.
Autophagy is a type of cellular catabolic degradation response to nutrient starvation or metabolic stress. The main function of autophagy is to maintain intracellular metabolic homeostasis through ...degradation of unfolded or aggregated proteins and organelles. Although autophagic regulation is a complicated process, solid evidence demonstrates that the PI3K-Akt-mTOR, LKB1-AMPK-mTOR and p53 are the main upstream regulators of the autophagic pathway. Currently, there is a bulk of data indicating the important function of autophagy in cancer. It is noteworthy that autophagy facilitates the cancer cells' resistance to chemotherapy and radiation treatment. The abrogation of autophagy potentiates the re-sensitization of therapeutic resistant cancer cells to the anticancer treatment
via autophagy inhibitors, such as 3-MA, CQ and BA, or knockdown of the autophagy related molecules. In this review, we summarize the accumulation of evidence for autophagy's involvement in mediating resistance of cancer cells to anticancer therapy and suggest that autophagy might be a potential therapeutic target in anticancer drug resistance in the future.
Gastrointestinal cancer (GIC) poses a serious threat to human health globally. Curcumin (CUR), a hydrophobic polyphenol extracted from the rhizome of
Curcuma longa
, has shown reliable anticancer ...function and low toxicity, thereby offering broad research prospects. Numerous studies have demonstrated the pharmacological mechanisms underlying the effectiveness of CUR against GIC, including the induction of apoptosis and autophagy, arrest of the cell cycle, inhibition of the epithelial–mesenchymal transition (EMT) processes, inhibition of cell invasion and migration, regulation of multiple signaling pathways, sensitization to chemotherapy and reversal of resistance to such treatments, and regulation of the tumor survival environment. It has been confirmed that CUR exerts its antitumor effects on GIC through these mechanisms
in vitro
and
in vivo
. Moreover, treatment with CUR is safe and tolerable. Newly discovered types of regulated cell death (RCD), such as pyroptosis, necroptosis, and ferroptosis, may provide a new direction for research on the efficacy of CUR against GIC. In this review, we discuss the recently found pharmacological mechanisms underlying the effects of CUR against GIC (gastric and colorectal cancers). The objective is to provide a reference for further research on treatments against GIC.
Our objective is to develop a prognostic model focused on cuproptosis, aimed at predicting overall survival (OS) outcomes among Acute myeloid leukemia (AML) patients. The model utilized machine ...learning algorithms incorporating stacking. The GSE37642 dataset was used as the training data, and the GSE12417 and TCGA-LAML cohorts were used as the validation data. Stacking was used to merge the three prediction models, subsequently using a random survival forests algorithm to refit the final model using the stacking linear predictor and clinical factors. The prediction model, featuring stacking linear predictor and clinical factors, achieved AUC values of 0.840, 0.876 and 0.892 at 1, 2 and 3 years within the GSE37642 dataset. In external validation dataset, the corresponding AUCs were 0.741, 0.754 and 0.783. The predictive performance of the model in the external dataset surpasses that of the model simply incorporates all predictors. Additionally, the final model exhibited good calibration accuracy. In conclusion, our findings indicate that the novel prediction model refines the prognostic prediction for AML patients, while the stacking strategy displays potential for model integration.
Breast cancer seriously endangers women's health worldwide. Protein arginine methyltransferase 5 (PRMT5) is highly expressed in breast cancer and represents a potential druggable target for breast ...cancer treatment. However, because the currently available clinical PRMT5 inhibitors are relatively limited, there is an urgent need to develop new PRMT5 inhibitors. Our team previously found that the FDA-approved drug tadalafil can act as a PRMT5 inhibitor and enhance the sensitivity of breast cancer patients to doxorubicin treatment. To further improve the binding specificity of tadalafil to PRMT5, we chemically modified tadalafil, and designed three compounds, A, B, and C, based on the PRMT5 protein structure. These three compounds could bind to PRMT5 through different binding modes and inhibit histone arginine methylation. They arrested the proliferation and triggered the apoptosis of breast cancer cells in vitro and also promoted the antitumor effects of the chemotherapy drugs cisplatin, doxorubicin, and olaparib in combination regimens. Among them, compound A possessed the highest potency. Finally, the anti-breast cancer effects of PRMT5 inhibitor A and its ability to enhance chemosensitivity were further verified in a xenograft mouse model. These results indicate that the new PRMT5 inhibitors A, B, and C may be potential candidates for breast cancer treatment.
Disseminated adenovirus infection is a complication with a relatively high mortality rate among patients undergoing hematopoietic stem cell transplantation. The low efficacy and poor availability of ...current treatment options are of major concern. Programmed cell death 1 (PD-1) blockade has been used to treat several chronic viral infections. Herein, we report a case of disseminated adenovirus infection in the early posttransplant period. The patient was diagnosed with diffuse large B-cell lymphoma at first and underwent 8 cycles of chemotherapy, including rituximab. She was subsequently diagnosed with acute myeloid leukemia and received haploidentical transplantation. She was diagnosed with Epstein‒Barr virus (EBV)-positive posttransplant lymphoproliferative disorder (PTLD) 2 months after the transplant, and 3 doses of rituximab were administered. The patient was diagnosed with disseminated adenovirus infection with upper respiratory tract, gastrointestinal tract and blood involved at 3 months after transplantation. She was first treated with a reduction in immunosuppression, cidofovir and ribavirin. Then, the patient received salvage treatment with the PD-1 inhibitor sintilimab (200 mg) after achieving no response to conventional therapy. The adenovirus was cleared 3 weeks later, and concomitant EBV was also cleared. Although the patient developed graft-versus-host disease of the liver after the administration of the PD-1 inhibitor, she was cured with steroid-free therapy. Therefore, PD-1 blockade immunotherapy can be considered a promising treatment option for patients with disseminated adenovirus infection after transplantation, with fully weighing the hazards of infection and the side effects of this therapy.
B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are ...often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia.
8p11 myeloproliferative syndrome is a rare hematological malignancy with aggressive course caused by the various translocation of
FGFR1
. In this study, a novel
FGFR1
fusion was identified by RNA ...sequencing in a 28-year-old male patient with acute B-lymphoblastic leukemia. The patient harbors an in-frame fusion between
KIF5B
exon 15 and
FGFR1
exon 10. The
FGFR1
fusion and its protein expression was validated by Sanger sequencing and Western blot. Meanwhile, cytogenetic analysis reported a normal karyotype and targeted DNA sequencing identified no driver mutations, respectively. Despite he achieved complete remission after induction regimen, a relapse occurred and he became refractory to chemotherapy, and salvage haploidentical hematopoietic stem cell transplantation failed to control the progressive disease. In conclusion, we present the first case of
KIF5B-FGFR1
fusion in hematological malignancy. These findings extend the spectrum of translocation in 8p11 myeloproliferative syndrome, and demonstrate the great prospect of RNA sequencing in clinical practice again.
The clinical outcome of Philadelphia chromosome-negative B cell acute lymphoblastic leukemia (Ph-neg B-ALL) varies considerably from one person to another after clinical treatment due to lack of ...targeted therapies and leukemia's heterogeneity. Ferroptosis is a recently discovered programmed cell death strongly correlated with cancers. Nevertheless, few related studies have reported its significance in acute lymphoblastic leukemia.
Herein, we collected clinical data of 80 Ph-neg B-ALL patients diagnosed in our center and performed RNA-seq with their initial bone marrow fluid samples. Throughout unsupervised machine learning K-means clustering with 24 ferroptosis related genes (FRGs), the clustered patients were parted into three variant risk groups and were performed with bioinformatics analysis.
As a result, we discovered significant heterogeneity of both immune microenvironment and genomic variance. Furthermore, the immune check point inhibitors response and potential implementation of Sorafenib in Ph-neg B-ALL was also analyzed in our cohort. Lastly, one prognostic model based on 8 FRGs was developed to evaluate the risk of Ph-neg B-ALL patients.
Jointly, our study proved the crucial role of ferroptosis in Ph-neg B-ALL and Sorafenib is likely to improve the survival of high-risk Ph-neg B-ALL patients.
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