Role of reactive oxygen species in myelodysplastic syndromes.

Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy.

Mechanism of Pressure Difference Variations on Heavy Oil Start-Up and Percolation Effects.

To investigate the influence of pressure difference changes on the micro start-up and percolation of heavy oil, a micro visualization displacement device was used to characterize the start-up time and oil-water percolation state of heavy oil. The mechanism of different pressure differences, as well as the frequency and amplitude of pressure difference changes, on the start-up and percolation balance of heavy oil was clarified. The results indicate that high-pressure difference and pressure difference changes can reduce the start-up time of heavy oil. A reasonable frequency of pressure difference changes effectively promotes the balance between positive and negative pressure shear and fluid-solid response. Large pressure difference changes can effectively break the viscous and adsorption resistance during heavy oil start-up; reasonable pressure difference can exert the synergistic effect of pressure difference and infiltration, achieving a balance between the water wave and the initial water film thickening process as well as the continuous percolation process of wire drawing, oil droplets, and oil columns during the medium-to-high water content period; a reasonable frequency of pressure difference variation during the high water content period can promote the superposition of inertia effects at the oil-water interface and break the balance of the oil-water interface. A large amplitude of pressure difference variation is beneficial for the strong deformation of the oil-water interface and the shear dislocation peeling of the oil-solid interface. Therefore, a relatively high amplitude of pressure difference variation and a reasonable frequency of pressure difference variation, as well as the synergistic effect of pressure difference and infiltration, are the keys to effectively start heavy oil and improving oil recovery during the ultrahigh water-cut period.

Manganese(III) Phthalocyanine Complex Nanoparticle-Loaded Glucose Oxidase to Enhance Tumor Inhibition through Energy Metabolism and Macrophage Polarization.

Elevated levels of reactive oxygen species (ROS) have demonstrated efficacy in eliminating tumor cells by modifying the tumor microenvironment and inducing the polarization of tumor-associated macrophages (TAMs). Nevertheless, the transient nature and limited diffusion distance inherent in ROS present significant challenges in cancer treatment. In response to these limitations, we have developed a nanoparticle (MnClPc-HSA@GOx) that not only inhibits tumor energy metabolism but also facilitates the transition of TAMs from the M2 type (anti-inflammatory type) to the M1 type (proinflammatory type). MnClPc-HSA@GOx comprises a manganese phthalocyanine complex (MnClPc) enveloped in human serum albumin (HSA), with glucose oxidase (GOx) loaded onto MnClPc@HSA nanoparticles. GOx was employed to catalyze the decomposition of glucose to produce H2O2 and gluconic acid. Additionally, in the presence of MnClPc, it catalyzes the conversion of H2O2 into •O2- and 1O2. Results indicate that the nanoparticle effectively impedes the glucose supply to tumor cells and suppresses their energy metabolism. Simultaneously, the ROS-mediated polarization of TAMs induces a shift from M2 to M1 macrophages, resulting in a potent inhibitory effect on tumors. This dual-action strategy holds promising clinical inhibition applications in the treatment of cancer.

Biochemical component analysis of human myopic corneal stroma using the Raman spectrum.

PURPOSE: This study aimed to measure the Raman spectrum of the human corneal stroma lens obtained from small incision lenticule extraction surgery (SMILE) in Asian myopic eyes using a confocal Raman micro-spectrometer built in the laboratory. METHODS: Forty-three myopic patients who underwent SMILE with equivalent diopters between - 4.00 and - 6.00 D were selected, and the right eye data were collected. Corneal stroma lenses were obtained during surgery, and the Raman spectra were measured after air drying. The complete Raman spectrum of human myopic corneal stroma lens tissue was obtained within the range of 700-4000 cm-1. RESULTS: Thirteen characteristic peaks were found, with the stronger peaks appearing at 937 cm-1, corresponding to proline, valine, and the protein skeleton of the human myopic corneal stroma lens; 1243 cm-1, corresponding to collagen protein; 1448 cm-1, corresponding to the collagen protein and phospholipids; and 2940 cm-1, corresponding to the amino acid and lipids, which was the strongest Raman peak. CONCLUSION: These results demonstrated that Raman spectroscopy has much potential as a fast, cost-effective, and reliable diagnostic tool in the diagnosis and treatment of eye diseases, including myopia, keratoconus, and corneal infection.

Risk factors and cognitive correlates of white matter hyperintensities in ethnically diverse populations without dementia: The COSMIC consortium.

INTRODUCTION: White matter hyperintensities (WMHs) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well documented in populations of different ethnicities and/or from different geographical regions. METHODS: We investigated how WMHs were associated with vascular risk factors and cognition in both Whites and Asians, using data from five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N = 1946). WMH volumes (whole brain, periventricular, and deep) were quantified with UBO Detector and harmonized using the ComBat model. We also harmonized various vascular risk factors and scores for global cognition and individual cognitive domains. RESULTS: Factors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake, and insufficient physical activity. Hypertension and stroke had stronger associations with WMH volumes in Whites than in Asians. No associations between WMH volumes and cognitive performance were found after correction for multiple testing. CONCLUSION: The current study highlights ethnic differences in the contributions of vascular risk factors to WMHs.

The nucleocapsid protein facilitates p53 ubiquitination-dependent proteasomal degradation via recruiting host ubiquitin ligase COP1 in PEDV infection.

Porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric pathogen of the coronavirus family and caused severe economic losses to the global swine industry. Previous studies have established that p53 is a host restriction factor for PEDV infection, and p53 degradation occurs in PEDV-infected cells. However, the underlying molecular mechanisms through which PEDV viral proteins regulate p53 degradation remain unclear. In this study, we found that PEDV infection or expression of the nucleocapsid protein downregulates p53 through a post-translational mechanism: increasing the ubiquitination of p53 and preventing its nuclear translocation. We also show that the PEDV N protein functions by recruiting the E3 ubiquitin ligase COP1 and suppressing COP1 self-ubiquitination and protein degradation, thereby augmenting COP1-mediated degradation of p53. Additionally, COP1 knockdown compromises N-mediated p53 degradation. Functional mapping using truncation analysis showed that the N-terminal domains of N protein were responsible for interacting with COP1 and critical for COP1 stability and p53 degradation. The results presented here suggest the COP1-dependent mechanism for PEDV N protein to abolish p53 activity. This study significantly increases our understanding of PEDV in antagonizing the host antiviral factor p53 and will help initiate novel antiviral strategies against PEDV.

White matter brain age as a biomarker of cerebrovascular burden in the ageing brain.

As the brain ages, it almost invariably accumulates vascular pathology, which differentially affects the cerebral white matter. A rich body of research has investigated the link between vascular risk factors and the brain. One of the less studied questions is that among various modifiable vascular risk factors, which is the most debilitating one for white matter health? A white matter specific brain age was developed to evaluate the overall white matter health from diffusion weighted imaging, using a three-dimensional convolutional neural network deep learning model in both cross-sectional UK biobank participants (n = 37,327) and a longitudinal subset (n = 1409). White matter brain age gap (WMBAG) was the difference between the white matter age and the chronological age. Participants with one, two, and three or more vascular risk factors, compared to those without any, showed an elevated WMBAG of 0.54, 1.23, and 1.94 years, respectively. Diabetes was most strongly associated with an increased WMBAG (1.39 years, p < 0.001) among all risk factors followed by hypertension (0.87 years, p < 0.001) and smoking (0.69 years, p < 0.001). Baseline WMBAG was associated significantly with processing speed, executive and global cognition. Significant associations of diabetes and hypertension with poor processing speed and executive function were found to be mediated through the WMBAG. White matter specific brain age can be successfully targeted for the examination of the most relevant risk factors and cognition, and for tracking an individual's cerebrovascular ageing process. It also provides clinical basis for the better management of specific risk factors.

Prediction model for haematoma after tissue expander placement: A retrospective cohort study of 7080 cases over 20 years.

Haematoma is an early complication of tissue expander placement and can lead to infection, capsule contracture and various complications, hindering successful reconstruction. However, no scientific models can accurately predict the risk of haematoma following tissue expansion. Therefore, this study aimed to develop and validate a prediction model for haematoma following tissue expander placement. The medical records of patients who underwent expander placement between 2001 and 2021 were obtained from the clinical database of the Department of Plastic Surgery at the Xijing Hospital. A total of 4579 consecutive patients with 7080 expanders and 179 expanded pocket haematomas were analysed. Multivariate logistic regression analysis identified adult age (P = 0.006), male sex (P < 0.001), scar reconstruction (P = 0.019), perioperative hypertension (P < 0.001), face and neck location (P = 0.002) and activated partial thromboplastin time above the normal range (P < 0.001) as risk factors for haematoma. Therefore, these were included in the prediction model, and a nomogram was constructed. The discrimination of the nomogram was robust (area under the curve: 0.78; 95% confidence interval: 0.72-0.83). Further, the prediction model had a strong fit (Hosmer-Lemeshow test, P = 0.066) and maintained similar discrimination after considering performance optimism (bootstrapped area under the curve: 0.79; 95% confidence interval: 0.73-0.84). This clinical prediction model was created using a generalisable dataset and can be utilised to obtain valid haematoma predictions after expander placement, assisting surgeons in implementing preventive measures or interventions to reduce the occurrence of haematoma.

Macrophage ß-arrestin-1 deteriorates DSS-induced colitis through interaction with NF-κB signaling.

ß-arrestin-1 has been demonstrated to participate in the regulation of inflammatory reactions in several diseases. Thus, this study aimed to investigate the role of macrophage ß-arrestin-1 in the pathogenesis and progression of ulcerative colitis (UC). A myeloid ß-arrestin-1 conditional knockout mouse model was generated to explore the role of macrophage ß-arrestin-1. DSS was employed for the establishment of an ulcerative colitis mouse model, using TNF-α as an inflammatory stressor in vitro. The expression level of ß-arrestin-1 was detected via western blot and immunofluorescence assays, whilst disease severity was evaluated by clinical score and H&E staining in the DSS-induced colitis model. In the in vitro experiments, the levels of inflammatory cytokines were examined using real-time PCR. NF-κB activation was detected through the double luciferase reporter system, western blot, and electrophoretic mobility shift assay (EMSA). BAY11-7082 was used to inhibit NF-κB activation. Our results exposed that the level of ß-arrestin-1 was increased in monocytes/macrophages derived from DSS-induced colitis mice or under the TNF-α challenge. Moreover, conditionally knocking out the expression of myeloid ß-arrestin-1 alleviated disease severity, while knocking out the expression of ß-arrestin-1 decreased the levels of inflammatory cytokines. Additionally, NF-κB was identified as a central regulatory element of ß-arrestin-1 promoter, and using BAY11-7082 to inhibit NF-κB activation lowered the level of ß-arrestin-1 under TNF-α challenge. ß-arrestin-1 led to the activation of the NF-κB signaling pathway by enhancing binding to IκBα and IKK under the TNF-α challenge. Taken together, our findings demonstrated macrophage ß-arrestin-1 contributes to the deterioration of DSS-induced colitis through the interaction with NF-κB signaling, thus highlighting a novel target for the treatment of UC.

Clinical practice guidelines for the nutrition of colorectal cancer patients: a systematic review.

PURPOSE: The aim of this study is to rigorously assess the methodological quality of published clinical practice guidelines (CPGs) related to nutrition among colorectal cancer patients, to compile consensus recommendations, and to evaluate the quality of the included CPGs. METHODS: The systematic search covered eight electronic databases, two relevant professional association websites, and six guideline websites from their inception up to January 22, 2023. The methodological quality of the eligible guidelines was evaluated using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument, and then, consensus recommendations were synthesized. The scores for each domain were expressed as the mean ± standard deviation (SD). Using the mean score as the benchmark for comparison, they were subsequently ranked from highest to lowest. The included guidelines were then categorized as having "high," "moderate," or "low" quality based on their scores. RESULTS: The literature search yielded ten guidelines. The findings indicated that the "Clarity of presentation" domain had the highest mean score (65.2 ± 7.7). This demonstrates how the guidelines effectively articulate recommendations. Additionally, the "Scope and purpose" domain achieved a mean score of 60.7 ± 10.9, followed by "Rigor of development" (51.7 ± 15.7), "Editorial independence" (51.1 ± 21), "Stakeholder involvement" (48 ± 16.8), and "Applicability" domains (47.5 ± 17.3). Two CPGs received an overall rating of "high quality" and were recommended; four CPGs received an overall rating of "moderate" and were recommended with modifications; and four CPGs received an overall rating of "low quality" and were not recommended. Furthermore, this study compiled twenty consensus recommendations related to nine distinct clinical issues. CONCLUSION: This study identified disparities in the methodological quality of the included CPGs, particularly in the "Applicability" domain, thus emphasizing the need for advancement in clinical feasibility and implementation. Notably, there is few guidelines specifically targeting colorectal cancer nutrition. These synthesized findings provided an intuitive, convenient, and comprehensive reference for evaluating nutrition among colorectal cancer patients. When applying these results, users should make careful decisions based on their specific situations.

Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting ferroptosis.

Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity.

Identification of a novel genomic variance of BRAF1 in papillary thyroid carcinoma: A case report.

RATIONALE: Papillary thyroid carcinoma (PTC), the predominant subtypes accounting for approximately 85% of thyroid carcinomas, has a rapidly increasing global incidence rate. Statistically, approximately 74.6% PTC patients had the genomic variants of BRAF, especially BRAFV600E mutation, which has been reported to stratify patients and guide clinic-therapies. However, some PTC patients may carry other nonclassical mutation patterns of BRAF, due to the complex of genomic instability. And the spectrum of BRAF mutation was not fully characterized. We reported a novel BRAF mutation pattern of PTC. PATIENT CONCERNS: A 59-year-old woman was admitted to our hospital because of the slight enlargement of bilateral cervical lymph nodes in July 2023. DIAGNOSIS: Ultrasonography revealed that the bilateral thyroid nodules of the patients both presented 1 hypoechoic nodule, which was graded as 3 of the elastic score, and the small calcification in the right lobe (Chinese-Thyroid Imaging Reporting and Data System 4c). Pathological diagnosis showed the interstitial collagen change and focal follicular epithelial papillary hyperplasia with atypical hyperplasia of the bilateral thyroid. Further puncture pathology showed that the patient had a malignant thyroid lesion with the phenotypes of papillary carcinoma and diagnosed with malignancy subsequently. Additionally, the patient harbored a novel insert on BRAF exon 15, a 6-base fragment AGACAG inserting between c.1798 and c.1799. INTERVENTIONS: The patient was undergone on microwave ablation of thyroid carcinoma on July 28, 2023. After the surgery, the patient was treated on anti-infection, cold saline external application of bilateral thyroid swelling supportive treatment. OUTCOMES: No postoperative complications or recurrence and metastasis were found. LESSONS: This is the first case of the novel nonclassical genomic variant of BRAF. Our study extends the spectrum of BRAF mutations. The patient had a favorable response to microwave ablation, indicating that in spite of the association between this mutation and high-grade malignant phenotype, this genomic variant of BRAF did not have a detrimental effect on the response of clinical treatment.

Mass spectrometry analysis of intact protein N-glycosylation signatures of cells and sera in pancreatic adenocarcinomas. / èƒ°è ºç™Œç»†èƒžå’Œè¡€æ¸ å®Œæ•´è›‹ç™½è´¨N-糖基化特征的质谱分析.

Pancreatic cancer is among the most malignant cancers, and thus early intervention is the key to better survival outcomes. However, no methods have been derived that can reliably identify early precursors of development into malignancy. Therefore, it is urgent to discover early molecular changes during pancreatic tumorigenesis. As aberrant glycosylation is closely associated with cancer progression, numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis; however, detailed glycoproteomic information, especially site-specific N-glycosylation changes in pancreatic cancer with and without drug treatment, needs to be further explored. Herein, we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans, glycosites, and intact glycopeptides in pancreatic cancer cells and patient sera. The profiling of N-glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells, whereas human sera, which contain many secreted glycoproteins, had significant changes of glycans at their specific glycosites. These results indicated the potential role for tumor-specific glycosylation as disease biomarkers. We also found that AMG-510, a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation, profoundly reduced the glycosylation level in MIA PaCa-2 cells, suggesting that KRAS plays a role in the cellular glycosylation process, and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.

Immunotherapies of acute myeloid leukemia: Rationale, clinical evidence and perspective.

Acute myeloid leukemia (AML) is a prevalent hematological malignancy that exhibits a wide array of molecular abnormalities. Although traditional treatment modalities such as chemotherapy and allogeneic stem cell transplantation (HSCT) have become standard therapeutic approaches, a considerable number of patients continue to face relapse and encounter a bleak prognosis. The emergence of immune escape, immunosuppression, minimal residual disease (MRD), and other contributing factors collectively contribute to this challenge. Recent research has increasingly highlighted the notable distinctions between AML tumor microenvironments and those of healthy individuals. In order to investigate the potential therapeutic mechanisms, this study examines the intricate transformations occurring between leukemic cells and their surrounding cells within the tumor microenvironment (TME) of AML. This review classifies immunotherapies into four distinct categories: cancer vaccines, immune checkpoint inhibitors (ICIs), antibody-based immunotherapies, and adoptive T-cell therapies. The results of numerous clinical trials strongly indicate that the identification of optimal combinations of novel agents, either in conjunction with each other or with chemotherapy, represents a crucial advancement in this field. In this review, we aim to explore the current and emerging immunotherapeutic methodologies applicable to AML patients, identify promising targets, and emphasize the crucial requirement to augment patient outcomes. The application of these strategies presents substantial therapeutic prospects within the realm of precision medicine for AML, encompassing the potential to ameliorate patient outcomes.

Safety and efficacy of peripheral blood stem cells collection in healthy children and pediatric patients with thalassemia major weighing 20 kg or less.

BACKGROUND: Peripheral blood stem cell (PBSC) collection in children poses challenges due to their small size, low body weight (BW), and unique pediatric physiology, especially among children weighing 20 kg (kg) or less. METHODS: PBSC collection data of both healthy children and patients with thalassemia major (TM) weighing 20 kg or less between January 2013 and December 2020 were reviewed. Moreover, PBSCs characteristics along with various aspects of efficiency and safety between healthy donors and patients with TM were compared. RESULTS: A total of 262 PBSC procedures were performed on 255 children. Of these, 91 procedures were carried out on 85 allogeneic healthy donors, and 171 auto-backup collections were performed on 170 patients with TM to ensure PBSC availability and prevent transplantation failure. A minimum pre-apheresis hemoglobin (HGB) level of 60 g/L was discovered to be safe and feasible in patients with TM. The median CD34+ cell dose in the PBSC product during the initial apheresis procedure was higher in healthy donors compared to patients with TM (7.29 ± 5.28 × 106 cells/kg vs5.88 ± 4.23 × 106 cells/kg, P = .043). The total CD34+ cells/kg recipient weight exhibited a positive correlation with pre-apheresis monocyte counts, but a negative correlation with donor weight. Apheresis significantly reduced hematocrit and platelet counts in the allogeneic group compared to the autologous group. Patients with TM experienced a higher occurrence of bone pain related to granulocyte colony-stimulating factor treatment. Notably, no serious complications related to PBSCs mobilization, central venous catheter placement, or the apheresis procedure were observed in either group. CONCLUSIONS: PBSCs collection was both safe and effective in healthy children and pediatric patients with TM weighing 20 kg or less.

FOXL2 and NR5A1 induce human fibroblasts into steroidogenic ovarian granulosa-like cells.

Human granulosa cells in different stages are essential for maintaining normal ovarian function, and granulosa cell defect is the main cause of ovarian dysfunction. To address this problem, it is necessary to induce functional granulosa cells at different stages in vitro. In this study, we established a reprogramming method to induce early- and late-stage granulosa cells with different steroidogenic abilities. We used an AMH-fluorescence-reporter system to screen candidate factors for cellular reprogramming and generated human induced granulosa-like cells (hiGC) by overexpressing FOXL2 and NR5A1. AMH-EGFP+ hiGC resembled human cumulus cells in transcriptome profiling and secreted high levels of oestrogen and progesterone, similar to late-stage granulosa cells at antral or preovulatory stage. Moreover, we identified CD55 as a cell surface marker that can be used to isolate early-stage granulosa cells. CD55+ AMH-EGFP- hiGC secreted high levels of oestrogen but low levels of progesterone, and their transcriptome profiles were more similar to early-stage granulosa cells. More importantly, CD55+ hiGC transplantation alleviated polycystic ovary syndrome (PCOS) in a mouse model. Therefore, hiGC provides a cellular model to study the developmental program of human granulosa cells and has potential to treat PCOS.

Lipid concomitant γ-oryzanol decreased oil absorbency of French fries by changing the microstructure of French fries and physical properties of frying oil.

BACKGROUND: The aim of this research was to evaluate the possibility of lipid concomitant γ-oryzanol reducing oil absorbency of fried foods and the underlying mechanism. Therefore, the influence of γ-oryzanol on moisture and oil content, and distribution and micromorphology of French fries and the viscosity, fatty acid composition and total polar compounds content of rice bran oil (RBO) after frying were studied. RESULTS: Our results showed that the incorporation of low concentration of γ-oryzanol [low addition group (LAG)] (5.754 g/kg) decreased the oil absorbency and porous structure of French fries during frying. Additionally, LAG incorporation inhibited the degradation of linoleic acid, decreased the growth rate of saturated fatty acids, total polar compounds and viscosity of frying oil. CONCLUSIONS: Consequently, it was recommended to incorporate a small amount of γ-oryzanol in frying oil because it could inhibit oil absorption behavior of French fries. © 2023 Society of Chemical Industry.

Using anti-PD-L1 antibody conjugated gold nanoshelled poly (Lactic-co-glycolic acid) nanocapsules loaded with doxorubicin: A theranostic agent for ultrasound imaging and photothermal/chemo combination therapy of triple negative breast cancer.

Triple negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and it is difficult to progress through traditional chemotherapy. Therefore, the treatment of TNBC urgently requires agents with effective diagnostic and therapeutic capabilities. In this study, we obtained programmed death-ligand 1 (PD-L1) antibody conjugated gold nanoshelled poly(lactic-co-glycolic acid) (PLGA) nanocapsules (NCs) encapsulating doxorubicin (DOX) (DOX@PLGA@Au-PD-L1 NCs). PLGA NCs encapsulating DOX were prepared by a modified single-emulsion oil-in-water (O/W) solvent evaporation method, and gold nanoshells were formed on the surface by gold seed growth method, which were coupled with PD-L1 antibodies by carbodiimide method. The fabricated DOX@PLGA@Au-PD-L1 NCs exhibited promising contrast enhancement in vitro ultrasound imaging. Furthermore, DOX encapsulated in NCs displayed good pH-responsive and photo-triggered drug release properties. After irradiating 200 µg/mL NCs solution with a laser for 10 min, the solution temperature increased by nearly 23°C, indicating that the NCs had good photothermal conversion ability. The targeting experiments confirmed that the NCs had specific target binding ability to TNBC cells overexpressing PD-L1 molecules. Cell experiments exhibited that the agent significantly reduced the survival rate of TNBC cells through photochemotherapy combination therapy. As a multifunctional diagnostic agent, DOX@PLGA@Au-PD-L1 NCs could be used for ultrasound targeted contrast imaging and photochemotherapy combination therapy of TNBC cells, providing a promising idea for early diagnosis and treatment of TNBC.

Inhibiting the compensatory elevation of xCT collaborates with disulfiram/copper-induced GSH consumption for cascade ferroptosis and cuproptosis.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death globally, which is characterized by complicated pathophysiology, high recurrence rate, and poor prognosis. Our previous study has demonstrated that disulfiram (DSF)/Cu could be repurposed for the treatment of HCC by inducing ferroptosis. However, the effectiveness of DSF/Cu may be compromised by compensatory mechanisms that weaken its sensitivity. The mechanisms underlying these compensatory responses are currently unknown. Herein, we found DSF/Cu induces endoplasmic reticulum stress with disrupted ER structures, increased Ca2+ level and activated expression of ATF4. Further studies verified that DSF/Cu induces both ferroptosis and cuproptosis, accompanied by the depletion of GSH, elevation of lipid peroxides, and compensatory increase of xCT. Comparing ferroptosis and cuproptosis, it is interesting to note that GSH acts at the crossing point of the regulation network and therefore, we hypothesized that compensatory elevation of xCT may be a key aspect of the therapeutic target. Mechanically, knockdown of ATF4 facilitated the DSF/Cu-induced cell death and exacerbated the generation of lipid peroxides under the challenge of DSF/Cu. However, ATF4 knockdown was unable to block the compensatory elevation of xCT and the GSH reduction. Notably, we found that DSF/Cu induced the accumulation of ubiquitinated proteins, promoted the half-life of xCT protein, and dramatically dampened the ubiquitination-proteasome mediated degradation of xCT. Moreover, both pharmacologically and genetically suppressing xCT exacerbated DSF/Cu-induced cell death. In conclusion, the current work provides an in-depth study of the mechanism of DSF/Cu-induced cell death and describes a framework for the further understanding of the crosstalk between ferroptosis and cuproptosis. Inhibiting the compensatory increase of xCT renders HCC cells more susceptible to DSF/Cu, which may provide a promising synergistic strategy to sensitize tumor therapy and overcome drug resistance, as it activates different programmed cell death.