Stabilization of Ni by rhamnolipid modified nano zero-valent iron in soil: Effect of simulated acid rain and microbial response.

Nickel (Ni), as one of the essential micronutrients, exists widely in nature, but high concentration of Ni in soil can pose certain biological toxicity. Nano zero-valent iron (nZVI) and rhamnolipid modified nZVI (RL@nZVI) can effectively stabilize Ni in soil. In this study, the stabilization effect of nZVI and RL@nZVI on the Ni-polluted soil under simulated acid rain and the microbial community response during the soil remediation under different Ni levels (200, 600, and 1800 mg/kg) were investigated. The results show that the addition of nZVI and RL@nZVI increased the pH of leachate to neutral and decreased the amount of Ni in leachate (23.33%-47.06% by nZVI and 50.01%-70.47% by RL@nZVI), indicating that nZVI and RL@nZVI could reduce the potential radial migration risk of Ni in soil under simulated acid rain. The addition of RL@nZVI was beneficial to recover the soil bacterial community diversity, which was inhibited by Ni pollution, and rhamnolipid coating could reduce the toxicity of nZVI. The dominant bacteria in RL@nZVI-treated soil with low, medium, and high Ni pollution were Firmicutes, Proteobacteria and Actinobacteria, respectively. Soil potential, total organic carbon, and pH were the main driving factors affecting the bacterial community structure, while Ni stress only caused changes in the relative abundance of some tolerant bacteria.

Serum levels of 25-OH vitamin D levels predict cognitive impairments among acute coronary syndrome patients.

BACKGROUND: The cognitive impairment after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) has become a crucial clinical concern that cannot be ignored. However, studies on the early warning factors of cognitive impairment after PCI are still insufficient. METHODS: This study reviewed the postoperative cognitive function of 284 patients who underwent PCI in our hospital from June 2019 to June 2022. During the 21-day follow-up, all participants included in the analysis were divided into the cognitive impairment (CI) group (n = 82) and the noncognitive impairment (NCI) group (n = 186) according to their Montreal cognitive assessment (MoCA) scale. Participants' serum 25(OH)D3 levels on admission and serum neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP) and S100ß levels were measured 21 days after surgery. RESULTS: Age more than 65 years, hypertension, operation time longer than 60 min, left ventricular ejection fraction less than 50% and serum 25(OH)D3 less than 31.41 ng/ml were the risk factors for cognitive dysfunction in ACS patients 21 days after PCI. Serum levels of 25(OH)D3, NSE, S100ß and GFAP were significantly higher in patients with cognitive impairment than in patients without cognitive impairment. CONCLUSION: Postoperative serum NSE, S100ß and GFAP levels were significantly negatively correlated with serum 25(OH)D3 levels at admission. The serum 25(OH)D3 level is a risk factor and predictor of cognitive impairment in patients with ACS after PCI.

NEDD4 ameliorates myocardial reperfusion injury by preventing macrophages pyroptosis.

OBJECTIVES: The inflammatory cascade and cell death post-myocardial ischemia reperfusion (MI/R) are very complex. Despite the understanding that macrophage inflammation has a pivotal role in the pathophysiology of MI/R, the contribution of macrophage inflammatory signals in tailoring the function of vascular endothelium remains unknown. MATERIALS AND METHODS: In the present study, we analyzed the effects of NEDD4 on the NLRP3 inflammasome activation-mediated pyroptosis in vitro after an acute pro-inflammatory stimulus and in vivo in a MI/R mouse model. TTC and Evan's blue dye, Thioflavin S, immunohistochemistry staining, and ELISA were performed in wild-type and NEDD4 deficiency mice. THP-1 cells were transfected with si-NEDD4 or si-SF3A2. HEK293T cells were transfected with NEDD4 or SF3A2 overexpression plasmid. ELISA analyzed the inflammatory cytokines in the cell supernatant. The levels of NEDD4, SF3A2, and NLRP3/GSDMD pathway were determined by Western blot. Protein interactions were evaluated by immunoprecipitation. The protein colocalization in cells was monitored using a fluorescence microscope. RESULTS: NEDD4 inhibited NLRP3 inflammasome activation and pyroptosis in THP-1 cells treated with lipopolysaccharide (LPS) and nigericin (Nig). Mechanistically, NEDD4 maintained the stability of NLRP3 through direct interaction with the SF3A2, whereas the latter association with NLRP3 indirectly interacted with NEDD4 promoting proteasomal degradation of NLRP3. Deletion of NLRP3 expression further inhibited the caspase cascade to induce pyroptosis. Interestingly, inhibiting NLRP3 inflammasome activation in THP-1 cells could prevent cardiac microvascular endothelial cells (CMECs) injury. In addition, NEDD4 deficiency decreased animal survival and increased myocardial infarct size, no-reflow area, and promoted macrophages infiltration post-MI/R. CONCLUSIONS: NEDD4 could be a potential therapeutic target in microvascular injury following myocardial reperfusion. Video Abstract.

Simultaneous stabilization of Pb, Cd, and As in soil by rhamnolipid coated sulfidated nano zero-valent iron: Effects and mechanisms.

Sulfidation effectively improves the electron transfer efficiency of nanoscale zero-valent iron (nZVI), but decreases the specific surface area of nZVI. In this study, sulfidated nZVI (S-nZVI) coated with rhamnolipid (RL-S-nZVI) was synthesized and used to stabilize Pb, Cd, and As in combined polluted soil. The stabilization efficiency of 0.3% (wt) RL-S-nZVI to water soluble Pb, Cd, and As in soil reached 88.76%, 72%, and 63%, respectively. Rhamnolipid coating inhibited the reduction of specific surface area and successfully encapsulated nZVI, thus reducing the oxidation of Fe0. The types of iron oxides in RL-S-nZVI were reduced compared to S-nZVI, but the content and strength of Fe0 iron were obviously enhanced. Furthermore, rhamnolipid functional groups (-COOH and -COO-) were also involved in the stabilization process. In addition, the stabilization efficiency of RL-S-nZVI to the bioavailable Pb, Cd, and As in soil increased by 41%, 41%, and 50%, respectively, compared with nZVI. The presence of organic acids, especially citric acid, improved the stabilization efficiency of RL-S-nZVI to the three metals. The result of BCR sequential extraction indicated that RL-S-nZVI increased the residual state of Pb, Cd, and As and reduced the acid-soluble and reducible state after 28 days of soil incubation. XRD and XPS analyses showed that the stabilization mechanisms of RL-S-nZVI on heavy metals involved in ion exchange, surface complexation, adsorption, co-precipitation, chemisorption, and redox.

Simultaneous immobilization of arsenic, lead, and cadmium in soil by magnesium-aluminum modified biochar: Influences of organic acids, aging, and rainfall.

Magnesium-aluminum modified biochar (MABs) has an outstanding effect on the simultaneous immobilization of arsenic (As), lead (Pb), and cadmium (Cd) in soil, but the stability of remediation effect of MAB under various natural conditions is still unknown. In this study, we investigated the effects of organic acids, dry-wet cycles (DW), freeze-thaw cycles (FT), and rainfall (pH 4, 7, and 8) on the immobilization of As, Pb, and Cd by MAB. The results showed that oxalic acid decreased the immobilization efficiencies of As, Pb, and Cd by 15.5%-38.5%; meanwhile, humic acid reduced the immobilization efficiency of Pb by 89.7%, but elevated that of Cd by 19.5%. The immobilization mechanisms of MAB-5 on three metals were mainly involved in ion exchange and surface-complexation. Compared with the 7th round, the immobilization efficiencies of As, Pb, and Cd by MAB in the 28th round was decreased by 17%-28% in DW, but was increased by 11%-18% in FT. In addition, MAB was transformed into hydrotalcite after FT and DW. After experiencing simulated rainfall, MAB caused more As, Pb, and Cd to be retained in the upper soil layer, and the immobilization effect of MBA was more significant under the stimulated rainfall with higher pH. The study provides a more theoretical basis for the application of MAB in the actual site remediation.

The Differences in Clinical Characteristic and Outcomes of New Onset Typical versus Atypical Right Branch Bundle Block in Acute Myocardial Infarction.

Objective: The purpose of this study is to explore the clinical characteristics and estimate the new-onset atypical right branch bundle block (ATRBBB) predictive value in short-term and long-term mortality by comparing the typical right branch bundle block (TRBBB) subset in acute myocardial infarction (AMI) patients. Methods: A total of 224 AMI patients combined with new onset RBBB who received primary coronary angiography were included, being admitted to Henan Provincial People's Hospital in China from July 2010 to June 2021. Patients were divided into typical RBBB group (n = 104) and atypical RBBB group (n = 120). The differences in clinical characteristics between the two groups were analyzed. Logistic and Cox regression analysis were performed to identify independent predictors of in-hospital Major Adverse Cardiovascular Events (MACE). Result: The ATRBBB group had a higher proportion of smoking and alcohol consumption, higher body mass index, worse cardiac function (killip ≧ II proportion), higher peak value of CK-MB, lower LVEF%, longer total ischemia time, higher proportion of LAD (left anterior descending coronary artery) occlusion, and multivessel lesions, compared to the TRBBB group. The ATRBBB group had a higher proportion of in-hospital MACE and 1-year all-cause mortality compared to the TRBBB group. ATRBBB was an independent predictor of in-hospital MACE and 1-year mortality in patients with AMI combined with new onset RBBB. Conclusions: ATRBBB group had more serious clinical symptoms and clinical prognosis. New ATRBBB is an independent predictor of in-hospital MACE and 1-year death in patients with AMI combined with RBBB. If the infarct-related vessel was opened immediately, the evolution of TRBBB to ATRBBB may be avoided, leading to a better prognosis.

[WITHDRAWN] miR-144-3p Functions as a Tumor Suppressor in Endometrial Cancer by Targeting PRR11.

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Transcriptomics Reveals the ERF2-bHLH2-CML5 Module Responses to H2S and ROS in Postharvest Calcium Deficiency Apples.

Calcium deficiency usually causes accelerated quality deterioration in postharvest fruit, whereas the underlining mechanism is still unclear. Here, we report that calcium deficiency induced the development of bitter pit on the surface of apple peels compared with the healthy appearance in control apples during postharvest storage. Physiological analysis indicates that calcium-deficient peels contained higher levels of superoxide anion (O2•-), malondialdehyde (MDA), total phenol, flavonoid contents and polyphenol oxidase (PPO) activity, and reduced calcium, H2S production, anthocyanin, soluble protein content, and peroxidase (POD) activity compared with those in calcium-sufficient peels. The principal component analysis (PCA) results show that calcium content, ROS, and H2S production were the main factors between calcium-deficient and calcium-sufficient apple peels. Transcriptome data indicated that four calmodulin-like proteins (CMLs), seven AP2/ERFs, and three bHLHs transcripts were significantly differentially expressed in calcium-deficient apple peels. RT-qPCR and correlation analyses further revealed that CML5 expression was significantly positively correlated with the expression of ERF2/17, bHLH2, and H2S production related genes. In addition, transcriptional co-activation of CML5 by ERF2 and bHLH2 was demonstrated by apple transient expression assays and dual-luciferase reporter system experiments. Therefore, these findings provide a basis for studying the molecular mechanism of postharvest quality decline in calcium-deficient apples and the potential interaction between Ca2+ and endogenous H2S.

FBXW4 Is Highly Expressed and Associated With Poor Survival in Acute Myeloid Leukemia.

The F-box and WD repeat domain-containing (FBXW) proteins play an important role in ubiquitin proteasome by inducing protein degradation. Ten FBXW proteins have been identified in humans. The functions of FBXW proteins, like FBXW7, have been well-established in many human cancers. However, little is known about their transcriptional expression profiles and relationship with prognosis in acute myeloid leukemia (AML). Here we investigated the roles of FBXW proteins in AML by analyzing their mRNA expression profiles and association with clinical features using data from EMBL-EBI, the Cancer Cell Line Encyclopedia, Gene Expression Profiling Interactive Analysis, and cBioPortal databases. Our results showed that the mRNA level of FBXW proteins were highly detected by microarray in 14 AML cell lines, although there were no obvious differences. The expression of FBXW4 was significantly higher in AML patients compared with that in normal controls (P < 0.01). Patients whose age was ≥60 years old had a higher FBXW4 expression when compared with those who were <60 years old (P < 0.05). Cytogenetic favorable-risk group patients had a much lower FBXW4 expression than the intermediate- and poor-risk group patients (P < 0.0001). Moreover, patients with high FBXW4 expression exhibited significantly shorter event-free survival (EFS) and overall survival (OS) than those with low FBXW4 expression (median EFS: 5.3 vs. 10.0 months, P = 0.025; median OS: 8.1 vs. 19.0 months, P= 0.015). A multivariate analysis indicated that high FBXW4 expression was an independent risk factor for poor EFS in AML patients who received intensive chemotherapy followed by allo-SCT. In summary, our data suggested that FBXW4 is aberrantly expressed in AML and high FBXW4 expression might be a poor prognostic biomarker; future functional and mechanistic studies will further illuminate the roles of FBXW4 in AML.

Altered Cofactor Preference of Thermostable StDAPDH by a Single Mutation at K159.

D-amino acid production from 2-keto acid by reductive amination is an attractive pathway because of its high yield and environmental safety. StDAPDH, a meso-diaminopimelate dehydrogenase (meso-DAPDH) from Symbiobacterium thermophilum, was the first meso-DAPDH to show amination of 2-keto acids. Furthermore, StDAPDH shows excellent thermostability compared to other meso-DAPDHs. However, the cofactor of StDAPDH is NADP(H), which is less common than NAD(H) in industrial applications. Therefore, cofactor engineering for StDAPDH is needed. In this study, the highly conserved cofactor binding sites around the adenosine moiety of NADPH were targeted to determine cofactor specificity. Lysine residues within a loop were found to be critical for the cofactor specificity of StDAPDH. Replacement of lysine with arginine resulted in the activity of pyruvic acid with NADH as the cofactor. The affinity of K159R to pyruvic acid was equal with NADH or NADPH as the cofactor, regardless of the mutation. Molecular dynamics simulations revealed that the large steric hindrance of arginine and the interaction of the salt bridge between NADH and arginine may have restricted the free movement of NADH, which prompted the formation of a stable active conformation of mutant K159R. These results provide further understanding of the catalytic mechanism of StDAPDH and guidance for the cofactor engineering of StDAPDH.

BCR-ABL1 transcript decline ratio combined BCR-ABL1IS as a precise predictor for imatinib response and outcome in the patients with chronic myeloid leukemia.

Purpose: The early BCR-ABL1 reduction had the prognostic impact of the chronic-phase chronic myeloid leukemia (CML-CP) patients. This study was to find a more precise early prognosis index at 3 months in the patients with newly diagnosed CML-CP, especially for the patients with BCR-ABL1IS >10%. Methods: We retrospectively analyzed the data of 79 newly diagnosed CML-CP patients from October 2013 to April 2017. All patients took imatinib regularly and continuously and monitored BCR-ABL1 transcript level at baseline and 3, 6, 9, 12, 18 months after starting imatinib treatment. Results: Among the 44(55.7%) patients with BCR/ABL1IS ≤10% at 3 months after imatinib treatment, 12(27.3%) cases did not achieve major molecular response (MMR) at 12 months, and 7(14.9%) patients with the halving time BCR-ABL1 transcript ≤40 days failed to achieve MMR at 12 months. However, approximately twenty-six percent of the patients with BCR-ABL1IS >10% still obtained MMR. Moreover, the patients with BCR-ABL1IS ≤10% and halving time ≤40 days had a significantly better MMR than that of the patients with the BCR-ABL1IS ≤10% and halving time >40 days (88.6% versus 11.1%, P <0.001). However, the patients with the BCR-ABL1IS >10% and halving time >40 days rarely achieved MMR at 12 months. Conclusion: These data indicated that the halving time of BCR-ABL1 transcript was also an important prognostic factor as that of the BCR-ABL1IS. Combined observations of these two prognosis indexes are more accurate predictor for the long-term molecular response, especially for the CML-CP patients with BCR-ABL1IS >10%, and which is helpful for TKI switching as early as possible to improve patients' survival and reduce drug costs.

RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia.

The recombination mediated by recombination activating gene (RAG) is not only the dominant mutational process but also the predominant driver of oncogenic genomic rearrangement in acute lymphoblastic leukemia (ALL). It is further responsible for leukemic clonal evolution. In this study, significant RAG1 increase is observed in the subsets of B-ALL patients, and high expression of RAG1 is observed to be correlated with high proliferation markers. IKZF1-encoded protein, IKAROS, directly binds to the RAG1 promoter and regulates RAG1 expression in leukemic cells. CK2 inhibitor by increasing IKAROS activity significantly suppresses RAG1 expression in ALL in an IKAROS-dependent manner. Patients with IKZF1 deletion have significantly higher expression of RAG1 compared to that without IKZF1 deletion. CK2 inhibitor treatment also results in an increase in IKZF1 binding to the RAG1 promoter and suppression of RAG1 expression in primary ALL cells. Taken together, these results demonstrate that RAG1 high expression is associated with high proliferation markers in B-ALL. Our data for the first time proved that RAG1 expression is directly suppressed by IKAROS. Our results also reveal drive oncogenesis of B-ALL is driven by high expression of RAG1 with IKAROS dysfunction together, which have significance in an integrated prognostic model for adult ALL.

AMPK Inhibition Suppresses the Malignant Phenotype of Pancreatic Cancer Cells in Part by Attenuating Aerobic Glycolysis.

Pancreatic cancer is a highly aggressive tumor characterized by enhanced aerobic glycolysis. AMP-activated protein kinase (AMPK), which is identified as a well-known regulator of glycolysis, plays an essential role in tumorigenesis. In the present study, we aim to explore the function of AMPK in pancreatic cancer cells and attempt to clarify the possible underlying mechanism. The Cancer Genome Atlas (TCGA) data showed that elevated AMPK expression highly correlated with lower median survival time. In an in vitro study, inhibition of AMPK blocked the proliferation, migration, and invasion ability of four cell lines under normoxia and hypoxia. Additionally, AMPK suppression led to cell cycle arrest and remarkably induced apoptosis. Furthermore, the lactic acid content, ATP content, and the glucose consumption rate were significantly reduced in all four cell lines under different conditions, accompanied by down-regulation of glycolytic biomarkers including phosphorylated mammalian target of rapamycin (p-mTOR)/total mTOR (t-mTOR), Pyruvate kinase M2 (Pkm2), and Hexokinase 2 (Hk2). Collectively, our data showed that AMPK activation is highly involved in pancreatic cancer progression and exerts its pro-tumorigenic functions partly by sustaining glycolytic activity. Hence, AMPK is expected to be a potential therapeutic target for pancreatic cancer.

Efficacy and toxicity of cladribine for the treatment of refractory acute myeloid leukemia: a meta-analysis.

Purpose: To investigate the overall efficacy and toxicity of cladribine and cladribine-based chemotherapy in the treatment of patients with refractory acute myeloid leukemia (AML) based on meta-analysis. Methods: PubMed, EMBASE database, and the Cochrane Library were searched for relevant studies. Eligible studies were clinical trials of refractory AML assigned to cladribine with data on efficacy including complete remission (CR) rate, overall response rate (ORR) and overall survival. Toxicity was evaluated based on the early death rate and the incidence of grade 3 and 4 adverse events (AEs). Results: A total of 10 clinical trials including 422 refractory AML patients were analyzed. The overall CR rate was 42.2% (95% CI: 31.0-54.3%). And the ORR of seven trials including 235 patients was 49.7% (95% CI: 33.5-66.0%). The overall early death rate of 260 patients enrolled in five trials was 6.8% (95% CI: 4.3-10.6%). Thrombocytopenia, anemia, neutropenia, and infection were the most common grade 3 and 4 AEs. Conclusion: Cladribine is effective for refractory AML, and its efficacy can be increased with the combination of cladribine, cytarabine, and granulocyte-colony stimulating factor regimen.

Mutations in EZH2 are associated with poor prognosis for patients with myeloid neoplasms.

EZH2 is a component of the polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that methylates lysine 27 of histone 3. EZH2 mutations are associated with oncogenesis and progression of cancers. However, the relationship between the clinical outcome of patients with myeloid malignancies and EZH2 mutations is controversial. Therefore, we performed a meta-analysis of 8 studies (n = 2243 patients) that evaluates the correlation between EZH2 mutations and overall survival (OS) in patients with myeloid neoplasms. EZH2 mutations were associated with significantly worse OS (hazard ratio [HR] = 2.37, 95% confidential interval (CI), 1.48-3.79). In a word, EZH2 mutations indicate a poor prognosis for patients with myeloid neoplasms.

[Efficacy Analysis of Unrelated Umbilical Cord Blood Transplantation for the Treatment of Wiskott-Aldrich Syndrome].

OBJECTIVE: To explore the clinical efficacy and safety of unrelated umbilical cord blood transplantation (UCBT) for the treatment of Wiskott-Aldrich syndrome(WAS). METHODS: Five pediatric patients with WAS received single UCBT were retrospectively analyzed. The median age of these male patients was 268 days (range, 3 days -695 days). Among them, 2 patients were transplanted with a 6/6 matched cord blood graft，the other 3 patients received a 5/6 matched cord blood graft. Myeloablative conditioning regimen was applied, and all patients received a combination of cyclosporine and mycophenolate mofetil for the prophylaxis of graft versus host disease (GVHD). The recovery time of neutrophils and platelets as well as chimerism after transplantation were taken as the evidence of hematopoietic reconstruction. RESULTS: All the five pediatric patients had hematopoietic recovery. A median time of neutrophil cells after transplantation was at 15.8 days (range,11 days -25 days), and platelet recovery was at a median of 20.4 days(range,12 days-30 days). Chimerism data were available for 5 patients at 30 days after UCBT, 4 out of the 5 patients had full donor chimerism and only one patient had mixed chimerism. There were 2 cases with pre-engraftment syndrome, 3 cases with acute GVHD gradeⅠ-Ⅲ, 4 cases with pulmonary infection and cytomegalovirus infection, but chronic GVHD was not observed in 5 cases. Four patients were alive with a median follow-up of 12.3 months (range, 5 months-17 months), and one patient had died at 22 days after UCBT. CONCLUSION: Unrelated umbilical cord blood transplantation is a safe and effective treatment method for Wiskott-Aldrich syndrome.

Plant homeodomain finger protein 2 as a novel IKAROS target in acute lymphoblastic leukemia.

AIM: Clinical significance of plant homeodomain finger 2 (PHF2) expressions is explored in acute lymphoblastic leukemia (ALL) patients. METHODS: mRNA level was examined by qPCR. The retroviral gene expression, shRNA knockdown and chromatin-immunoprecipitation are used to observe IKAROS regulation on PHF2 transcription. RESULTS: PHF2 expression is significantly reduced in subsets of ALL patients, and PHF2 low expression correlates with leukemia cell proliferation and an elevation of several poor prognostic markers in B-cell ALL. IKAROS directly promotes PHF2 expression and patients with IKAROS deletion have significantly lower PHF2 expression. Casein kinase II (CK2) inhibitor significantly promotes PHF2 expression in an IKAROS-dependent manner, and casein kinase II inhibitor treatment also results in an increase of PHF2 expression and enrichment of IKAROS and H3K4me3 at PHF2 promoter in primary cells. CONCLUSION: Our results demonstrate that the IKAROS promotes PHF2 expression, and suggest that PHF2 low expression works with the IKAROS gene deletion to drive oncogenesis of ALL.

pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer.

Multidrug resistance (MDR) remains a major challenge for providing effective chemotherapy for many cancer patients. To address this issue, we report an intelligent polymer-based drug co-delivery system which could enhance and accelerate cellular uptake and reverse MDR. The nanodrug delivery systems were constructed by encapsulating disulfiram (DSF), a P-glyco-protein (P-gp) inhibitor, into the hydrophobic core of poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLL) block copolymer micelles, as well as 2,3-dimethylmaleic anhydride (DMA) and paclitaxel (PTX) were grafted on the side chain of l-lysine simultaneously. The surface charge of the drug-loaded micelles represents as negative in plasma (pH 7.4), which is helpful to prolong the circulation time, and in a weak acid environment of tumor tissue (pH 6.5-6.8) it can be reversed to positive, which is in favor of their entering into the cancer cells. In addition, the carrier could release DSF and PTX successively inside cells. The results of in vitro studies show that, compared to the control group, the DSF and PTX co-loaded micelles with charge reversal exhibits more effective cellular uptake and significantly increased cytotoxicity of PTX to MCF-7/ADR cells which may be due to the inhibitory effect of DSF on the efflux function of P-gp. Accordingly, such a smart pH-sensitive nanosystem, in our opinion, possesses significant potential to achieve combinational drug delivery and overcome drug resistance in cancer therapy.

USP17-mediated deubiquitination and stabilization of HDAC2 in cigarette smoke extract-induced inflammation.

Histone deacetylase HDAC2 regulates genes transcription via removing the acetyl group from histones. Glucocorticoids, the most potent anti-inflammatory treatment available for inflammatory diseases, inhibit the expression of inflammatory genes by recruiting HDAC2 to activated genes. In the lungs of patients who smoke and have chronic obstructive pulmonary disease (COPD) or asthma, glucocorticoids are not effective enough to suppress airway inflammation, which is so called "glucocorticoid resistance", due to decreased HDAC2 level caused by cigarette smoke. We report that the ubiquitin-specific protease USP17 interacts with HDAC2. USP17 deubiquitinates and stabilizes the protein level of HDAC2. In cigarette smoke extract-exposed airway epithelial cells and macrophages, HDAC2 is excessively ubiquitinated and degraded in the proteasome attributed to low expression of USP17. Furthermore, over-expression of USP17 blocks the destruction of HDAC2 induced by cigarette smoke extract. These results provide a new insight into the mechanisms of glucocorticoid resistance in airway inflammatory disease. Small molecules which can specifically induce the expression of USP17 might be useful in reversing glucocorticoid resistance.