Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition.

EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors.

The ROS1 fusion kinase is an attractive antitumor target. Though with significant clinical efficacy, the well-known first-generation ROS1 inhibitor (ROS1i) crizotinib inevitably developed acquired resistance due to secondary point mutations in the ROS1 kinase. Novel ROS1is effective against mutations conferring secondary crizotinib resistance, especially G2032R, are urgently needed. In the present study, we evaluated the antitumor efficacy of SAF-189s, the new-generation ROS1/ALK inhibitor, against ROS1 fusion wild-type and crizotinib-resistant mutants. We showed that SAF-189s potently inhibited ROS1 kinase and its known acquired clinically resistant mutants, including the highly resistant G2032R mutant. SAF-189s displayed subnanomolar to nanomolar IC50 values against ROS1 wild-type and mutant kinase activity and a selectivity vs. other 288 protein kinases tested. SAF-189s blocked cellular ROS1 signaling, and in turn potently inhibited the cell proliferation in HCC78 cells and BaF3 cells expressing ROS1 fusion wild-type and resistance mutants. In nude mice bearing BaF3/CD74-ROS1 or BaF3/CD74-ROS1G2032R xenografts, oral administration of SAF-189s dose dependently suppressed the growth of both ROS1 wild-type- and G2032R mutant-driven tumors. In a patient-derived xenograft model of SDC4-ROS1 fusion NSCLC, oral administration of SAF-189s (20 mg/kg every day) induced tumor regression and exhibited notable prolonged and durable efficacy. In addition, SAF-189s was more potent than crizotinib and comparable to lorlatinib, the most advanced ROS1i known against the ROS1G2032R. Collectively, these results suggest the promising potential of SAF-189s for the treatment of patients with the ROS1 fusion G2032R mutation who relapse on crizotinib. It is now recruiting both crizotinib-relapsed and naive ROS1-positive NSCLC patients in a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT04237805).

Green and efficient degradation of cefoperazone sodium by Bi4O5Br2 leading to the production of non-toxic products: Performance and degradation pathway.

Photocatalytic process represents a promising approach to overcome the pollution challenge associated with the antibiotics-containing wastewater. This study provides a green, efficient and novel approach to remove cephalosporins, particularly cefoperazone sodium (CFP). Bi4O5Br2 was chosen for the first time to systematically study its degradation for CFP, including the analysis of material structure, degradation performance, the structure and toxicity of the transformation products, etc. The degradation rate results indicated that Bi4O5Br2 had an excellent catalytic activity leading to 78% CFP removal compared with the pure BiOBr (38%) within 120 min of visible light irradiation. In addition, the Bi4O5Br2 presents high stability and good organic carbon removal efficiency. The effects of the solution pH (3.12 - 8.75) on catalytic activity revealed that CFP was mainly photocatalyzed under acidic conditions and hydrolyzed under alkaline conditions. Combined with active species and degradation product identification, the photocatalytic degradation pathways of CFP by Bi4O5Br2 was proposed, including hydrolysis, oxidation, reduction and decarboxylation. Most importantly, the identified products were all hydrolysis rather than oxidation byproducts transformed from the intermediate of ß-lactam bond cleavage in CFP molecule, quite different from the mostly previous studies. Furthermore, the final products were demonstrated to be less toxic through the toxicity analysis. Overall, this study illustrates the detailed mechanism of CFP degradation by Bi4O5Br2 and confirms Bi4O5Br2 to be a promising material for the photodegradation of CFP.

Antitumor activity of a novel Aurora A/B kinases inhibitor TY-011 against gastric cancer by inducing DNA damage.

TY-011, a novel Aurora A/B kinases inhibitor, was found in our previous study to exhibit prominent inhibitory effects on growth of gastric cancer, both in vitro and in vivo. To clarify the mechanisms of TY-011 in inhibiting proliferation of gastric cancer cells, the effects of TY-011 on mitosis, cell cycle, apoptosis and cellular DNA were checked in the present study. Our results showed that TY-011 treatment induced aberrant mitosis, G2/M phase arrest and apoptosis. Importantly, TY-011 induced evident DNA damage in MGC-803 and MKN-45 human gastric cancer cells, which was further characterized as DNA double-strand break. Furthermore, cells treated with TY-011 appeared to generate multiple spindle fibers emanating from several spindle poles, leading to poly-merotelic kinetochore. These results suggested that TY-011 induced abnormal microtubule-kinetochores attachment and thus DNA damage, apoptosis and finally inhibition of cell proliferation of human gastric cancer cells.

Preliminary study on the electrocatalytic performance of an iron biochar catalyst prepared from iron-enriched plants.

Eichhornia crassipes is a hyperaccumulator of metals and has been widely used to remove metal pollutants from water, but disposal of contaminated plants is problematic. Biochar prepared from plants is commonly used to remediate soils and sequester carbon. Here, the catalytic activity of biochar prepared from plants enriched with iron was investigated as a potentially beneficial use of metal-contaminated plants. In a 30-day hydroponic experiment, E. crassipes was exposed to different concentrations of Fe(III) (0, 4, 8, 16, 32 and 64 mg/L), and Fe-biochar (Fe-BC) was prepared by pyrolysis of the plant roots. The biochar was characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectrometry (EDS), Brunauer-Emmett-Teller (BET) analysis, X-ray photoelectron spectroscopy (XPS) and atomic absorption spectrometry (AAS). The original root morphology was visible and iron was present as γ-Fe2O3 and Fe3O4. The biochar enriched with Fe(III) at 8 mg/L (8-Fe-BC) had the smallest specific surface area (SSA, 13.54 m2/g) and the highest Fe content (27.9 mg/g). Fe-BC catalytic activity was tested in the electrocatalytic reduction of H2O2 using cyclic voltammetry (CV). The largest reduction current (1.82 mA/cm2) was displayed by 8-Fe-BC, indicating the highest potential catalytic activity. We report here, for the first time, on the catalytic activity of biochar made from iron-enriched plants and demonstrate the potential for reusing metal-contaminated plants to produce a biochar catalyst.

AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition.

Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291. The anti-tumor effects of AZD9291 on breast cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected. MicroRNA array assay, luciferase reporter assay, and qRT-PCR were conducted to identify the interaction and regulation among AZD9291, EZH2, and miR-34a. We discovered that, AZD9291, a potent and selective EGFR inhibitor, disrupted the interaction of EZH2-EED, leading to impairment of PRC2 activity and downregulation of EZH2 protein. In addition, AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor, miR-34a. Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.

ES2 enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells in vitro and in vivo.

ES2 is a new type of jatrophane diterpenoid ester isolated from the fructus E. sororia, a traditional Uyghur medicine in China. Here we reported the multidrug resistance (MDR) reversal effect of ES2 in vitro and in vivo by modulating the function of ATP-binding cassette subfamily B member 1 (ABCB1). ES2 exhibited low cytotoxicity to ABCB1-overexpressing MDR cells and their parental sensitive cells, but sensitized the MDR cells and ABCB1-transfected HEK293 cells to chemotherapeutic drugs that are ABCB1 substrates. The reversal ability of ES2 was primarily due to the inhibition of the efflux function of ABCB1. Moreover, ES2 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. There was no change in the expression of ABCB1 in the presence of ES2. The molecular docking analysis indicated that ES2 bond to the drug-binding site of ABCB1 transporter. Importantly, ES2 significantly enhanced the anti-tumor effect of vinorelbine against KBv200 cell xenografts in nude mice. Overall, these findings demonstrate that ES2 inhibits the ABCB1 transporter function and consequently reverses ABCB1-mediated MDR, indicating the potential use of ES2 in combination therapy with conventional chemotherapeutic drugs for cancer treatment.

Brönsted Catalyzed Hydrolysis of Microcystin-LR by Siderite.

Six naturally occurring minerals were employed to catalyze the hydrolysis of microcystin-LR (MC-LR) in water. After preliminary screening experiments, siderite stood out among these minerals due to its higher activity and selectivity. In comparison with kaolinite, which is known to act as a Lewis acid catalyst, siderite was found to act primarily as a Brönsted acid catalyst in the hydrolysis of MC-LR. More interestingly, we found that the presence of humic acid significantly inhibited catalytic efficiency of kaolinite, while the efficiency of siderite remained high (∼98%). Reaction intermediates detected by LC-ESI/MS were used to indicate cleavage points in the macrocyclic ring of MC-LR, and XPS was used to characterize siderite interaction with MC-LR. Detailed analysis of the in situ ATR-FTIR absorption spectra of MC-LR indicated hydrogen bonding at the siderite-water-MC-LR interface. A metastable ring, involving hydrogen bonding, between surface bicarbonate of siderite and an amide of MC-LR was proposed to explain the higher activity and selectivity toward MC-LR. Furthermore, siderite was found to reduce the toxicity of MC-LR to mice by hydrolyzing MC-LR peptide bonds. The study demonstrates the potential of siderite, an earth-abundant and biocompatible mineral, for removing MC-LR from water.

Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α.

BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-α (FAPα) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPα-based prodrug strategy to synthesize a dipeptide (Z-Gly-Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPα (rhFAPα) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPα-negative normal tissues, such as heart and kidney. In HCT-116 and MGC-803 cells with low levels of FAPα expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC50 value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPα or tumor homogenate. In HCT-116 tumor-bearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPα-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy.

Design, Synthesis, and Biological Evaluation of New Cathepsin B-Sensitive Camptothecin Nanoparticles Equipped with a Novel Multifuctional Linker.

Traditional antitumor drugs such as camptothecin and paclitaxel derivatives are widely used in cancer chemotherapy. However, the major defects of those agents include severe toxicity and poor water solubility. With these in mind, a novel multifunctional linker was designed and two Cathepsin B (CTB) sensitive CPT conjugates (9a and 9b) were synthesized. Through click chemistry, additional functional group mPEG2000 can be easily introduced into these conjugates. The introduction of mPEG2000 fragment resulted in the formation of nanoparticles 1a and 1b (average particle sizes were 216.9 and 257.9 nm, respectively) with significantly increased water solubility (more than 19 000-fold). The release of therapeutic drug SN-38 in the presence of CTB was confirmed by HPLC and prodrug 1a showed potent in vitro cytotoxicity against all tested cell lines. Impressively, compared with irinotecan, CTB sensitive prodrug 1a displayed similar in vivo efficacy with remarkable decreased in vivo toxicity.

W-N heteroatom-interface in melon carbon nitride/N-doped tungsten oxide Z-Scheme photocatalyst toward improved photocatalytic hydrogen generation activity.

The construction of heterointerface in photocatalyst is an efficient approach to boost the separation and utilization efficiency of charge carriers, which is challenging and crucial in photocatalysis. Here, the construction of melon-structured carbon nitride/N-doped WO3 (MCN/NWx) heterojunction photocatalyst was achieved by a method of prealcoholysis combined with thermal polymerization, where N-doping of WO3 was achieved in-situ in the formation of heterojunction. The promoted charge separation efficiency was realized through the charge transfer from the conduction band of N-doped WO3 to the valence band of the MCN. Density functional theory calculation results showed that the formation of the W-N heteroatom-interface led to the increase of density of states at the heterointerface and decrease of the band gap. The MCN/NWx nanocomposite featured a metallic band structure of the nanocomposite photocatalysts, resulting in the enhanced photocatalytic activity. The photocatalytic hydrogen evolution activity of the MCN/NW2 was enhanced about 2.5 times than that of MCN. This research provides a novel insight into the construction of a novel heteroatom-junction that boosts the separation efficiency of charge carriers, and thereby improves the photocatalytic activity.

Role of low-molecular-weight organic compounds on photochemical formation of Mn(III)-ligands in aqueous systems: Implications for BPA removal.

Aqueous trivalent manganese [Mn(III)], an important reactive intermediate, is ubiquitous in natural surface water containing humic acid (HA). However, the effect of low-molecular-weight organic acids (LMWOAs) on the formation, stability and reactivity of Mn(III) intermediate is still unknown. In this study, six LMWOAs, including oxalic acid (Oxa), salicylic acid (Sal), catechol (Cat), caffeic acid (Caf), gallic acid (Gal) and ethylene diamine tetraacetic acid (EDTA), were selected to investigate the effects of LMWOAs on the degradation of BPA induced by in situ formed Mn(III)-L in the HA/Mn(II) system under light irradiation. The chromophoric constituents of HA could absorb light radiation and generate superoxide radical to promote the oxidation of Mn(II) to form Mn(III), which was further involved in transformation of BPA. Our results implied that different LMWOAs did significantly impact on Mn(III) production and its degradation of BPA due to their different functional group. EDTA, Oxa and Sal extensively increased the Mn(III) concentration from 50 to 100 µM compared to the system without LMWOAs, following the order of EDTA > Oxa > Sal, and also enhanced the degradation of BPA with the similar patterns. In contrast, Cat, Caf and Gal had an inhibitory effect on the formation of Mn(III), which is likely because they consumed the superoxide radicals generated from irradiated HA, resulting in the inhibition of Mn(II) oxidation and further BPA removal. The product identification and theoretical calculation indicated that a single electron transfer process occurred between Mn(III)-L and BPA, forming BPA radicals and subsequent self-coupling products. Our results demonstrated that the LMWOAs with different structures could alter the cycling process of Mn via complexation and redox reactions, which would provide new implications for the removal of organic pollutants in surface water.

Involvement of mitogen-activated protein kinase in signal transducer and activator of transcription-1 mediated differentiation induced by bortezomib in acute myeloid leukemia cells.

In this paper we report a new myeloid differentiation effect of bortezomib (BTZ) in acute myeloid leukemia (AML) cell lines and primary patient-derived AML cells; this effect was assayed by investigating growth-inhibition, cell morphology, differentiation markers, and nitro-blue tetrazolium reduction. We show that BTZ induces the phosphorylation of several mitogen-activated protein (MAP) kinases, including MEK/ERK, c-Jun N-terminal kinase (JNK), and p38 MAPK. BTZ-induced cell differentiation is almost completely reversed by PD98059, an inhibitor of MEK, which also attenuates the increase in phospho-JNK p46. However, p38 activation does not appear to be required for the differentiation induced by BTZ. Furthermore, the differentiation effect of BTZ is associated with increased protein level of signal transducer and activator of transcription-1 (STAT1), a molecular determinant of myeloid differentiation, due to effects on both its synthesis and degradation. In short, this study reveals that BTZ activates the MEK/ERK cascade, which further up-regulates the expression and activity of the key myeloid transcription factor STAT1, thus promoting myeloid differentiation. These findings contribute to an unexpected potential mechanism for the antitumor activity of BTZ in AML.

Exploring the reactivity of multicomponent photocatalysts: insight into the complex valence band of BiOBr.

The band structure of multicomponent semiconductor photocatalysts, as well as their reactivity distinction under different wavelengths of light, is still unclear. BiOBr, which is a typical multicomponent semiconductor, may have two possible valence-band structures, that is, two discrete valence bands constructed respectively from O 2p and Br 4p orbitals, or one valence band derived from the hybridization of these orbitals. In this work, aqueous photocatalytic hydroxylation is applied as the probe reaction to investigate the nature and reactions of photogenerated holes in BiOBr. Three organic compounds (microcystin-LR, aniline, and benzoic acid) with different oxidation potentials were selected as substrates. Isotope labeling (H(2)(18)O as the solvent) was used to determine the source of the O atom in the hydroxyl group of the products, which distinguishes the contribution of different hydroxylation pathways. Furthermore, a spin-trapping ESR method was used to quantify the reactive oxygen species ((.)OH and (.)OOH) formed in the reaction system. The different isotope abundances of the hydroxyl O atom of the products formed, as well as the reverse trend of the (.)OH/(.)OOH ratio with the oxidative resistance of the substrate under UV and visible irradiation, reveal that BiOBr has two separate valence bands, which have different oxidation ability and respond to UV and visible light, respectively. This study shows that the band structure of semiconductor photocatalysts can be reliably analyzed with an isotope labeling method.

Effect of duloxetine on pain relief after total knee arthroplasty: A meta-analysis of randomized controlled trials.

BACKGROUND: Postoperative pain is one of the most feared complications of total knee arthroplasty. Recently, randomized controlled trials have compared the efficacy of duloxetine in patients undergoing total knee arthroplasty. However, there is no definite answer as to the efficacy and safety of duloxetine. METHODS: Randomized controlled trials about relevant studies were searched from PubMed (1996 to July 2022), Embase (1996 to July 2022), and Cochrane Library (CENTRAL, July 2022). RESULTS: Six high-quality studies containing 532 patients met the inclusion criteria. Results show patients in the duloxetine group had better performance in terms of visual analog scale (P < .05), equivalent morphine consumption (P < .05), and length of stay (P < .05). CONCLUSION: Duloxetine can be used to reduce pain after knee arthroplasty in selected patients.

Combined effects of fluoroquinolone antibiotics and organophosphate flame retardants on Microcystis aeruginosa.

As freshwater harmful algal blooms continue to rise in frequency and severity, increasing focus is made on the effects of mixed pollutants and the dominant cyanobacterial species Microcystis aeruginosa (M. aeruginosa). However, few studies have investigated whether M. aeruginosa has a synergistic relationship with two common pollutants, namely, organophosphate flame retardants (OPFRs) and fluoroquinolone antibiotics (FQs). In this paper, three FQs and three OPFRs commonly detected in freshwaters were selected to construct a ternary mixture of FQs, a ternary mixture of OPFRs, and a six-component mixture of OPFRs and FQs. The effects of single substance and mixture on the growth of M. aeruginosa were determined at 24, 48, 72, and 96 h, and the toxicities of the mixture were evaluated by concentration addition model and independent action model. The results showed that the mixture of FQs and the mixture of OPFRs do not show toxicological interaction. However, partial mixtures of OPFRs and FQs showed antagonism or synergism at different concentrations and times. This indicated that combined toxicities of OPFRs and FQs on M. aeruginosa were mixture ratio dependent, concentration dependent and time dependent. This study improves our understanding of the role of OPFRs and FQs in cyanobacterial outbreaks of Microcystis.

Histone deacetylase inhibitors promote breast cancer metastasis by elevating NEDD9 expression.

Histone deacetylase (HDAC) is a kind of protease that modifies histone to regulate gene expression, and is usually abnormally activated in tumors. The approved pan-HDAC inhibitors have demonstrated clinical benefits for patients in some hematologic malignancies. Only limited therapeutic success in breast cancer has been observed in clinical trials. In this study, we declare that pan-HDAC inhibitors targeting NEDD9-FAK pathway exacerbate breast cancer metastasis in preclinical models, which may severely impede their clinical success. NEDD9 is not an oncogene, however, it has been demonstrated recently that there are high level or activity changes of NEDD9 in a variety of cancer, including leukemia, colon cancer, and breast cancer. Mechanistically, pan-HDAC inhibitors enhance H3K9 acetylation at the nedd9 gene promoter via inhibition of HDAC4 activity, thus increase NEDD9 expression, and then activate FAK phosphorylation. The realization that pan-HDAC inhibitors can alter the natural history of breast cancer by increasing invasion warrants clinical attention. In addition, although NEDD9 has been reported to have a hand in breast cancer metastasis, it has not received much attention, and no therapeutic strategies have been developed. Notably, we demonstrate that FAK inhibitors can reverse breast cancer metastasis induced by upregulation of NEDD9 via pan-HDAC inhibitors, which may offer a potential combination therapy for breast cancer.

The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer.

OBJECTIVE: The novel compound GCJ-490A has been discovered as a pan-histone deacetylase (HDAC) inhibitor that exerts potent inhibitory activity against HDAC1, HDAC3, and HDAC6. Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue, we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer (NSCLC) in vitro and in vivo in this study. METHODS: The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation, apoptosis, and colony formation assays. NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo. Western blot assays, luciferase reporter assays, chromatin immunoprecipitation assays, quantitative real time-PCR, immunohistochemistry, and transcription factor activity assays were used to elucidate possible mechanisms. RESULTS: GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo. Interestingly, inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKα promoter and enhanced IKKα transcription, thus decreasing c-Met. Moreover, this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. CONCLUSIONS: These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.

Carbon nitride-based Z-scheme heterojunctions for solar-driven advanced oxidation processes.

Solar-driven advanced oxidation processes (AOPs) via direct photodegradation or indirect photocatalytic activation of typical oxidants, such as hydrogen peroxide (H2O2), peroxymonosulfate (PMS), and peroxydisulfate (PDS), have been deemed to be an efficient technology for wastewater remediation. Artificial Z-scheme structured materials represent a promising class of photocatalysts due to their spatially separated charge carriers and strong redox abilities. Herein, we summarize the development of metal-free graphitic carbon nitride (g-C3N4, CN)-based direct and indirect Z-scheme photocatalysts for solar-driven AOPs in removing organic pollutants from water. In the work, the classification of AOPs, definition and validation of Z-schemes are summarized firstly. The innovative engineering strategies (e.g., morphology and dimensionality control, element doping, defect engineering, cocatalyst loading, and tandem Z-scheme construction) over CN-based direct Z-scheme structure are then examined. Rational design of indirect CN-based Z-scheme systems using different charge mediators, such as solid conductive materials and soluble ion pairs, is further discussed. Through examining the relationship between the Z-scheme structure and activity (charge transfer and separation, light absorption, and reaction kinetics), we aim to provide more insights into the construction strategies and structure modification on CN-based Z-schemes towards improving their catalytic performances in AOPs. Lastly, limitations, challenges, and perspectives on future development in this emerging field are proposed.

Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer.

Tumor associated macrophages (TAMs) play an important role in tumorigenesis, development and anti-cancer drug therapy. However, very few epigenetic compounds have been elucidated to affect tumor growth by educating TAMs in the tumor microenvironment (TME). Herein, we identified that EZH2 performs a crucial role in the regulation of TAMs infiltration and protumoral polarization by interacting with human breast cancer (BC) cells. We showed that EZH2 inhibitors-treated BC cells induced M2 macrophage polarization in vitro and in vivo, while EZH2 knockdown exhibited the opposite effect. Mechanistically, inhibition of EZH2 histone methyltransferase alone by EZH2 inhibitors in breast cancer cells could reduce the enrichment of H3K27me3 on CCL2 gene promoter, elevate CCL2 transcription and secretion, contributing to the induction of M2 macrophage polarization and recruitment in TME, which reveal a potential explanation behind the frustrating results of EZH2 inhibitors against breast cancer. On the contrary, EZH2 depletion led to DNA demethylation and subsequent upregulation of miR-124-3p level, which inhibited its target CCL2 expression in the tumor cells, causing arrest of TAMs M2 polarization. Taken together, these data suggested that EZH2 can exert opposite regulatory effects on TAMs polarization through its enzymatic or non-enzymatic activities. Our results also imply that the effect of antitumor drugs on TAMs may affect its therapeutic efficacy, and the combined application with TAMs modifiers should be warranted to achieve great clinical success.